Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4].[N+:20]([O-])([O-:22])=[O:21].[Na+]>S(=O)(=O)(O)O>[F:19][C:2]([F:1])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21])[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4]
Reactant: O=C(Nc1ccc2[nH]c(=O)c(=O)[nH]c2c1)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 39 g (0.14 mol) of 6-trifluoroacetamido-2,3(1H,4H)-quinoxalinedione in 500 ml of concentrated sulfuric acid was cooled to 0° C., 12.1 g (0.14 mol) of sodium nitrate were added a little at a time, and the mixture was stirred at room temperature for 30 minutes. It was then poured into ice-water, and the crude product was filtered off and worked up by conventional methods.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:28]=[CH:27][C:16]([CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[CH:19]3)=[CH:15][CH:14]=2)[O:11][CH:12]=1>>[ClH:6].[N:1]1([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:17][N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[CH:19]4)=[CH:27][CH:28]=3)[O:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClCc1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Product: Cl
Product: c1ccc2c(c1)ncn2Cc1ccc(-c2nc(CN3CCCC3)co2)cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A mixture of pyrrolidine (0.032 g, 0.46 mmol) and 1-[4-(4-chloromethyl-oxazol-2-yl)-benzyl]-1H-benzoimidazole (0.05 g, 0.15 mmol) in a sealed tube at room temperature was stirred for 30 minutes. The tube was unsealed and the reaction mixture was concentrated in vacuo to remove the excess pyrrolidine. The residue was purified by column chromatography (silica, CHCl3/CH3OH 4%). The purified free base was treated with methanolic HCl solution, stirred for several minutes at room temperature and evaporated to dryness to afford the title product as a white solid in 51% yield, identified by NMR and mass spectral analyses. 1H NMR (300 MHz, DMSO-d6): 9.35 (s, 1H); 8.33 (s, 1H); 8.00 (d, 2H); 7.85 (m, 1H); 7.74 (m, 1H); 7.59 (d, 2H); 7.49 (m, 2H); 5.79 (s, 2H); 4.35 (s, 2H); 3.36 (m br, 4H); 1.98 (m, 4H)). LCMS (ESI+) 359 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.NC1C(C(O)=O)=NC(C2C=CC(F)=CC=2)=C(C(F)(F)F)C=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:21]2[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1[NH2:11])=[O:4]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: Cc1ccc(B(O)O)cn1
Agent: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Product: COC(=O)c1nc(-c2ccc(C)nc2)c(C(F)(F)F)cc1N

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 2-methylpyridine-5-boronic acid analogously to 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate G); LC-MS Rt 0.96 min [M+H]+ 312 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s), 7.69 (1H, dd), 7.32 (1H, d), 7.10 (2H, s), 3.82 (3H, s), 2.52 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[S:20](Cl)(=[O:23])(=[O:22])N.[CH3:25][N:26]([CH:28]=O)C>C1COCC1.[OH-].[Na+]>[CH3:25][N:26]([CH3:28])[S:20]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:6]#[N:7])=[CH:8][CH:9]=1)(=[O:23])=[O:22]
Reactant: NS(=O)(=O)Cl
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)Nc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
To a solution of 6-amino-nicotinonitrile (2.4 g, 20.15 mmol) in DMF (40 mL) was added a 1 M solution of NaHMDS (22.0 mL, 22.0 mmol) in THF followed by sulfamoyl chloride (3.0 mL, 27.9 mmol). The mixture was stirred overnight and was then diluted with 1 N aqueous sodium hydroxide and a mixture of ether-hexanes. The aqueous layer was separated. The organic layer was extracted with 1 N aqueous sodium hydroxide (2×30 mL). The combined aqueous layers were washed with ether (3×30 mL), made acidic with 1 N aqueous HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with brine (3×30 mL), dried over magnesium sulfate, treated with activated carbon, filtered through diatomaceous earth and concentrated in vacuo. The solid was adsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes (compound precipitated on the column but dissolved over time at high ethyl acetate concentration) to afford 6-(dimethylaminosulfonylamino)-3-cyanopyridine as a white solid
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH:23](I)([CH3:25])[CH3:24]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reaction time: 1 h

