Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:14]([C:13]2[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)=[N:10][O:11][C:12]=2[CH3:17])=[O:16])[CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 89.6 %

Procedure:
Combine 3-(3,5-dichloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid (0.35 g, 0.0013 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.38 g, 0.0013 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25, 0.0013 mol), 1-hydroxy-7-azabenzo-triazole (0.18 g, 0.0013 mol), and N,N-diisopropylethyl amine (0.67 mL, 0.0039 mol) in N,N-dimethylformamide (8 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Concentrate and elute over silica gel using ethyl acetate/dichloromethane to give 0.603 g (90%) of the desired amide. MS(ES): (M+1)+ 517.2, 519.2 m/z.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:21]([CH2:31][O:32][CH2:33][CH3:34])=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:15]1[C:14]2[N:20]=[C:21]([CH2:31][O:32][CH2:33][CH3:34])[N:22]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reaction time: 5 h

Procedure:
N-[2-(7-Benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (1.77 g, 3.83 mmol) was dissolved in dichloromethane (100 mL) and aqueous ammonium hydroxide (10 mL) was added, followed by para-toluenesulfonyl chloride (0.73 g, 3.83 mmol). After stirring for 5 hours, the organic and aqueous phases were separated and the organic fraction was washed twice with saturated sodium bicarbonate and then once with brine. The organic fraction was then dried over sodium sulfate, filtered, and concentrated to give a dark orange solid. The solid was purified by flash column chromatography on silica gel (eluting with a gradient of 6-7.5% methanol in dichloromethane) followed by recrystallization from acetonitrile to provide 1.27 g of N-[2-(4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a white powder, mp 202.0-205.0° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: Cc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.280 g, 1.48 mmol) and 7-methyl-3-(piperidin-4-yl)-1H-indole (0.290 g, 1.39 mmol) using ethanol as reaction solvent. Yield 0.320 g (57%) as a tan foam. FDMS m/e=404 (M+ of free base). α[D]589 =11.6 (c=0.98, dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].CS([Cl:17])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>ClCCl>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1c(F)cc(CO)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1c(F)cc(CCl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of [3,5-difluoro-4-(methylthio)-phenyl]-methanol (24.0 g, 0.126 mol) in dichloromethane (300 mL) cooled in an ice bath was added methanesulfonylchloride (16.9 g, 0.147 mol) in portions followed by diisopropyl-ethylamine in portions. The mixture was allowed to warm to room temperature, and stirred for 18 hours. 4-dimethyl-aminopyridine was added and the mixture was heated to reflux for 2 hours, cooled, and stirred at room temperature for 18 hours. The mixture was poured into dilute HCl and extracted with dichloromethane once (75 mL) after separating. The combined extracts were washed with dilute sodium chloride, dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% ethyl acetate in hexanes gave 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene as a clear colorless liquid (24.9 g, 95%). 1H NMR (CDCl3/400 MHz) 6.92-6.96 (m, 2H), 4.49 (s, 2H), 2.44 (s, 3H). HRMS m/z 207.9893 (M+, calcd 207.9925).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]N1C(=O)CCC1=O.O>C(O)(=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (1 g, 5.5 mmol) in acetic acid (5 mL) at room temperature was added N-chlorosuccinimide (0.953 g, 7.14 mmol). The reaction was sealed and heated via microwave for 2 h at 80° C. The resulting mixture was poured into water (ca. 20 mL), cooled to 0° C., and the product collected by filtration. 1H-NMR (2:1 CDCl3/CD3OD, 500 MHz) δ 8.24 (d, J=2.7 Hz, 1H), 8.14 (d, J=2.8 Hz, 1H); 13C NMR (126 MHz, 2:1 CDCl3/CD3OD) δ ppm 167.8, 145.7, 139.6, 132.8, 130.9, 118.5, 116.1. Mass spec.: 215.18 (M−H)−.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.8 G. of 1 -acetamido-4-methylthiomethoxy-2-nitrobenzene is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to give 1-amino-4-methylthiomethoxy-2-nitrobenzene as a red oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([C:7](N)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[OH-:13].[Ba+2].[OH-]>>[CH3:1][C:2]1([CH3:12])[CH:6]([C:7]([OH:13])=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1
Reactant: [OH-]
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1
Agent: [Ba+2]
Product: CC1(C)CC(C(=O)O)C(C)(C)N1

