Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.ClCCl.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCc2ccc(N)cc2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 62.1 %

Procedure:
In a 250 ml Parr flask, 2.85 g (7.4 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide is dissolved in 30 ml of an absolute ethanol/dichloromethane mixture (1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue crystallizes spontaneously. It is left to rest overnight, the crystals are filtered out and rinsed with a mixture of diethyl ether (45 ml) and acetone (5 ml). 1.63 g (62%) of a white powder is obtained. Melting point: 188-189° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[K].C(=O)([O-])[O-]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:12]2[CH:13]=[CH:14][C:10]([Cl:9])=[N:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2ncccc2Cl)n1
Temperature: 100 °C

Procedure:
To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformamide (400 mL) was added potassium, carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100° C. for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were altered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH2:10][C:9]([C:12]3[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][C:13]=3[O:27][CH3:28])=[CH:8]2)[C@@H:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4].C(O)(=O)C>[OH-].[Pd+2].[OH-].CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH:10]=[C:9]([C:12]3[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:24])([F:25])[F:26])[CH:15]=[CH:14][C:13]=3[O:27][CH3:28])[CH2:8]2)[C@@H:6]1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(C=C(c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(CC(c3cc(-n4ccnc4C(F)(F)F)ccc3OC)=CO2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 67 mg (0.13 mmol) of (5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester (from Example 69), 20% palladium(II) hydroxide on carbon (32 mg), acetic acid (1.2 mL), and methanol (6.0 mL) was stirred at RT under hydrogen at atmospheric pressure. After 20 min., the catalyst was removed using a 0.45 micron filter and washed with additional methanol. The filtrate was concentrated and the residue was purified by preparative TLC, eluting five times in 3% ethyl ether in dichloromethane. This yielded 15 mg of the title compound and 30 mg of (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.C>CO>[C:13]1([N:19]2[C:5]([OH:7])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
A mixture of 44 ml (0.3 mol) of ethyl trifluoroacetoacetate and 33 mL (335.4 mmol) of phenylhydrazine in 60 ml of methanol containing 6 ml of conc. HCl solution was refluxed with stirring for 1.5 hours. After adding activated charcoal with stirring, the hot mixture was filtered. The residue was washed with methanol (2×70 ml), diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 54.3 g (79%) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole as a pale solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[N:5]=1)=[O:3]
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Reactant: COC(OC)N(C)C
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 120 °C
Yield: 87 %

Procedure:
A microwave vial containing 3-acetyl-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.363 g, 1.2 mmol) and N,N-dimethylformamide dimethylacetal (2.5 mL) was heated at 120° C. for 20 min. The crude material was concentrated and purified by flash column chromatography (silica gel; methylene chloride to 1:9 methanol/methylene chloride) to provide 3-[3-(dimethylamino)prop-2-enoyl]-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.365 g, 87%) as an orange solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[NH:13][N:14]=2)=[C:6]([O:19][CH3:20])[CH:5]=1.Cl>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][N:14]=2)=[C:6]([O:19][CH3:20])[CH:5]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2OC)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Ethanol (1 ml) and a 20% sodium hydroxide aqueous solution were mixed with methyl 5-(4-chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylate (100 mg) obtained in the Step 18-1-2, and the mixture was heated under reflux. After one hour, the mixture was allowed to cool to a room temperature and acidified with 2-N hydrochloric acid. The precipitated crystal was separated by filtration to give the title compound (90 mg, 95%).
Reaction SMILES: [Na].[CH:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2O)[CH:7]=1.CS([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O.Cl>O.CO>[C:37]([NH:36][CH2:35][CH2:34][C:11]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[CH:4]=[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]3[C:31]([CH:30]=[CH:29][CH:28]=[C:27]3[CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:33]=1)[CH:2]=[CH:7]2)(=[O:39])[CH3:38]
Reactant: Oc1cccc2ccccc12
Reactant: CC(=O)NCCc1cccc2ccc(OCCCCCOS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(=O)NCCc1cccc2ccc(OCCCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc12

