Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:45])[C@@H:14]([NH:30][C:31](=[O:44])[C@@H:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6].C(=O)(O)[O-].[Na+].[I:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][CH:61]=1)[CH2:57][NH2:58].C(OCC)(=O)C>O1CCCC1>[C:40]([O:39][C:37](=[O:38])[NH:36][C@H:32]([C:31](=[O:44])[NH:30][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24])[CH:17]=1)[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5](=[O:6])[NH:58][CH2:57][C:56]2[CH:59]=[CH:60][CH:61]=[C:54]([I:53])[CH:55]=2)[NH:8]1)=[O:45])[CH:33]([CH3:34])[CH3:35])([CH3:41])([CH3:43])[CH3:42]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: NCc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)NCc2cccc(I)c2)N1
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (987 mg, 1.337 mmol) in tetrahydrofuran (20 mL) was treated with sodium bicarbonate (337 mg, 4.011 mmol) and 3-Iodo-benzylamine (467 mg, 2.005 mmol). After overnight stirring, ethyl acetate and silica were added and the volatiles removed in vacuo. The product was purified by silica gel chromatography using iso-hexanes/ethyl acetate, 1:0 then 1:2 to afford the title compound (374 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 3H), 0.18 (s 3H), 0.81 (d, J=6.9 Hz, 3H), 0.86 (d, J=7.1 Hz, 3H), 0.97 (s, 9H), 1.46 (s, 9H), 1.61-1.70 (m, 2H), 1.73-1.83 (m, 1H), 1.84-1.94 (m, 1H), 1.96-2.05 (m, 1H), 2.53-2.66 (m, 1H), 2.81-3.01 (m, 3H), 3.34-3.45 (m, 1H), 3.74 (t, J=6.0 Hz, 1H), 3.98-4.09 (m, 1H), 4.31-4.51 (m, 2H), 4.79-4.88 (m, 1H), 5.75 (q, J=8.7 Hz, 1H), 6.38-6.49 (m, 1H), 6.67-6.73 (m, 1H), 6.74-6.78 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 7.03-7.15 (m, 2H), 7.31 (s, 1H), 7.33-7.43 (m, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.67 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCOCCO
Yield: 93.2 %

Procedure:
A suspension of 30.0 g (202.5 mmol) of phthalic anhydride, 20 mL (21.0 g, 199.4 mmol) of 2-(2-aminoethoxy)-ethanol in 400 mL of benzene was added 1.0×10-2 g (5.3×10-5 mmol) of TsOH.H2O. The reaction flask was connected to a Dean-Stark condenser and then heated to reflux for 14 h. The solvent was removed at reduced pressure and the residue was purified by SiO2 column chromatography (hexanes/AcOEt 1:1 then CHCl3 /MeOH 20:1) gave 43.7 g (93.1%) of 13 as a light yellow syrup. This syrup slowly crystallized on standing at room temperature overnight as needle-like crystals. mp 66°-66.5° C. Rf (hexanes/AcOEt 1:1) 0.17. 1H NMR (CDCl3) d 2.41 (t, 1H, J=6.2 Hz, OH), 3.57-3.93 (m, 8H), 7.69-7.87 (m, 4H). 13C NMR (CDCl3) d 37.52, 61.62, 68.24, 72.24, 123.36, 131.97, 134.00, 168.38 (C=O). Anal Calcd for C12H13NO4 : C, 61.28; H, 5.53; N, 5.96. Found: C, 61.34; H, 5.62; N, 5.94.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([CH2:16][C:17](=O)[CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCCCC>O>[C:2]([NH:6][N:7]=[C:17]([CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Cc1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Product: CC(Cc1ccccc1)=NNC(C)(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 50.46 g t-butyl hydrazine hydrochloride and 32 g of 50 percent aqueous sodium hydroxide in 70 ml of water is stirred in an ice water bath. About 50.22 g of phenylacetone is added with stirring. The mixture is stirred and allowed to warm to ambient temperature over about 12 hours. Pentane (300 ml) is added to the solution with agitation, and then separated. The pentane layer is washed twice with water, dried over anhydrous sodium sulfate, and filtered. The pentane is removed under vacuum. The title compound is isolated as a fraction distilled under 0.9 mm pressure at 89° C.-103° C. About 56.5 g of the title compound are recovered for a 74 percent yield, based upon the phenylacetone added.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C:25]([NH:27][C:28]2[CH:32]=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=2)=[O:26])[CH:8]=[C:9]([O:11][C:12]2[CH:24]=[CH:23][C:15]3[C:16](=[O:22])[N:17]([CH3:21])[CH2:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH:10]=1)[CH3:3]>CO>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([O:11][C:12]2[CH:24]=[CH:23][C:15]3[C:16](=[O:22])[N:17]([CH3:21])[CH2:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH:10]=1)[C:25]([NH:27][C:28]1[CH:32]=[CH:31][NH:30][N:29]=1)=[O:26])[CH3:1]
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: CO
Product: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-[({3-[(1-methylethyl)oxy]-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate (42 mg, 0.08 mmol), in methanol (2 mL) was heated at 140° C. in a microwave reactor for 30 minutes. The solution was cooled to RT and pressure, the methanol evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (13 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 3.15 (s, 3H), 3.5 (t, 2H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (s, 1H), 6.7 (m, 2H), 6.75 (s, 1H), 7.1 (d, 1H), 7.25 (d, 1H), 7.45 (d, 1H), 7.8 (d, 1H), 9.4 (s, 1H); m/z 437 (M+H)+
Reaction SMILES: C(N)CC1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[C:19]1([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:47][CH:48]([CH3:52])[C:49](Cl)=[O:50]>O.C(Cl)Cl>[Cl:47][CH:48]([CH3:52])[C:49]([N:26]1[CH2:27][CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:50]
Reactant: CC(Cl)C(=O)Cl
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Agent: NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccc2cnccc2c1
Solvent: ClCCl
Product: CC(Cl)C(=O)N1CCc2ccccc2C1c1ccccc1