Procedure:
To (2R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.5 g) and Na2CO3 (8.32 g) was added dry EtOH (135 ml) and isopropyl iodide (2.16 ml) and the mixture heated at reflux for 18 hours under argon. The solvent was then removed under reduced pressure, 5% MeOH/DCM (50 ml) added, the mixture stirred for 1 hour in a stoppered flask, filtered and washed through with DCM (2×10 ml). The filtrate was applied directly to a 120 g-silica Redisep® cartridge and purified using 10-70% MeOH/DCM. After evaporation, the product was isolated as a white foam (4.50 g), which was used without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26][C:27](C)([O-:29])C.[K+].ClCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][OH:29])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Reactant: CC(C)(C)[O-]
Agent: OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccc(F)cc1C
Reaction time: 48 h

Procedure:
A solution of 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-hydroxyquinoline (3.2 g, 9.4 mmol) and potassium t-butoxide (1.83 g, 15 mmol) in tetrahydrofuran (75 ml) was warmed to reflux, 2-chloroethanol (1.3 ml, 20 mmol) added, and heating continued for 2 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 5% methanol in dichloromethane) gave initially recovered starting material, followed by product fractions which were recrystallised from ethyl acetate/petroleum ether, then from methanol to give 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline as a hygroscopic solid (0.82 g, 23%), m.p. 130°-133°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][N:18]=[N+]=[N-])=[O:10])=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>CO.[Pd].ClCCl>[CH:9]([OH:10])=[O:8].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][NH2:18])=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN=[N+]=[N-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN)cc1
Product: O=CO
Temperature: 45 °C
Reaction time: 2 h
Yield: 144.3 %

Procedure:
To a solution of the thus obtained (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-azidomethylpyrrolidine (5.57 g: 18.18 mmole) in methanol (30 ml) are added, 5% palladium on charcoal (560 mg) and ammonium formate (2.3 g). The mixture is stirred at 45° C. for 2 hours. The reaction mixture is diluted with dichloromethane (50 ml), filtered to remove the catalyst, and concentrated in vacuo. The residue is crystallized from a mixture of dichloromethane and ether and washed with ether to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-aminomethylpyrrolidine formate (4.28 g). Yield: 72%. NMR δ(CDCl3 --CD3OD) ppm: 1.6 to 1.82(m, 1H), 2.1 to 2.3(m, 1H), 2.7 to 3.7(m, 4H), 3.81(s, 3H), 4.1 to 4.4(m, 2H), 5.04(s, 2H), 6.88(d, J=8.8 Hz, 2H), 7.28(d, J=8.8 Hz, 2H), 8.47(s, 1H). IR ν (CHCl3) cm-1 : 3678, 3412, 1678, 1602.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[O:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:9]1[O:10][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: Cc1ccc(C=O)o1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(C)o1)CC(=O)O
Yield: 20.9 %

Procedure:
Sodium ethylate (74.2 g, 1.09 mol) was added under vigorous stirring to a solution of 5-methyl-2-furaldehyde 1 (100 g, 0.91 mol) and diethyl succinate (316 g, 1.81 mol) in ethanol (1 L). The reaction mixture was refluxed for 8 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 500 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, acidified with 10% HCl to pH 2, and subjected to extraction with 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 45 g (0.19 mol, 21%) of the desired compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[N:14]=[CH:13][NH:12][C:11]=2[CH:10]=1>>[CH:1]1([CH2:4][O:5][C:9]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[N:14]=[CH:13][NH:12][C:11]=3[CH:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Agent: [H-]
Agent: [Na+]
Product: O=c1nc[nH]c2cc(OCC3CC3)cnc12
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a glass microwave reaction vessel (2-5 ml) were charged with cyclopropylmethanol (3.1 ml, 38.6 mmol) and sodium hydride (60% dispersion in mineral oil) (416 mg, 17.35 mmol). The reaction mixture was stirred at RT for several min. Finally 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (350 mg, 1.928 mmol) (from intermediate 11, step 1 & 2) was added, and the mixture was heated in a Initiator microwave reactor at 140° C. for 10 min. Then it was quenched with water and sat. NH4Cl and extracted with EtOAc for five times. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a mixture. It was washed with Et2O and the brown solid was collected by filtration to yield 7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg, 0.230 mmol, 12% yield) as brown solid which was used for next step directly. MS m/z=218.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:14]1([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A room temperature solution of 1.8839 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (5 mL) is treated with 1.8069 gms. 1′,1′-carbonyl-diimidizole. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 1.0 mL morpholine. The reaction is heated overnight at 35° C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The aqueous layer is re-extracted four more times with ethyl acetate. The combined organics are evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-morpholin-4-yl-2-(4-nitro-phenyl)-ethanone is isolated as a white solid in the amount of 1.4009 gms.
Reaction SMILES: [NH2:1][C:2](=[N:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:32]2[NH:36][C:35](=[O:37])[N:34]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:33]=2)[C:11]2[C:12]([F:31])=[C:13]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.Cl[CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58].C(=O)([O-])O.[K+].CN(C=O)C>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:32]2[N:36]=[C:35]([O:37][CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[N:34]([C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)[N:33]=2)[C:11]2[C:12]([F:31])=[C:13]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCOC(=O)C(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 45 °C
Reaction time: 20 h
Yield: 33.5 %