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, add sodium (0.07 g 0.0030 at. g.) in small portions. When the sodium has been completely used up, add naphthol (0.82 g, 3.6 mmol). Stir using a magnetic stirrer for 20 minutes. Remove the methanol by evaporation under reduced pressure. Take up the resulting residue in 15 ml of dimethylformamide. Add the compound obtained in Step C (1.2 g, 3 mmol) and heat at reflux for 12 hours. Allow the reaction mixture to cool and pour it into a mixture of 100 ml of water and 10 ml of 3M hydrochloric acid. Extract the aqueous phase twice with ethyl acetate. Wash the organic phase with an aqueous 10% sodium hydroxide solution and then with water. Dry over magnesium sulphate and remove the ethyl acetate by evaporation under reduced pressure. Recrystallise the resulting solid residue from acetonitrile.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (730 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with 6 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol) to obtain the title compound (486 mg).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:20][N:21]=[CH:22][C:23](=[N:28][O:29][CH3:30])[CH2:24][C:25]([CH3:27])=[CH2:26])[CH3:19])[C:8]([O:10][CH3:11])=[O:9]>>[CH3:4][O:5][CH:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:20][N:21]=[CH:22][C:23](=[N:28][O:29][CH3:30])[CH:24]=[C:25]([CH3:26])[CH3:27])[CH3:19])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)CC(C=NOC(C)c1ccccc1C(=COC)C(=O)OC)=NOC
Agent: C[O-]
Agent: [Na+]
Product: COC=C(C(=O)OC)c1ccccc1C(C)ON=CC(C=C(C)C)=NOC
Temperature: 23 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
4.9 g of solid sodium methoxide were added to 16.7 g of methyl 3-methoxy-2-[2-(2-methoxyimino-1,4-dimethylpent-4-enylideneamino-oxymethyl)phenyl]acrylate from Example 7, and the mixture was stirred at 23° C. for 1 hour. Work-up was carried out similarly to Example 6. Chromatographic purification over silica gel using cyclohexane/methyl tert-butyl ether (9:1) gave 7.1 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([CH2:8][C:9]#[N:10])=[O:7].[C:14]1([N:20](C2C=CC=CC=2)[CH:21]=N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([C:8](=[CH:21][NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]#[N:10])=[O:7]
Reactant: COc1cccc(C(=O)CC#N)c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)C(C#N)=CNc2ccccc2)c1
Temperature: 100 °C

Procedure:
A solution of 3-methoxybenzoylacetonitrile (1.20 g, 68.5 mmol, 1.0 eq) and diphenylformamidine (1.34 g, 68.5 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product. HPLC (4 minute 10-90 gradient) tR 3.05 min; MS m/z 279.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH3:50])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([S:17][C:18]3[C@H:19]([CH3:49])[C@@H:20]4[C@@H:37]([C@H:38]([O:40][Si](C(C)(C)C)(C)C)[CH3:39])[C:36](=[O:48])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:4][N:5]([CH3:50])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([S:17][C:18]3[C@H:19]([CH3:49])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:48])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CC(N)=O)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CC(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(carbamoylmethyl-methyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl)thio-6-[(R)-1-t-butyidimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (932 mg, 1.27 mmol) (obtained as described in Reference Example 44(2)) in tetrahydrofuran (50 ml) were added acetic acid (0.22 ml, 3.81 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (3.81 ml, 3.81 mmol) in an ice bath and the mixture was stirred at room temperature for 2 days. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate Were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate: methanol (10:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(carbamoylmethyl-methyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (424 mg, yield 53%) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1.[NH2:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24]>>[CH2:42]([O:41][CH2:40][C@H:22]([NH:21][C:13](=[O:15])[CH2:12][N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:3]=2[Cl:2])[CH2:11][CH2:10]1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(Cc2c(F)cccc2Cl)CC1
Agent: Cl
Product: O=C(CN1CCN(Cc2c(F)cccc2Cl)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 40.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 239, (S)-3-(benzyloxy)-2-(2-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (20.8 mg, 40.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.37 (m, 2H), 7.29 (m, 5H), 7.21 (t, 3H), 7.04-6.98 (m, 4H), 4.68 (m, 1H), 4.51 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.60 (s, 2H), 2.96 (m, 2H), 2.51 (m, 8H). MS (EI) for C35H35ClF2N4O4. found 650.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[NH2:19][C:20]1[C:21]([CH3:29])=[N:22][N:23]([CH2:26][CH:27]=[CH2:28])[C:24]=1Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=[C:24]2[N:23]([CH2:26][CH:27]=[CH2:28])[NH:22][C:21]([CH3:29])=[C:20]2[N:19]=1
Reactant: Cc1cc(N)c(C(=O)c2ccccc2Cl)cc1C
Reactant: C=CCn1nc(C)c(N)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C21
Temperature: 170 °C

Procedure:
A mixture of 3.0 g (0.0116 mole) of (2-amino-4,5-dimethylphenyl)-(2-chlorophenyl)-methanone (Xw), 2.0 g (0.0116 mole) of 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), 2.21 g (0.0116 mole) of p-toluenesulfonic acid monohydrate and 40 mL of isopropanol was heated in a sealed tube at 170° C. for 90 minutes. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and then washed twice with saturated sodium bicarbonate solution. The aqueous washes were reextracted with ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Trituration of the residue with hexane gave the intermediate 5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVw), as a yellow solid. Purification of the filtrates by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:1) provided additional XIVw and was combined with the material obtained above for a total yield of 2.7 g of XIVw as a yellow solid, which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:12]=1[CH3:13])=[O:7])C>O1CCOCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]cc(CCc2ccc(Cl)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(CCc2ccc(Cl)cc2)c[nH]c1C(=O)O
Temperature: 80 °C
Yield: 66 %