Procedure:
2,2,5,5-tetramethyl pyrroline-3-carboxylic acid was prepared by the hydrolysis of 2,2,5,5-tetramethyl pyrroline-3-carboxamide (Frinton; recrystallized from benzene) with barium hydroxide. The acid was recrystallized from water to provide an off-white solid. The measured mp was 300 (dec.) in a sealed tube; the reported mp was 300 dec. (Pauly 1902; Rozantsev 1970).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:6]1=[O:16])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:3]([N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:14][C:13](=[O:15])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)[C:6]1=[O:16])[CH3:4]
Reactant: CCN1C(=O)CC2(CNC(=O)C2)C1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A suspension of sodium hydride (2.20 g of 60% oil suspension (0.055 mole) washed with toluene) in 50 ml N,N-dimethylformamide was treated gradually with a solution of 10.0 g (0.051 mole) 2-ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 100 ml N,N-dimethylformamide. After stirring 15 minutes, there was added dropwise 6.4 ml (0.055 mole) benzyl chloride and the mixture was stirred overnight, concentrated in vacuo and shaken with water-methylene chloride. The organic layers were dried, evaporated, and the product crystallized from toluene-hexane to afford 11.1 g of the title compound, mp 125-126.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][N:13]([C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH:11]=1
Reactant: CSc1cccc(C2=CCNCC2)c1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC=C(c2cccc(SC)c2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylthio)phenyl]-1,2,3,6-tetrahydropyridine (1.35 g, 6.05 mmol) and triethyl amine (1.2 ml, 7.2 mmol) in methylen chloride (20 ml) at 0° C., a solution of methyl chloroformate (0.49 g, 6.6 mmol) in methylen chloride (5 ml), was added dropwise. The mixture was stirred for 15 min at 0° C. and for 1 h at ambient temperature. The reaction was quenched with aqueous sodium carbonate (10%, 50 ml), the phases were separated and the aqueous phase was extracted with methylen chloride (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.95 g). MS m/z (rel. intensity, 70 eV) 281 (M+, 65), 267 (16), 266 (bp), 147 (27), 146 (25).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1.Cl.[Cl:16][C:17]1[C:18]([F:48])=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:46][CH3:47])=[C:31]([CH2:34][N:35]([CH3:45])[C:36]4([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1>CN(C)C=O>[Cl:16][C:17]1[C:18]([F:48])=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:46][CH3:47])=[C:31]([CH2:34][N:35]([CH3:45])[C:36]4([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][N:39]([CH2:13][CH:10]5[CH2:12][CH2:11]5)[CH2:38][CH2:37]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: BrCC1CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(CC2CC2)CC1
Temperature: 100 °C
Yield: 27.9 %

Procedure:
DIPEA (0.068 g, 0.522 mmol) and cyclopropylmethylbromide (0.035 g, 0.260 mmol) were added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-c arboxamide hydrochloride (0.10 g, 0.172 mmol) in dimethylformamide (1 ml). The reaction mixture was heated at 100° C. for 5 hours, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give the title product (0.0253 g, 27.8%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 0.00 (m, 2H), 0.41 (m, 2H), 0.76 (m, 1H), 1.77 (m, 2H), 2.03-2.13 (m, 7H), 2.81 (m, 2H), 3.32 (m, 2H), 3.61 (s, 2H), 3.91 (s, 3H), 7.06 (s, 1H), 7.14 (s, 2H), 7.26 (t, 1H), 7.47-7.53 (m, 2H), 8.32 (s, 1H), 8.38 (s, 1H), 9.70 (s, 1H); Mass Spectrum: (M+H)+ 527.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>C1(C)C=CC=CC=1>[C:18]([CH2:20][C:21]([NH:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:22])([OH:19])=[O:17]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)CC(=O)O)c(C(=O)O)cc1OC
Yield: 98.9 %

