Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C@@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@@H:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccccc1)OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (40 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (2.33 mL, 13.3 mmol) and (S)-2-hydroxy-3-phenylpropanoic acid (HO-PhLac-OH, 2.22 g, 13.3 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-3-phenylpropanoic acid (Fmoc-Pro-PhLac-OH) (Compound SP634) (3.00 g, 6.18 mmol, 70%).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[N:16]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(F)cc1F
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2F)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 2,4-difluoroaniline as starting materials, the title compound was obtained as a white powder (yield 47%).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH2:4]1
Reactant: Clc1ccc(Br)nc1
Reactant: O=C1NC[C@H](CCl)O1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1O[C@@H](CCl)CN1c1ccc(Cl)cn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A mixture of (5R)-5-(chloromethyl)-1,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 5), 2-bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium tribenzylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2×) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.32 g, 59%). Mass spectrum (ESI) 249.0 (M+2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([S:24][CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(=O)C.CCOCC>C(OCC)(=O)C>[NH2:27][CH2:26][CH2:25][S:24][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1ccccc1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C(NC(=O)OCc1ccccc1)C(SCCN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 90.1 %

Procedure:
To a stirred cooled (ice-bath) solution of methyl 2-{[(benzyloxy)carbonyl]amino}-3-({2-[(tert-butoxycarbonyl)amino]ethyl}thio)-3-phenylpropanoate (7a) (1.20 g) and methanol (0.284 mL) in ethyl acetate (2 mL) was added dropwise from a syringe acetyl chloride (0.43 mL) and the mixture stirred in the ice bath for an additional 10 min and then at RT for 50 min. Excess Et2O was added and the white solid collected, dissolved in water, treated with an excess of sat. aqueous K2CO3 and extracted once with CH2Cl2 and twice with Et2O. The dried organics (MgSO4) were filtered and the solvent removed to yield the title compound as an oil (0.86 g, 90%). The proton NMR displayed a mixture of diastereomers of approximate ratio 7:3; the major diastereomer is reported. 1H NMR (300 MHz, CDCl3) δ1.46 (s, 2H, exchangeable), 2.47 (t, 2H), 2.76 (t, 2H), 3.66 (s, 3H), 3.35 (d, 1H), 4.75 (t, 1H), 5.09 (m, 2H), 5.76 (d, 1H, exchangeable), 7.28-7.34 (m, 10H). MS APCI, m/z=389(M+1). HPLC Method A: 2.27 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([N:7]([CH3:23])[C:8]1[CH:13]=[C:12]([CH2:14][O:15]C2CCCCO2)[CH:11]=[CH:10][C:9]=1[CH3:22])=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:22])=[C:8]([N:7]([CH3:23])[C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: COCCC(=O)N(C)c1cc(COC2CCCCO2)ccc1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COCCC(=O)N(C)c1cc(CO)ccc1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The solution of 4.50 g of 3-methoxy-N-methyl-N-[2-methyl-5-(tetrahydropyran-2-yloxymethyl)phenyl]propionamide in 70 ml of ethanol is admixed with 0.350 g of pyridinium p-toluenesulphonate and stirred at 60° C. over 2 hours. The reaction mixture is cooled and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (3:1 EtOAc-heptane); Rt=2.60.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]([CH3:27])[C:20]2=[O:28].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]([CH3:27])[C:20]3=[O:28])[CH:4]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ccc2ncn(C)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Tert-butyl 4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenylcarbamate 26 (3.0 g, 7.89 mmol) was added to 50 mL of 10% TFA in DCM. After 1 hr, the reaction mixture was neutralized with 75 mL saturated Na2CO3, extracted into EtOAc (3×100 mL), dried over MgSO4 and concentrated in vacuo to yield the desired product (2.078 g, 7.41 mmol, 94% yield). 1H NMR (300 MHz, D6 DMSO): δ 7.91 (s, 1H), 7.71 (d, 1H, J=2.7 Hz), 7.61 (s, 1H, J=8.8 Hz), 7.37 (dd, 1H, J=2.7 Hz, J=8.8 Hz), 7.31 (s, 1H), 7.03 (d, 1H, J=8.0 Hz), 6.67 (d, 1H, J=2.3 Hz), 6.40 (dd, 1H, J=2.4 Hz, J=8.0 Hz), 5.80 (br s, 1H), 3.63 (s, 3H), 2.16 (s, 3H), 1.64 (s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz, D6 DMSO): δ 160.73, 146.90, 144.88, 142.13, 138.84, 132.85, 131.08, 130.76, 126.96, 125.08, 122.78, 118.25, 115.49, 110.06, 34.87, 18.51. ESMS: m/z 281.2 [MH]+
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Solvent: CO
