Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=[O:20])[CH2:3]1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:25]([N:13]1[C:7]2[C:8]([CH3:12])=[N:9][C:10]3[CH2:11][C:2]([CH3:21])([CH3:1])[CH2:3][C:4](=[O:20])[C:5]=3[C:6]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)[CH3:26]
Reactant: Cc1nc2c(c3c1[nH]c1ccccc13)C(=O)CC(C)(C)C2
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2c3c(nc(C)c21)CC(C)(C)CC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,3,6-trimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 4 (0.28 g, 1 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added dropwise at room temperature under stirring to a suspension of sodium hydride (60% dispersion in mineral oil, 0.051 g, 1.3 mmol) in anhydrous N,N-dimethylformamide (4 mL). The reaction mixture was stirred for 2 h at room temperature, and then 1-iodoethane (0.19 g, 1.2 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was completed (4 h, thin layer chromatography control). The reaction mixture was diluted with water (25 mL) and brine (10 mL), and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and ethyl acetate was distilled off in vacuum to give the crude product (0.18 g, 60%). Crystallization from hexanes yielded the pure product as light orange crystals; m.p. 174-177° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH2:20].N1C=CC=CC=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH:20][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(NC(=O)C3CC3)ncc2c1

Procedure:
To 4-bromo-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (46 mg, 140 μmol) and pyridine (110 μl, 1.4 mmol) in dichloromethane (3.0 mL) at ambient temperature was added dropwise cyclopropanecarbonyl chloride (60 μl, 0.66 mmol). After 1 h the mixture was poured into saturated aqueous sodium bicarbonate, extracted twice into dichloromethane and the combined organic phases dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (57 mg, quant.). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.26 (s, 1H), 8.27-8.14 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.49-7.33 (m, 1H), 7.21 (t, J=9.2 Hz, 2H), 2.25 (s, 3H), 1.98-1.84 (m, 1H), 0.90-0.78 (m, 4H). LCMS (Method E): RT 5.299 min, M+H+=399.0 & 401.0.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH:30][CH2:31][CH:32]([CH2:34]O)[OH:33].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: OCC(O)CO
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 4 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:38](=[O:40])[NH:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (20.0 g, 53.27 mmol, 1.0 equiv; example 1/step 4) in toluene (200 mL) and N-ethyldiisopropylamine (17.21 g, 133.17 mol, 2.5 equiv) was added a solution of triphosgene (18.97 g, 63.92 mmol, 1.2 equiv) in toluene (200 mL) and the reaction mixture stirred at 70° C. for 1.5 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was further washed with a mixture of hexane/ethyl acetate (95:5) to yield 15.5 g (73%) of the title product as wvhite solid. 1H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.72 (d, J=10.8, 2H), 2.17-2.23 (m, 2H), 2.88 (br s, 2H), 4.09 (d, J=8.6 Hz, 2H), 4.38 (t, J=12.2 Hz, 1H), 4.77 (d, J=5.3 Hz, 2H), 5.26 (d, J=10.4 Hz, 1H), 5.40 (dd, J=17.2 Hz, J=1.4 Hz, 1H), 5.99-6.09 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.69-7.71 (m, 1H), 11.17 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.04, 28.43, 50.32, 64.78, 78.79, 108.13, 109.18, 117.70, 121.69, 121.71, 122.67, 128.20, 132.81, 133.39, 153.78, 153.82, 165.36. MS (ISP): 402.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.O[N:33]1[C:37]2C=CC=CC=2N=N1.[Cl-].C[NH3+].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][N:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH:33][CH3:37])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
A mixture of [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (280 mg), N-ethyl-N′-(37-dimethylaminopropyl)carbodiimide hydrochloride (233 mg), 1-hydroxybenzotriazole (164 mg), methylammonium chloride (82 mg), triethylamine (0.2 mL) and N,N-dimethylformamide (12 mL) was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/75/25 to 10/90/0, volume ratio) to give a pale yellow amorphous solid. The amorphous solid was crystallized from ethyl acetate-diethyl ether to give white crystals. The crystals were washed with methanol-acetone to give the title compound (178 mg, 62%) as colorless crystals. MS 475 (MH+). mp 207-209° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[CH3:16][C:4]1([CH3:17])[C:3](=[O:18])[C:2]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:43][CH:44]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 53.6 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (100 mg, 0.32 mmol, 1 eq), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (115 mg, 0.32 mmol, 1 eq), and Cs2CO3 (521 mg, 1.6 mmol, 5 eq) in toluene (7 mL) and water (2.5 mL) was degassed. Then Pd (dppf)Cl2 (52 mg, 0.06 mmol, 0.2 eq) was added under an inert atmosphere and the solution was again degassed. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (80 mg, 54%) as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J=8.5 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 8.00 (t, J=7.9 Hz, 2H), 7.82-7.76 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 1.48 (s, 6H). MS: [M+H]: m/z=467.1. HPLC: 89%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16](=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:16](=[O:24])[C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
4-(Difluoromethoxy)aniline (0.94 mmol, 149 mg) dissolved in dry CH3CN (2.3 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.39 mmol, 115 mg) and the reaction mixture was subjected to microwave heating single node 140° C., one h. The reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 122 mg (75%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.51 (dd,1H), 7.92 (bs, 1H), 7.79-7.74 (m, 1H), 7.34 (dd, 1H), 7.20-7.07 (m, 3H), 7.00-6.94 (m, 2H), 6.78 (s, 4H), 6.59 (t, J=74.1 Hz, 1H), 4.76 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: CCOc1cc(N2CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 57 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and piperazine was used in place of N-methylpiperazine. In this manner, 86 mg (57%) of the captioned compound was obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[O:53][CH2:52]C1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH:23]2[CH2:52][OH:53])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1COCCN1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and morpholin-3-ylmethanol and isolated as light-yellow gum (13.3 mg, 68%). MS(m/e): 417.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=[O:11])[C:4](=[O:5])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1>C1C=CC=CC=1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:12][C:10]([CH:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:9][C:7]1=[O:8])=[O:11]
Reactant: O=Cc1cccs1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC1=CC(=O)C(C(=O)C=Cc2cccs2)C(=O)O1
Temperature: 50 °C
Reaction time: 7 h
Yield: 57.2 %

