Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].F[C:24]1C=C(C(O)C)C=C(F)C=1C1N=C(C(O)=O)C=CC=1F.[H-].[Na+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:24])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)O)cc2F)n1
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Reaction time: 0.03 h
Yield: 63 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]1([CH3:41])[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][C:33]1([CH3:41])[O:37][C@@H:36]([CH2:38][CH2:39][NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])[CH2:35][O:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Reactant: CC1(C)OC[C@H](CCN)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Yield: 63.6 %

Procedure:
A mixture rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (125 mg, 0.267 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 mg, 1.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 114.1 mg, 0.3 mmol) and iPr2NEt (0.3 mL, 3.22 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (101 mg, 63.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N3O3S+H [(M+H)+]: 594.2097. found: 594.2096.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].I.[O:14]=O>>[O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=O
Agent: I
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 50 °C

Procedure:
1200 g of an aqueous solution of 360 g (2 mol) of glucose (HI MESH; a product of Aito Co., Ltd.) and 5.4 g (1.5 wt. % based on glucose) of the catalyst prepared as above were placed in a 2.5 l reaction vessel provided with a stirrer, thermometer, alkali dropping funnel, pH electrodes and oxygen inlet. Oxygen gas was introduced into the aqueous solution under vigorous stirring while the temperature was maintained at 50±1° C. As the reaction proceeded, gluconic acid was formed. Gluconic acid was neutralized with a 40 wt. % aqueous sodium hydroxide solution added dropwise thereto so as to maintain the pH of the aqueous solution at 9.5±0.2. 1.0 h after the initiation of the reaction, a theoretical amount (2 mol) of the alkali was consumed. Thereafter, no more alkali was consumed and the reaction no more proceeded. Thus, the completion of the reaction was evident.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: C[C@@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Pyridine (0.3 mL, 3.7 mmol) was added to a stirring solution of (2R,5R)-1,5-dibenzyl-2-methylpiperazine (0.28 g, 1.0 mmol) and methyl chloroformate (0.10 g, 0.087 ml, 1.1 mmol) in CH2Cl2 (11 ml). After stirring at ambient temperature for 1 day, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 5% MeOH in CH2Cl2) to afford pure product (0.17 g, 49% yield over the two steps). MS (ESI) 339 (M+H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=O)[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CO>[N:22]1([C:12]2[CH2:13][CH2:14][C@@:15]3([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]4[C@@H:17]3[CH2:18][CH2:19][C@@:2]3([CH3:1])[C@H:6]4[CH2:5][CH2:4][C:3]3=[O:21])[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CO
Product: C[C@]12CCC(N3CCCC3)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h

Procedure:
A solution of 113.5 parts of crude androst-4-ene-3,17-dione in 427 parts of methanol is heated to just below reflux temperature. To the resulting stirred solution there is added 4.3 parts of pyrrolidine. After five minutes, more pyrrolidine is added at a steady rate so that 33.2 parts are added over a period of 25 minutes. The warm mixture is then stirred for an additional 15 minutes before it is cooled to 5°-10° C. The solid product which formed during the reaction is then separated by filtration and washed several times with methanol at 10° C. The solid is then dried to give 3-(1-pyrrolidinyl)androsta-3,5-dien-17-one melting at about 217°-220° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1.[CH3:9][O-].[Na+]>CO.S(=O)(=O)(O)O>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1
Reactant: C[O-]
Reactant: O=C(O)c1cn[nH]c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn[nH]c1

Procedure:
4-Pyrazolecarboxylic acid (514 mg) was dissolved in methanol (10 ml) and sulfuric acid (0.25 ml), and the mixture was stirred at room temperature for 2 hours, followed by refluxing under heating for 4 hours. After cooling, a 28% solution (0.95 ml) of sodium methylate in methanol was added to the reaction mixture for neutralization and the solvent was distilled away. Chloroform was added to the residue, and the residue was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled away to give 433 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[NH:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1.O>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[NH:19][CH:20]([CH3:21])[CH3:22])[CH2:6][CH2:7]1
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1C(=O)NN1CCN(C)CC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(N)cc1C(=O)NN1CCN(C)CC1

Procedure:
2.0 g (6.5 mmol) of N-(4-methylpiperazin-1-yl)-2-isopropylamino-5-nitrobenzamide were dissolved in 40 ml of glacier acetic acid and 6.8 g of zinc powder were added gradually at 45-50° C. For workup, 40 ml of water were added, the mixture was extracted once with ethyl acetate, the water phase was alkalized with NaOH, and the mixture was extracted repeatedly with methylene chloride. The residue remaining after drying and concentration (1.9 g) could be used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:6][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[N+:24]([O-])=O)=[N:4]1)[CH3:2].[H][H]>CO.[Pt]>[NH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCn1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1-c1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CCn1nc(Oc2ccc(F)cc2N)cc1-c1cccc(C#N)c1
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
Platinum (3% on carbon, poisoned with 0.6% vanadium, 24 mg, 3.8 mmol, 0.005 equiv) was added to a solution of 3-[1-ethyl-3-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-5-yl]benzonitrile (266 mg, 0.755 mmol, 1 equiv) in methanol (7.6 mL). The reaction flask was capped with a three way valve attached to a vacuum line and a hydrogen balloon. The reaction flask was alternately evacuated and charged with hydrogen for 3 cycles, and finally left under an atmosphere of hydrogen at 22° C. The reaction mixture was stirred for 40 minutes, then filtered through celite with the aid of methanol. Concentrated to afford 3-[3-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-5-yl]benzonitrile (243 mg, 90% pure) as a light-yellow solid. Calcd (M+1)+: 323.1. Found: 323.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CO)cc3)cc2)CC1
Yield: 4.2 %