Product: Nc1ccc(OCC(=O)OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
27.0 g (0.094 mmol) of benzyl 2-(4-nitrophenoxy)acetate are dissolved in 1200 ml of methanol and hydrogenated in the presence of 5 g of rhodium-on-charcoal with hydrogen at room temperature under 3 bar. After about 2 hours, the uptake of hydrogen has ended and, after the catalyst has been filtered off with suction, the mother liquor is concentrated to dryness in vacuo. The residue is suspended in about 300 ml of methylene chloride and, after filtration, the filtrate is concentrated to dryness.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:12][C:11]([C@@H:14]1[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[CH:10][CH:9]=3.[ClH:27].CCOCC>O1CCOCC1>[ClH:27].[N:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:12][C:11]([C@@H:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[CH:10][CH:9]=3
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c4ncccc4c3c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cnc2[nH]c3ccc([C@H]4CNCCO4)cc3c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
(S)-tert-Butyl 2-(9H-pyrido[2,3-b]indol-6-yl)morpholine-4-carboxylate (22 mg, 0.062 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 0.19 ml, 0.75 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(9H-pyrido[2,3-b]indol-6-yl)morpholine hydrochloride (17 mg, 94%) as a light yellow solid. MS (ISP): 254.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Brc1c[nH]cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (2.73 g, 10.0 mmol) and commercially available 4-bromo-imidazole (2.21 g, 15.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (3.20 g, 84%). MS (ISP) 383.0 [(M+H)+]; mp 166-168° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Cc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.08 g of 4,5-dimethyl-1,3-dioxol-2-one was dissolved in 24 mL of benzene, to which 3.25 g of N-bromosuccinimide and 86 mg of 2,2′-azobis(isobutyronitrile) were added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and consequently, a solution of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in benzene was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[C:15]=3[F:23])[N:12]=[N:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[CH:36]=2)O1.C(=O)(O)[O-].[Na+]>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].COCCOC>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)[CH:36]=2)=[CH:3][C:4]=1[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[C:15]=2[F:23])[N:12]=[N:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: COc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)c(F)c1F
Temperature: 70 °C
Yield: 50.6 %

Procedure:
To a round-bottom flask charged with 5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1078, 3.832 g, 10 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1098, 4.150 g, 11.00 mmol) and DME (100 mL) was flushed with N2 for 20 min. An aqueous solution of sodium bicarbonate (25 mL of 1.2 M, 30.00 mmol) was added. Nitrogen flow was continued for another 40 min before the addition of PdCl2 dppf (731.7 mg, 1.00 mmol). The resulting suspension was heated at 70° C. for 15 hours, filtered though a layer of diatomaceous earth, and washed with brine. The volatiles were removed in vacuo to afford a residue, which was purified by silica gel chromatography, eluting with 20-100% EtOAc/hexanes to yield tert-butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1103, 2.8 g, 50.6%) as yellow solid; ESMS (M+H)=554.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16](=[O:23])[CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:16](=[O:23])[CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=C(c1cc(F)cc(OCc2ccccc2)c1)C1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1cc(O)cc(F)c1)C1CCOCC1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a suspension of palladium on carbon (1.5 g) in ethanol (30 mL) under N2 was added a solution of 4-[(3-benzyloxy-5-flourophenyl)oxomethyl]-tetrahydropyran (3.7 g, 12 mmol), prepared as in step 6, in ethanol (70 mL). The reaction mixture was flushed three times with hydrogen, was then stirred for three hours under positive hydrogen pressure. The reaction mixture was flushed with N2, filtered through a pad of celite, and concentrated in vacuo to yield 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran (2.17 g, 81%) as a white powder which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:8]2[NH:9][C:10](=O)[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:7]2[N:6]=1)[CH3:2].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:37]>>[Cl:37][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:7]2[N:6]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:8]2[N:9]=1