Procedure:
To a solution of 65.0 g (0.39 mole) of dehydroacetic acid and 47.0 g (0.42 mole) of thiophene-2-aldehyde in 370 ml of benzene was added dropwise 6.8 g of piperidine with cooling in an ice-water bath. After termination of the dropwise addition, the mixture was stirred at 50° C. for 7 hours. After the reaction, the solvent was concentrated under a reduced pressure. The precipitated crystal was collected by filtration and recrystallized from toluene to obtain 58.5 g (yield: 58%) of 3-(2-thienylacryloyl)-6-methyl-2H-pyran-2,4(3H)-dione in the form of a light crystal, m.p. 162°-164° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=CN(C)C>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[N:16]=[C:15]1[CH:26]=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Yield: 101.1 %

Procedure:
To a well stirred mixture of sodium periodate (2.24 g, 10.47 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (10 mL) was added 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.90 g, 2.62 mmol) all at once. The mixture warmed slightly to the touch and was stirred 1 h at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ethyl acetate. The phases were separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated to afford 0.802 g (97%) of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a 1:2 mixture of free aldehyde and hydrate which had: 1H NMR δ 9.52 (s,) [CHO], 8.20-7.45 (m, 7 H), 6.75 (d, J=7.4 Hz) [hydrate OH] and 6.49 (d, J=8 Hz) [hydrate OH], 5.14 (t, J=7.5 Hz) [hydrate methine CH].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:14])[C:6]([Cl:13])=[CH:7][C:8]=2[Cl:12])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]([Cl:13])[C:5]([OH:14])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[N:3]2
Reactant: CN
Reactant: Oc1c(Cl)cc(Cl)c2ccc(Cl)nc12
Solvent: CCO
Product: CNc1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
2,5,7-Trichloro-8-hydroxyquinoline 10 (200 mg, 0.805 mmol) and a solution of methylamine in ethanol (12 mL of a 33% solution) were heated in a sealed vessel at 90° C. for 26 h, and cooled. The precipitate was then isolated via filtration and washed with diethyl ether. This provided pure 5,7-dichloro-2-methylamino-8-hydroxyquinoline (PBT 1047) as a pale yellow solid (186 mg, 95%). 1H NMR (DMSO-d6, 400 MHz): δ 8.80 (br, 1 H), 7.98 (d, J=9.1, 1 H), 7.48 (br, 1 H), 7.25 (s, 1 H), 6.90 (d, J=9.1, 1 H), 2.98 (d, J=4.8, 3 H); mass spectrum: m/z 243, 245 (M++1, 100 and 66%, respectively).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]#[N:21])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-:25].[Na+]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]([NH2:21])=[O:25])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:8][CH:9]=1
Reactant: CCc1nc2c(C)c(C#N)c(C)cc2n1-c1ccc(CCCl)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCc1nc2c(C)c(C(N)=O)c(C)cc2n1-c1ccc(CCCl)cc1
Yield: 83 %