Procedure:
The title compound (1.6 mg, 4%) was prepared from [4-(hydroxymethyl)phenyl]boronic acid (15.2 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 406 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH3:26])=[O:20]
Reactant: CC(C)(C)CN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2,2-dimethylpropylamine (0.310 g, 3.56 mmol), triethylamine (0.280 g, 2.77 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2,2-dimethylpropyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.660 g, 53.1% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H].[ClH:24]>C(O)C.O.[Pd]>[ClH:24].[ClH:24].[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCc3ccccc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(CCN2CCc3ccccc3C2)cc1

Procedure:
To a solution of the product of step (a) (11.0 g, 39.0 mmol) in 95% ethanol (150 ml), concentrated hydrochloric acid (7.5 ml) and water (50 ml) was added 10% Pd/C (1.0 g). The mixture was hydrogenated at 50 psig for 2.5 hours, until the theoretical amount of hydrogen was taken up. The catalyst was filtered and the filtrate concentrated to a solid residue. This was digested in absolute ethanol (75 ml), cooled, filtered and air dried; yield 11.4 g (90%) of the dihydrochloride salt.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=[O:23].O>O1CCCC1>[OH:23][CH:22]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:21][C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at −40° C. for 30 minutes. 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room temperature for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(1-hydroxy-3,3-dimethylbutyl)benzoate (640 mg, 95%). 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CC(N(C)C)=O>[N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])cnc1OCC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90° C. for 2 hours. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O.[OH-].[Li+].Cl>O.CS(C)=O>[F:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
Add 2-amino-5-methyl-thiophene-3-carbonitrile (10.0 g, 72.4 mmol) and 2,4-difluoro-1-nitro-benzene (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at 10-20° C. Adjust the pH to 7-8 with concentrated HCl (˜6 mL) and stir for 4 hours. Filter the crude product and rinse with 3:1/water: DMSO, then water. Dry at 50° C. to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%): 1H NMR (400 MHz, DMSO-d6) δ 9.83 (bs, 1H), 8.28 (m, 1H), 7.12 (s, 1H), 6.91 (m, 1H), 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H8FN3O2S 300.0219; found 300.0219.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([O:28]CC)=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[C:6]=2[F:33])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[C:6]=2[F:33])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC3)c(F)c(C)c2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CCC4)nc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of Example 5A (250 mg) in THF (30 mL) dichloromethane (10 mL) was treated with 1M LiOH (15 mL), stirred for 18 hours, treated with 10% citric acid, and extracted with dichloromethane; and the extract was concentrated.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(Cl)Cl>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCCC3)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (367 mg, 1 mmol) in dry DCM (15 mL) was added acetic acid (0.2 mL) followed by pyrrolidine (213 mg, 3 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium borohydride (318 mg, 1.5 mmol) was added at 0° C. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound (62 mg, yield 14%) as white solid. LC-MS (ESI) m/z: 423(M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.82-1.85 (m, 2H), 1.97 (s, 2H), 3.01-3.05 (m, 2H), 3.26 (d, 2H), 4.27 (d, 2H), 4.36 (d, 1H), 4.84 (d, 1H), 7.13-7.23 (m, 6H), 7.36-7.40 (m, 5H), 7.48 (s, 1H), 7.57-7.61 (t, 1H), 12.18 (s, 1H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16](=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)CCCc1ccc2c(c1)CC(N)C2

Procedure:
3 ml of perchloric acid and 3 g of 10% palladium-on-charcoal are added to 15 g (52.8 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate in 200 ml of glacial acetic acid and the mixture is hydrogenated at 50° C. and a hydrogen pressure of 5 bar. When the calculated amount of hydrogen has been absorbed, the catalyst is filtered off, the filtrate is evaporated, sodium hydroxide is added to the residue and the reaction product is extracted with ether. After drying and evaporation, the desired product is obtained in the form of an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.Cl[CH2:18][C:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([NH:30][C:31](=[O:47])[C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]=3[F:46])[CH:28]=2)[NH:23][CH:22]=1)=[O:20]>CCO>[F:46][C:33]1[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:41])=[O:42])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:31]([NH:30][C:27]1[CH:28]=[C:29]2[C:21]([C:19](=[O:20])[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH:11]([F:10])[CH2:12]3)=[CH:22][NH:23][C:24]2=[N:25][CH:26]=1)=[O:47]
Reactant: FC1CCCNC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN4CCCC(F)C4)c3c2)c1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Hunig's base (0.0196 mL, 0.106 mmol) and 3-fluoropiperidine (0.0148 g, 0.106 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.0106 mmol) in EtOH (0.2 mL), which was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified via column chromatography (5% to 10% MeOH/DCM) to provide 2,6-difluoro-N-(3-(2-(3-fluoropiperidin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (3 mg, 52.6%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.92 (m, 1H), 8.62-8.63 (m, 1H), 8.60 (s, 1H), 7.63-7.69 (m, 1H), 7.13-7.16 (m, 1H), 4.60-4.80 (m, 1H), 3.76 (s, 2H), 3.08-3.15 (m, 2H), 2.86-2.94 (m, 1H), 2.59-2.79 (m, 4H), 2.50-2.55 (m, 1H), 1.80-1.93 (m, 4H), 1.57-1.71 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=538.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>CCO>[NH:23]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:14]=1)=[O:17])[NH2:24]
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a suspension of methyl 4-[(3-phenylpropanoyl)amino]benzoate (1.40 g, 4.94 mmol) in EtOH (16 mL) was added hydrazine hydrate (3.6 mL). After stirring for 16 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 60° C. for 2 hrs gave 1.08 g of the title compound (77%) as a white solid in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).