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and benzoyl chloride were converted to 1-phenyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.0 g of this isoquinoline compound, 5 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1 ml 2-chloropropionyl chloride was added dropwise to the mixture. The mixture was stirred for 10 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (170° C. @ 0.1 mm Hg) to provide 2.3 g of a viscous yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1cncn1-c1ccc(CC)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1ccc(-n2cncc2CO)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of ethyl 1-(4-ethylphenyl)-1H-imidazole-5-carboxylate (C17) (6.5 g, 27 mmol) in tetrahydrofuran (45 mL) was added lithium aluminum hydride (1 M solution in tetrahydrofuran, 27 mL, 27 mmol), and the reaction mixture was stirred at −78° C. for 0.5 hours, then warmed to room temperature and stirred for an additional 2 hours. Saturated aqueous potassium tartrate solution was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (10 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the resulting pale yellow oil using silica gel chromatography (Gradient: 0% to 5% methanol in ethyl acetate) provided the product. Yield: 3.8 g, 18.8 mmol, 70%. LCMS m/z 203.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.29 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 4.57 (s, 2H), 2.35-2.53 (br s, 1H), 7.13-7.14 (br s, 1H), 7.35 (br AB quartet, JAB=8.5 Hz, ΔνAB=27 Hz, 4H), 7.62 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Cl[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([N:17]=[C:22]1[NH:21][CH2:20][CH2:19][O:23]1)[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: Clc1cccc(C(Cc2ccncc2)N=C2NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanamine (0.30 g, 1.13 mmol) in dichloromethane (6.0 mL) was added chloroethylisocyanate (0.11 mL, 1.29 mol). The solution was stirred at room temperature for one hour. The solvent was removed under vacuum. The residue was added water, acetone, and heated at 100° C. for one hour. The mixture was cooled to room temperature, and basified with NaOH (2M) to pH>7. The aqueous layer was extracted with chloroform/isopropanol (3:1, 3×, 200 mL). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The filtrate was added silica gel, and the solvents were removed under vacuum. Purification by chromatography on silica gel (2% saturated ammonia methanol in dichloromethane) gave 1-(2,3-dichlorophenyl)-N-(oxazolidin-2-ylidene)-2-(pyridin-4-yl)ethanamine Compound 17 as a white solid (0.21 g, 0.63 mmol, 56% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]3N=[C:34]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[C:39]=4[CH2:48][C:49](O)=[O:50])[C:33]([C:52]([F:55])([F:54])[F:53])=[CH:32][N:31]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.C(=O)([O-])[O-].[NH4+:83].[NH4+:84]>CN(C=O)C.O>[NH2:83][C:49](=[O:50])[CH2:48][C:39]1[C:40]([C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][CH2:36][C:34]1[C:33]([C:52]([F:55])([F:53])[F:54])=[CH:32][N:31]=[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH:20]3[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)[N:84]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(=O)O)n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(N)=O)n3)cc2)CC1
Reaction time: 24 h