Procedure:
A solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (Example 329, step 6,997 mg, 2.95 mmol) in CH2SO4 (50 ml) was stirred at 80° C. for 15 h. The mixture was poured onto ice and was neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300 ml), then dried (Na2SO4). The solvent was removed to afford 871 mg (83%) of the title compound as white solids.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].C(C1NC=CN=1)(C1NC=CN=1)=O.[C:26]([O:30][C:31]([CH2:33][C:34](=[N:36]O)[NH2:35])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[NH2:36][C:34](=[N:35][O:10][C:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:12])[F:13])=[O:11])[CH2:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(N)=NO
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(N)=NOC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
30 g of 4-trifluoromethyl-3-pyridinecarboxylic acid is initially charged in 150 ml of dry THF and, a little at a time, admixed with 25.3 g of carbonyl-diimidazole. The mixture is stirred at room temperature for 30 min. 27.2 g of tert-butoxycarbonylacetamide oxime dissolved in 150 ml of THF are then added dropwise. The mixture is stirred overnight, the solvent is evaporated and the residue is taken up in ethyl acetate, washed three times with 1 M sulfuric acid and once with saturated sodium bicarbonate solution. Concentration of the ethyl acetate phase gives 28 g of the product as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][N:9]=[C:10]([C:14]1[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]=1[O:19][CH3:20])[C:11](O)=[O:12]>>[CH3:7][O:8][N:9]=[C:10]([C:14]1[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]=1[O:19][CH3:20])[C:11]([Cl:4])=[O:12]
Reactant: CON=C(C(=O)O)c1sc2ccccc2c1OC
Reactant: O=C(Cl)C(=O)Cl
Product: CON=C(C(=O)Cl)c1sc2ccccc2c1OC

Procedure:
Oxalyl chloride (0.72 ml, 8 mM) were reacted with 530 mg (2 mM) of α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetic acid according to the method of Example 6 to give α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetyl chloride. The acid chloride was dissolved in 20 ml of acetone and added dropwise to a cold (0° C.) stirred solution of 428 mg (2 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 20 ml of acetone and 20 ml of water containing 420 mg (5 mM) of sodium bicarbonate. The reaction mixture was stirred for thirty minutes at 0° C. and then was warmed to 25° C. and stirred for an additional three hours. The reaction mixture was concentrated to a volume of about 20 ml and then was washed with ethyl acetate. The aqueous layer was layered with fresh ethyl acetate and the slurry was diluted with 1N hydrochloric acid to pH 2.4. The organic layer was separated, washed with water, dried, and the solvent was removed by evaporation to give 670 mg (72% yield) of 7-[α-methoxyimino-α-(3-methoxy-2-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:26][CH:27]2[CH2:32][CH2:31][C@@H:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][C@@H:28]2[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=2)=[O:7])=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2N)ccc1OC
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc([C@H]2C[C@H](OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Temperature: 40 °C
Reaction time: 42 h
Yield: 102.6 %

Procedure:
555 mg of 2,6-dimethoxynicotinic acid and 581 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placed in a flask under nitrogen. 778 mg of acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound B1) and 2 mg of 4-dimethylaminopyridine both as solution in dichloromethane are added and the solution stirred for 1 h at 40° C., than 42 h at room temperature. The reaction is quenched with 5 ml of water. After phase separation the organic layer is washed with 2.5 ml of saturated potassium hydrogencarbonate solution. After drying the organic layer with magnesium sulfate the solvent is removed to give 1.227 g of the crude title compound which are used for the following step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:11](#[N:15])/[CH:12]=[CH:13]/[CH3:14]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:13]([CH3:14])[CH2:12][C:11]#[N:15])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C/C=C/C#N
Reactant: C1CC2(CCN1)OCCO2
Solvent: CO
Product: CC(CC#N)N1CCC2(CC1)OCCO2
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (8.00 g, 55.9 mmol) in MeOH (70 ml) was added crotononitrile (18.74 g, 279 mol). The mixture was heated at 50° C. for 16 hours. MeOH and excess crotononitrile were removed by evaporation under reduced pressure to give 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyronitrile (11.75 g, 100%) as a pale yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BH4-]>CC(O)C>[CH2:3]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1C=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Oc1ccccc1CNCc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Sodium borohydride (0.2 g) was added in small portions to 3 mL of dry 2-propanol in a nitrogen atmosphere. To this mixture was added dropwise a solution of 1.0 g of 2-(benzylimino-methyl)-phenol in 3 mL of 2-propanol. After complete addition, stirring was continued for 1 h. Then water was added in order to decompose excess borohydride, and the volatiles were removed in vacuo. The residue was redissolved in ethyl acetate, washed with water, dried (sodium sulfate) and concentrated yielding 0.9 g of 2-(benzylamino-methyl)-phenol as an oil. EI-MS. 213 (M+).