Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].C(S)CCCCCCCCCCC.O>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=[O:10]
Reactant: COc1ccccc1C(=O)c1ccccc1SC
Agent: CCCCCCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccccc1C(=O)c1ccccc1O
Yield: 59 %

Procedure:
To a mixture of 1.45 g (2-methoxyphenyl)(2-(methylthio)phenyl)methanone (G) and 1.437 g AlCl3 was added slowly 5 mL 1-dodecanethiol. The reaction was stirred overnight before 30 ml water was added. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate, and the volatiles removed by distillation under nitrogen. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.807 g product (3.31 mmol, 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CC=O)cc1F
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1F

Procedure:
A solution of 2-fluoro-4-(2-oxoethyl)benzonitrile (140 mg, 0.88 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (170 mg, 0.73 mmol) and NaBH(OAc)3 (620 mg, 2.9 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 20 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.13˜8.16 (d, J=8.6 Hz, 2H), 7.52˜7.55 (t, J=6.6 Hz, 1H), 7.36˜7.38 (d, J=8.6 Hz, 2H), 7.08˜7.12 (m, 2H), 2.89˜3.00 (m, 4H), 2.56˜2.78 (m, 12H). MS m/z: 383 (M+1)+. (0.24 μM)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][C:22]#[N:23])=[CH:18][CH:17]=1>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][CH2:21][C:22]#[N:23])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC#N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC#N)cc1
Yield: 91.9 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamonitrile (4.0 g), palladium-carbon (5%, 0.5 g ) and ethyl acetate (50 ml) was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, then the filtrate was concentrated under reduced pressure to leave 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionitrile (3.7 g, 93%). The product was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.109°-110° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:20]([C:16]1[CH:15]=[C:14]([CH:12]([OH:13])[CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[CH:19]=[CH:18][CH:17]=1)([OH:22])=[O:21]
Reactant: O=C(O)c1cccc(C=CC(=O)c2cccc(C(=O)O)c2)c1
Agent: [Rh]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: O=C(O)c1cccc(CCC(O)c2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,3′-Dicarboxychalcone (Example 4, step 2) (430 mg, 1.45 mmol) in ethanol (10 mL) containing aqueous NaOH (1 M, 2.90 mmol) was hydrogenated at 45 psi for 48 hours in the presence of Wilkinson's catalyst (67 mg, 0.07 mmol). The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in methanol (10 mL) and treated with NaBH4 (220 mg, 5.8 mmol) at rt. The reaction mixture was stirred for 16 hours at rt, quenched with the cautious addition of saturated aqueous NH4Cl and partitioned between EtOAc (50 mL) and aqueous HCl (1 M, 50 mL). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give 1,3-bis (m-carboxyphenyl)-1-propanol as a viscous oil. MS (APCI) m/z 299 (M+−1, 100%). 1H NMR (200 MHz, CDCl3); δ1.95-2.10, m, 2H; 2.68-2.83, m, 2H; 4.62-4.78, m, 1H; 7.03-7.60, m, 4H; 7.75-8.03, m, 4H.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[C:31]([OH:38])[CH:30]=1)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][S:26]([C:29]5[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[C:31]([OH:38])[CH:30]=5)(=[O:28])=[O:27])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 62.4 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (2.052 g, 6.171 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (5.840 g, 24.68 mmol). Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with a 15 & 25% EtOAc/hexane step gradient gave 2.05 g (62%) of the title compound. 1H NMR (DMSO-d6) δ 1.60 (s, 3 H), 2.16 (s, 6 H), 2.42 (s, 3 H), 7.17 (s, 2 H), 7.38-7.40 (m, 2 H), 7.47-7.56 (m, 3 H), 7.98 (d, 1 H), 8.09 (d, 1 H), 8.50 (s, 1 H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([S:30](F)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=3)=[O:22])[CH:14]=[N:13]2)=[CH:8][CH:7]=1>C(Cl)Cl>[CH:1]1([NH:4][S:30]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([C:15]3[CH:14]=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=4)[C:16]=3[C:17]([F:20])([F:18])[F:19])=[O:22])[CH:29]=[CH:28][CH:27]=2)(=[O:31])=[O:32])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(Nc1cccc(S(=O)(=O)F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Cyclopropyl amine (0.012 mL, 0.167 mmol) was added to 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (0.025 g, 0.055 mmol) in CH2Cl2 (10 ml). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyclopropylsulfamoyl-phenyl)-amide (0.015 g, 55%).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:37]3[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
A dimethyl sulfoxide solution (0.8 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (76.5 mg, 0.19 mmol) and cis-2,6-dimethylpiperazine (87.5 mg, 0.77 mmol) was heated at 140° C. and stirred for 2.5 hours. The resulting mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the resulting mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (91.1 mg, 100%) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:6](COCC[Si](C)(C)C)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][C:21](=O)OC(C)(C)C)[CH:3]=1.FC(F)(F)C(O)=O.COC(OC)N(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[N:5]([CH:21]=[N:20][C:19]3[CH:18]=[CH:17][S:16][C:15]=32)[N:6]=1
Reactant: Cc1cc(-c2sccc2NC(=O)OC(C)(C)C)nn1COCC[Si](C)(C)C
Agent: COC(OC)N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c3sccc3ncn2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [2-(5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-thienyl]carbamate (3.2 g, 7.8 mmol) in methylene chloride (23 mL) was added trifluoroacetic acid (23 mL). After stirring at room temperature for 5 h, the solvent was removed. The residue was dissolved in THF (40 mL) and treated with 1,1-dimethoxy-N,N-dimethylmethanamine (1.56 mL, 11.7 mmol). The resulting solution was heated at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude was purified with flash chromatography (eluting with a gradient of 0-20% ethyl acetate in hexanes) to give the desired product as white solid. 1H NMR (300 MHz, CD3OD) δ 9.09 (1H, s), 7.81 (1H, d, J=5.3 Hz), 7.45 (1H, d, J=5.3 Hz), 6.60 (1H, s), 2.49 (3H, s) ppm. LCMS calculated for C9H8N3S (M+H)+: m/z=190.0. Found: 190.0.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Cl.[OH-].[Na+]>O>[CH2:1]([NH:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(CCl)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNCc1ccccc1)OC
Temperature: 27.5 °C
Reaction time: 0.21 h