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Temperature: 25 °C

Procedure:
2-(Ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (132 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (381 mg). 1H NMR (CDCl3, 300 MHz): δ 8.11 (m, 2H), 7.73 (d, J=0.8.1 Hz, 2H), 7.26 (m, 4H), 6.87 (s, 1H), 4.70 (s, 2H), 6.66 (m, 2H), 2.41 (s, 3H), 1.26 (3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].C(O)(=O)C.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(N2CCN(CCc3ccc4ccccc4n3)CC2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 2-vinylquinoline (0.1 mole, 15g.) and glacial acetic acid (0.1 mole, 6 g.) in ethanol (95%, 100 ml.) N-phenylpiperazine (0.1 mole) was added and the solution was refluxed for 15 hrs. The solvent was removed and the remaining oil was heated in vacuo (1 mm. Hg) to 100°C. The oil left in the flask crystallized out on cooling and was recrystallized from ether-petroleum ether to give the titular product m.p. 79°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.C(#[N:27])C>>[NH2:27][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC#N
Reactant: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)cc1F
Product: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(N)c2)cc1F
Yield: 70 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. 4-(3-Fluoro-4-pivalamidophenoxy)picolinamide (110 mg, 0.33 mmol) in acetonitrile (4 mL) was converted to N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 70% yield). MS (ESI+): m/z 304.21 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[N:7][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccccc1C(=N)N
Product: COc1ccccc1-c1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=374.8 (M+H+), was prepared from 2-methoxybenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18].CN(C)C=O>C1COCC1>[CH3:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH2:4][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]
Reactant: OCc1ccccc1Br
Reactant: C=CCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccccc1CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To an ice cooled solution of methyl 3-butenoate (2.0 g, 20 mmol) in THF (20 ml) 9-borabicyclo(3,3,1)nonane (49 ml, 0.5M in tetrahydrofurane) was added within 1 hour. After additional stirring for 4.5 hours potassium carbonate (7.5 g, 54 mmol), 2-bromobenzyl alcohol (3.4 g, 18.2 mmol), dimethylformamide (60 ml) and palladium (dppf)-dichloride (0.665 g, 0.91 mmol) were added and the mixture was stirred at 60° C. overnight. After cooling the mixture was filtered over Celite and evaporated. The residue was purified by column chromatography (eluent hexane/ethyl acetate: 4:1 gradually to 1:1) to yield 2.46 g (65%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:34][CH:35]=4)=[O:41])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 98 %

Procedure:
The compound of example 49 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-phenoxy phenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].Cl.[NH2:18][OH:19]>CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:18][OH:19])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: O=Cc1ccc(CNC(=O)C2CC2)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc(C=NO)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
In a solution of 1.20 g of N-[(2-chloro-4-formylphenyl)methyl]cyclopropanecarboxamide in 40 mL of methanol and 10 mL of water, 0.50 g of hydroxylamine hydrochloride was added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with 50 mL of ethyl acetate, washed with water (30 mL×1), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 0.95 g of the aimed product as white crystal. Melting point 163.0 to 166.0° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:21])[C:11]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].O>CCOCC>[C:13]([C:11]1[C:10]([OH:21])=[CH:9][C:8]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:12]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14 g of 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 150 ml of ether and the solution is added to 62 ml of 2N aqueous sodium hydroxide solution and 25 ml of water. This mixture is vigorously stirred for 1 hour at room temperature. The ether phase is separated off and extracted once with 75 ml of water. The aqueous phase is washed once with 75 ml of ether. The combined aqueous phases are rendered acidic with 2N aqueous hydrochloric acid and extracted 3 times with 100 ml of methylene chloride each time. The combined methylene chloride extracts are dried over magnesium sulphate and concentrated by evaporation. Crystallisation of the residue from ether/petroleum ether yields 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid in the form of yellow crystals having a melting point of 167°-169°.