Procedure:
Freshly prepared aq. NaOH (1M in H2O, 10 equivalents) was added at room temperature to a stirred solution of 86 (1 equivalent) in a mixture of 1,4-dioxane and H2O (v/v 3:1). The reaction was heated to 80° C. until the reaction was judged complete by TLC. The product was extracted with Et2O, then the aqueous layer was made acid (pH=1) with the dropwise addition of 10% aq. HCl. The solid was filtered off and washed with water. The solid was dried under vacuum overnight to obtain 87. Yield: 66%. 1H-NMR (400 MHz, CD3OD): δ 2.19 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 6.58 (d, 1H), 7.11 (d, 2H), 7.22 (d, 2H) ppm. LC/MS: 100%, m/z=263. HPLC (200-400 nm): 95.93%
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[C:11]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:22][C:20](=[O:21])[C:19]([NH:18][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=c1oc(CBr)c(CBr)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (188 mg, 0.69 mmol) was dissolved in acetonitrile (5.0 mL). Thereto were added 2-(N-Boc-amino)isobutyric acid (70 mg, 0.35 mmol) and potassium carbonate (48 mg, 0.35 mmol). This mixture was stirred at 25° C. for 18 hours. After the ordinary post-treatment, the reaction product was purified by thin-layer chromatography (developed with chloroform) to obtain Compound S-33 (50 mg, yield 18%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][NH:13][CH3:14])=[CH:3]1.[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C.CCN(CC)CC>[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:13]([CH2:12][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])[N:2]([CH3:1])[CH:3]=2)[CH3:14])=[O:26])=[CH:18][CH:17]=1
Reactant: CNCc1cn(C)c2cccc(C)c12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: Cc1cccc2c1c(CN(C)C(=O)/C=C/c1ccc(N)nc1)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a stirred solution of 1,4-dimethyl-3-(methylaminomethyl)-1H-indole (188.2 mg, 1 mmole) and (E)-3-(6-aminopyridin-3-yl)acrylic acid (164 mg, 1 mmole) in dry DMF (12 mL) containing dry Et3N (4 mL) was added HOBt.H2O (153 mg, 1 mmole) and EDC (191.8 mg, 1 mmole). The reaction was stirred overnight under argon at ambient temperature, then was concentrated in vacuo. The residue was partitioned between EtOAc and 5% NaHCO3 solution, and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography on silica gel afforded the title compound (120 mg, 36%) as a white solid: MS (ES) m/e 335.2 (M+H)+.
Reaction SMILES: C(O)=O.[CH2:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O.[C:26](=O)=O.Cl.[OH-].[Na+]>O>[CH3:26][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCNCc1ccccc1
Reactant: O=C=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCCCCCCCCCCCN(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
To 8.96 g (0.105 mol.) of commercial formic acid (85~90%) which was cooled by cold water was gradually added 9.5 g (0.035 mol.) of N-benzyl-n-dodecylamine. Then 2.4 ml (0.0525 mol.) of formaldehyde (37%) was added to the mixture and heated at 90°~100° C. After several minutes, carbon dioxide gas generated, during which the mixture was cooled to room temperature. When the evolution of carbon dioxide stopped, the mixture was again refluxed at 90°~100° C. for 8 hours. After completing the reaction, 18 ml of 4 N-hydrochloric acid was added to the cooled reaction mixture, which was condensed to dryness under reduced pressure. The residue was dissolved in 5 ml of water. 10 ml of 18N-sodium hydroxide solution was added to the aqueous solution which was separated into an oily layer and an aqueous layer, the latter of which was extracted with benzene. The benzene extract was distilled under reduced pressure to obtain N-methyl-N-benzyl-n-dodecylamine, b.p. 146 ~ 149° C./0.4 mmHg.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=1>COCCOC>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:10]=[N:11][CH:12]=1
Reactant: CCN=C=O
Reactant: Nc1cncc(Br)c1
Solvent: COCCOC
Product: CCNC(=O)Nc1cncc(Br)c1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A mixture of EtNCO (1.6 ml, 20 mmol) and 5-bromo-pyridin-3-ylamine (1.73 g, 10 mmol) in DME (10 ml) was stirred and heated at 60° C. under N2. After 2 hours another aliquot of EtNCO (1.6 ml, 20 mmol) was added and the mixture was stirred at 60° C. for a further 16 hours. After cooling to RT the mixture was evaporated. The residue was triturated with EtOAc. The solid was collected by filtration and dried under vacuum to give the title compound (2.2 g) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 8.85 (1H, s), 8.43 (1H, d), 8.27 (1H, t), 8.21 (1H, d), 6.39 (1H, t), 3.19-3.05 (2H, m), 1.06 (3H, t).