Procedure:
Benzylamine (0.927 kg), chloroacetaldehydedimethylacetal (0.909 kg), sodium hydroxide solution (0.35 kg) in 2.72 L of water were charged into the flask under stirring at 25-30° C. for 10-15 min. Reaction mass was heated to 100-102° C. under stirring for 30 hrs. After completion of reaction, reaction mass was allowed to settle for 30 min. Two layers are separated and upper product layer was collected, distilled under high vacuum.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(=O)C.C=O.[CH3:10][N:11]1[C:16]2[C:17]([CH3:20])=[CH:18][NH:19][C:15]=2[C:14](=[O:21])[N:13]([CH3:22])[C:12]1=[O:23]>O>[CH3:1][N:2]([CH2:20][C:17]1[C:16]2[N:11]([CH3:10])[C:12](=[O:23])[N:13]([CH3:22])[C:14](=[O:21])[C:15]=2[NH:19][CH:18]=1)[CH3:3]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CNC
Agent: C=O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 50% dimethyl amine (0.4 mL), acetic acid (0.4 mL) and 38% formaldehyde (0.4 mL) were added, after which Intermediate 1 (0.4 g, 2.232 mmol) was added. The reaction mixture was refluxed for 10 min and then held for 20 min at 90° C. Reaction mixture was cooled to room temperature and diluted with water (25 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (25 mL), dried (Na2SO4) and filtered. The filtrate was evaporated to give a crude product which was recrystallised from acetonitrile to give 97 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.08 (s, 6H), 3.23 (s, 3H), 3.30 (s, 2H), 3.69 (s, 3H), 7.13 (s, 1H), 11.93 (br s, 1H); APCI-MS (m/z) 237.00 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([NH2:8])([CH3:7])[CH2:5][SH:6].[Cl:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>C1C=CC=CC=1>[NH2:8][C:4]([CH3:7])([CH3:3])[CH2:5][S:6][C:13]1[N:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: CC(C)(N)CS
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(N)CSc1ccc(Cl)nn1
Yield: 36.4 %

Procedure:
To a suspension of 1.32 g of 61% sodium hydride in 20 ml of benzene was added dropwise at room tmperature a solution of 2.6 g of 2-methyl-2-aminopropanethiol in 10 ml of benzene. Then, a solution of 4.1 g of 3,6-dichloropyridazine in 10 ml of benzene was added, and the mixture was refluxed for 6 hours. After cooling, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated to give 1.96 g of 3-(2-amino-2-methylpropylthio)-6-chloropyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Reaction time: 0.5 h
Yield: 928.3 %

Procedure:
To a solution of 5-aminoindane (10.0 g, 7.5 mmol) in CH2Cl2 (100 mL) was added dropwise acetic anhydride (9.2 g, 9.0 mmol) over a period of 1.5 min. After further stirring for 30 min, the mixture was quenched with 1M aqueous NaOH (100 mL). The CH2Cd2 layer was separated, washed successively with 1M aqueous HCl, brine, and was then dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate:hexanes (1:1) afforded 12.2 g (85%) of the title compound as a light brown powder.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Agent: Cl
Product: Nc1ccccc1CSc1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
The title compound was prepared by the method of Example 1 using 2.50 g of 2-mercapto-5-chlorobenzimidazole instead of 2-mercaptobenzimidazole and 2.42 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 2.47 g of the title compound. Anal. Calc'd. for C14H12N3ClS: C, 58.03; H, 4.17; N, 14.10; S, 11.06; Cl, 12.23. Found: C, 57.33; H, 4.06; N, 14.27; S, 10.99; Cl, 12.74.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:8]([C:20](OCC)=[O:21])[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[NH:4][N:3]=1.[C:33](O)(=[O:35])[CH3:34]>[Fe]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:7]2[C:8]3[C:20](=[O:21])[NH:17][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:9]=3[C:10]3[C:2]([NH:1][C:33](=[O:35])[CH3:34])=[N:3][NH:4][C:5]=3[N:6]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(N)c2c1-c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: COc1ccc(-c2nc3[nH]nc(NC(C)=O)c3c3c2c(=O)[nH]c2ccccc23)cc1
Reaction time: 5 h
Yield: 56 %