Procedure:
DIPEA (0.16 mL, 0.92 mmol) was added to a mixture of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)acetic acid (A96) (0.104 g, 0.160 mmol), HOBt (0.037 g, 0.27 mmol), and EDCl.HCl (0.056 g, 0.29 mmol) in DMF (5.0 mL) under a nitrogen atmosphere. After 15 minutes ammonium carbonate (0.077 g, 0.80 mmol) was added and stirring continued at room temperature for 24 hours. Additional HOBt (0.072 g, 0.53 mmol), EDCl.HCl (0.056 g, 0.29 mmol) and DIPEA (0.16 mL, 0.92 mmol) were added, then and after 15 minutes ammonium carbonate (0.121 g, 1.26 mmol) was also added and the resulting mixture stirred at room temperature for 16 hours. The resulting mixture was diluted with water (20 mL) then extracted with EtOAc (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A97 (75 mg, 72%); 1H NMR (400 MHz, d6-DMSO) δ 10.16 (s, 1H), 8.66 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.47 (s, 1H), 7.41 (dd, J=7.7, 7.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.96 (s, 1H), 4.07 (m, 2H), 3.74 (s, 2H), 3.09 (m, 4H), 2.79 (m, 2H), 2.62 (m, 1H), 1.74 (m, 2H), 1.49 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.63 min; m/z 652.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([OH:24])=O)[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.O[N:37]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([NH2:37])=[O:24])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 62.3 %

Procedure:
To an ice-cooled and stirred mixture of {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg) in N,N-dimethylformamide (7 mL) were added 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was cooled on an ice bath and 10% aqueous ammonia solution (1.0 mL) was added thereto. The mixture was stirred at room temperature for 5 h and partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give light yellow crystals, which were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (84 mg) as pale yellow crystals. MS 523 (MH+). mp 143-144° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[N:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc2ccccc2c(C)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Cc1cc2c([N+](=O)[O-])cccc2c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-Dimethylisoquinoline [(Chem. Lett., 1983, p.791), 2.39 g, 15.20 mM], in conc. sulfuric acid, (15 ml), was cooled to below 4° C. A solution of potassium nitrate (1.69 g, 16.72 mM) in conc. sulfuric acid was added dropwise, maintaining the temperature below 4° C. After complete addition the solution was stirred at this temperature for a further 2 h. then warmed to room temperature for 1 h. The reaction mixture was poured into ice water and the solution basified with sodium hydroxide and extracted with DCM. The extract was washed with brine, dried and concentrated to a yellow solid. Purification by silica gel chromatography afforded the title compound as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][OH:12]>C1COCC1>[CH3:1][C:2]1[O:6][C:5](/[CH:7]=[N:9]/[C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: Cc1ccc(C=O)o1
Solvent: C1CCOC1
Product: Cc1ccc(/C=N/[C@@H](CO)c2ccccc2)o1
Temperature: 25 °C

Procedure:
73.8 ml of 5-Methylfuran-2-carbaldehyde are added to 100 g of (R)-2-amino-2-phenyl-ethanol dissolved in 800 ml of THF. A reaction mixture obtained is heated at reflux for 5.5 hours and after cooling to rt solvent is evaporate. The title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Br:11])[C:5](O)=[O:6].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Br:11])[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(Br)c(Br)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1ccc(Br)c(Br)c1
Yield: 71.4 %