Procedure:
Under nitrogen atmosphere, a mixture of isonicotinic acid 2-{3-[(4-{amino[benzoylimino]methyl}phenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (31.3 mg), 2,2-dimethylpropionic acid chloromethyl ester (9.1 mg), potassium hydrogen carbonate (6.7 mg), and DMF (2 mL) was stirred at 45° C. for 20 hours. The mixture was poured into ethyl acetate (100 mL) and water (20 mL). After shaking the mixture, the organic layer was collected, sequentially washed three times with water (20 mL) and with saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (12.2 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)=[O:7].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:16]1[CH:15]=[CH:14][N:13]2[C:8]([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][S:17][C:18]3=[O:23])=[O:7])=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: O=S(CCCCCl)c1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 0.51 g (2.0 mmol) of 5-(4-chlorobutylsulfinyl)imidazo[1,2-a]pyridine and 0.355 g (2.0 mmol) of thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.30 ml (2.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=50/1) to yield 0.33 g (49.0%, light yellow oily substance) of the desired product.
Reaction SMILES: C(N(CC)CC)C.C(#N)C.[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][NH:30][CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=[CH:28][C:14]1=2)[CH3:12].[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O>[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])[CH:27]=[CH:28][C:14]1=2)[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine(0.15 ml) was added to a acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-yl-ethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.35 g). The mixture was cooled with ice. Benzenesulphonyl chloride(0.13 ml) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. Water was added to the residue, followed by extraction by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate=30:70). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-ether mixture to give the title compound(0.1 g) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×30 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid as a white solid. HRMS: calcd for C14H17ClO3, 268.0866; found (ESI_FT), 291.0748.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:38]2[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[N:28][C:27]=3[N:34]=[CH:35][N:36]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: CCc1ccc2c(Nc3cc(OCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1

Procedure:
The product from Example 27A was reacted with the product from Example 145A using the procedure from Example 10F substituting the product from Example 27A for the product from Example 10E and substituting the product from Example 145A for the product from Example 10B to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (t, J=7.72 Hz, 3H), 2.95 (q, J=7.72 Hz, 2H), 5.11 (s, 2H), 6.65 (d, J=8.82 Hz, 2H), 6.91-7.05 (m, 1H), 7.10 (d, J=8.46 Hz, 2H), 7.32-7.50 (m, 6H), 8.12 (d, J=6.99 Hz, 1H), 8.66-8.77 (m, 1H), 9.04 (d, J=8.82 Hz, 1H), 9.63 (s, 1H), 10.28 (s, 1H); MS (APCI) m/z 481 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1cccc(N)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1cccc(NC(=O)c2ccc(Cl)nc2)c1

Procedure:
6-Chloro-N-(3-methoxy-phenyl)-nicotinamide was prepared from 3-methoxyaniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H11N2OCl [M+H]+: 263.0582. Found: 263.0581.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:9][C:4]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C=Nc2c(C)cc(C)cc2C)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(c2ccccc2CNc2c(C)cc(C)cc2C)C(C)=C1C
Yield: 79.3 %

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,4,6-trimethylphenyl)amine (10.0 mmol) in acetic acid (7.0 mL) was added sodium borohydride (13.0 mmol). The mixture was reacted at room temperature for 1 hr. Water and toluene were then added the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(2,4,6-trimethylphenyl)amine (2.74 g, yield 69.5%) as a yellow oily substance.