Procedure:
55 mg (1 mmol) of iron is added to a solution of 87 mg (0.2 mmol) of ethyl 3-amino-6-(4-methoxyphenyl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate dissolved in 2 ml of acetic acid. The reaction medium is carried at 90° C. for 5 hours, and then the precipitate obtained is filtered on Dicalite and rinsed with a 98:2 dichloroethane/methanol mixture. The filtrate is concentrated to yield 45 mg (56%) of N-(5-(4-methoxyphenyl)-6-oxo-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-1-yl)acetamide in the form of a yellow solid.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25]C)=[C:17]2[CH:27]([OH:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=O)[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[C:27](=[O:39])[C:17]3[C:16](=[C:15]([O:14][CH3:1])[C:24]4[N:23]=[CH:22][CH:21]=[N:20][C:19]=4[C:18]=3[OH:25])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 247a (20 mg, 0.038 mmol, 1 equiv.) was added CH2Cl2 (1 mL) under a nitrogen atmosphere. Triethylsilane (200 μL) was added followed by trifluoroacetic acid (200 μL). The reaction was allowed to stir for 1 hour and then concentrated in vacuo until thoroughly dried. To the oil was Hexanes/Ethyl ether (15 mL, 1/1 ratio) and sonicated. The resulting solid was then filtered, washed in hexanes, and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 248 (38%, 7.2 mg, 0.0.14 mmol). 1H NMR (300 MHz) CDCl3 δ 8.95 (d, J=13.8 Hz, 2 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2 H), 4.79 (2 H), 4.55 (s, 2 H), 4.14 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.80. MS: 340.1 (M+1)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Product: Cc1nc(NC(=O)CCc2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-phenylpropionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 25% yield; m.p. 63-65° C.; 1H NMR (CDCl3, 300 MHz) δ 7.34-7.14 (m, 10H), 5.97 (t, J=4.9 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.06-2.93 (m, 2H), 2.79-2.64 (m, 2H), 2.54 (s, 3H); MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]O>S(=O)(=O)(O)O>[C:1]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1

Procedure:
To a solution of 10.00 g of 4-(4-cinnamoylphenyl)butyric acid in 50 ml of methanol, 0.25 ml of sulfuric acid was added, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure, and then the residue was added with water and extracted with ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=3:2) to yield 8.94 g of pale yellow crystals. Recrystallization from n-hexane gave pale yellow needles, mp 43°~44° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([CH:33]4[CH2:36][C:35]([CH3:38])([CH3:37])[CH2:34]4)[C:17]4[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([CH:33]4[CH2:36][C:35]([CH3:38])([CH3:37])[CH2:34]4)[C:17]4[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C4CC4)cn3)nc2)C2CC(C)(C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(C(Nc2ccc(-n3cc(C4CC4)cn3)nc2)c2ccc(C(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of crude (+/−)-ethyl N-{4-[{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}(3,3-dimethylcyclobutyl)methyl]benzoyl}-beta-alaninate (2.48 g, 4.91 mmol) was dissolved in methanol (4.8 ml) and tetrahydrofuran (2.4 ml) and treated with aqueous 2.0M lithium hydroxide (4.8 ml, 9.6 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. A yellow precipitate formed and was collected by filtration. The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21×250 mm. Mobile Phase: 50/50 CO2/methanol, (peak 1, 638 mg, 27% and peak 2, 682 g, 29%). Flow Rate: 65 mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm×25 cm; SFC Mobile Phase 50:50 CO2/Methanol, 2.5 mL/min, analytical retention time: 3.90 min (Isomer 2) and 9.30 (Isomer 1). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.60 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.84 (dd, J=8.8, 2.7 Hz, 1H), 4.14 (d, J=9.4 Hz, 1H), 3.56-3.67 (m, 2H), 2.40-2.47 (m, 2H), 1.96 (ddd, J=11.2, 8.0, 3.9 Hz, 1H), 1.60-1.74 (m, 3H), 1.54 (ddd, J=11.9, 8.4, 3.7 Hz, 1H), 1.28-1.34 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.81-0.86 (m, 2H), 0.50-0.56 (m, 2H) MS (M+1): 488.4.