Procedure:
3,4-Dibromobenzoic acid (28 g, described by Miller, J.C.S. 61, 1033 (1892)) was suspended with stirring in toluene (150 ml) at 50° C. Sodium dihydrobis(2-methoxyethoxy)aluminate (70% w/v, in toluene, 52 ml) was added over 30 minutes at 50° C. The mixture was heated on a steam bath for 1 hour, cooled to 20° C. and hydrolysed by the addition of hydrochloric acid (6N; 150 ml) with cooling. The mixture was separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated to give 3,4-dibromobenzyl alcohol (19 g) as a light red oil. The unpurified alcohol was dissolved in chloroform (60 ml) and the solution was heated at reflux. Thionyl chloride (20 ml) was added in portions over 10 minutes and the solution was heated at reflux for 1 hour. The reaction mixture was evaporated to give a light oily residue, which was repeatedly diluted with chloroform (3×50 ml) and the combined chloroformic solutions evaporated. The residue was dissolved in diethyl ether, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated. 3,4-Dibromobenzyl chloride (20 g) was obtained as a clear mobile oil of sufficient purity for further reaction.
Reaction SMILES: OC1C=CC(CS(C(C)CC(O)=O)=O)=CC=1.N[CH:18]1[C:33](=[O:34])[N:20]2[C:21]([C:30]([OH:32])=[O:31])=[C:22](COC(=O)N)[CH2:23][S:24][C@H:19]12>>[S:24]1[C@@H:19]2[CH2:18][C:33](=[O:34])[N:20]2[C:21]([C:30]([OH:32])=[O:31])=[CH:22][CH2:23]1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CC(CC(=O)O)S(=O)Cc1ccc(O)cc1
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12

Procedure:
484 mg. of 3-(p-hydroxybenzylsulfinyl)butyric acid and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 309 mg. of 7-[3-(p-hydroxybenzylsulfinyl)butyramido]-3-carbamoyloxymethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][CH:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19].C1C=CC=CC=1>C(O)(=O)C>[CH3:17][CH:18]([N:20]1[C:24]2[N:25]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:23]=2[CH:22]=[N:21]1)[CH3:19]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 2,4-dioxo-4-phenylbutanoate (5 g, 22.7 mmol), 1-(1-methylethyl)-1H-pyrazol-5-amine (2.84 g, 22.7 mmol), benzene (70 mL), and acetic Acid (44 mL) The crude product was purified by silica gel chromatography (eluent: 0 to 100% EtOAc/hexanes) to give 6.72 g (95%) as a pale yellow solid. LCMS E-S (M+H)=310.5. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.17-8.28 (m, 3H), 7.49-7.64 (m, 3H), 5.38 (quin, J=6.69 Hz, 1H), 4.49 (q, J=7.07 Hz, 2H), 1.57 (d, J=6.57 Hz, 6H), 1.44 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(F)cc1

Procedure:
A solution of 3-(p-fluorobenzoyl)propionic acid (58.8 g.) in anhydrous methanol (250 ml.) was treated with concentrated sulphuric acid (3.2 ml.) and the mixture heated at reflux temperature for 10 hours. It was then concentrated to a volume of 100 ml., cooled and diluted with ice-water. The resultant solid was collected and crystallised from ligroin to yield the ester (59.7 g.), m.p. 48°-50 ° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([CH3:32])=[N:34][CH:35]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)ccc3n2)cn1
Yield: 22.8 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), 6-methylnicotinoyl chloride (75 mg, 0.548 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (105 mg, 0.548 mmol), 1-hydroxybenzotriazole (74 mg, 0.548 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (44 mg, 23%) was obtained as a pale-green powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:4]=1)=[O:8])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol) in tetrahydrofuran (1.644 ml) and methanol (1.644 ml) at 25° C. was added hydrazine (0.10 ml, 3.29 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (silica, 5% MeOH in DCM (1% NH4OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 mL) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (79 mg, 0.17 mmol, 53% yield) as a yellow solid: LCMS (ES) m/z=380, 382 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=8.59 Hz, 1H) 8.10 (s, 1H) 7.99 (br. s., 3H) 7.55 (d, J=1.77 Hz, 1H) 6.48 (d, J=2.02 Hz, 1H) 4.22-4.28 (m, 1H) 3.81 (s, 3H) 2.90-2.95 (m, 2H) 1.74-1.78 (m, 1H) 1.62-1.65 (m, 4H) 1.48-1.51 (m, 1H) 1.37-1.39 (m, 2H) 1.09-1.13 (m, 2H) 0.92-0.96 (m, 2H).