Procedure:
4,5-Dimethoxyanthranilic acid (0.50 g, 2.5 mmol) was added to a solution of Meldrum's acid (0.42 g, 2.9 mmol) in toluene (5.0 mL) and treated according to Procedure 1. 2-[(Carboxyacetyl)amino]-4,5-dimethoxybenzoic acid (0.70 g, 97%) was obtained as a brown solid; δH (400 MHz, DMSO-d6) 3.43 (br s, 2H, CH2), 3.75 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 7.42 (s, 1H, H3), 8.24 (s, 1H, H6), 11.40 (s, 1H, NH).
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][N:4]=1.[O:11]1CCOCC1>O>[F:10][C:6]1[C:7]([I:9])=[CH:8][C:3](=[O:11])[NH:4][CH:5]=1
Reactant: Fc1cc(I)c(F)cn1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 50 %

Procedure:
Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness and the residue was triturated in water (20 mL). The solids were collected via filtration and washed with water (2×30 mL) and hexanes (3×30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.68 (d, J=2.34 Hz, 1 H) 11.50 (br. s., 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)=[O:37])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-naphthoyl chloride: ESMS m/e: 500.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])/[C:3](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)=[CH:4]\[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH4+:30].[OH-]>CS(C)=O.CCOC(C)=O>[NH2:30][C@@:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:16][CH:15]=1)([C:2]([F:28])([F:29])[F:1])[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)/C=C(/c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of Intermediate 2E (2.1 g, 5.04 mmol) in DMSO (50 mL) was added 15 N aq NH4OH (25 mL). The mixture was stirred in sealed pressure vessel for 2 days. The reaction was diluted with EtOAc (60 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography column (eluted with EtOAc in hexanes to provide racemic Intermediate 2F (2.2 g, 101%) as a white solid. LCMS Anal. Calc'd for C21H21F6NO2 433.39, found [M+H] 434.2. Separation of the individual enantiomers of Intermediate 2F was carried out using preparative chiral SFC method A: Racemic Intermediate 2F (2200 mg) provided Intermediate 2F, isomer 1 (817 mg) and Intermediate 2F, isomer 2 (790 mg). Enantiomeric purity determination of Intermediate 2F, isomer 1 and 2 was carried out using analytical SFC method A. Intermediate 2F, isomer 1: RT=2.2 min, 99% ee. Intermediate 2F, isomer 2: RT=2.8 min, 99% ee. X-ray crystal data collected for the camphorsulfonic acid salt of Intermediate 2F, isomer 1 showed the chiral center to have the R-configuration; therefore, the chiral center for Intermediate 2F, isomer 2 has the S-configuration.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]3[C:18]4[CH:26]=[C:25]([N+:27]([O-])=O)[C:24]([CH3:30])=[CH:23][C:19]=4[O:20][C:21](=[O:22])[C:14]=3[CH2:13]1)[CH2:2]2.[H][H]>CN(C)C=O.[Ni]>[NH2:27][C:25]1[C:24]([CH3:30])=[CH:23][C:19]2[O:20][C:21](=[O:22])[C:14]3[CH2:13][N:12]([CH2:11][CH2:10][N:3]4[CH2:2][CH:1]5[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[CH2:17][CH2:16][C:15]=3[C:18]=2[CH:26]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CCN1CC2CCC(CC2)C1)C3
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: Cc1cc2oc(=O)c3c(c2cc1N)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 51.4 %

Procedure:
A solution of 3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.5 g, 0.026 moles) in N,N-dimethylformamide (300 ml) is hydrogenated at 50 psi at 24° C. in the presence of Raney Nickel until the required amount of hydrogen has been taken up. The catalyst is filtered off and rinsed with hot N,N-dimethylformamide until free of organic material. The filtrate is slightly concentrated and cooled to give the product. Recrystallization from ethanol gave the product (5.1 g), mp 142°-143° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:7]2=[CH:8][CH:9]=[CH:10][C:11]3=[CH:12][CH:13]=[CH:14][C:5](=[C:6]23)[C:4](=O)[NH:3]1>O1CCCC1>[S:2]1(=[O:1])(=[O:16])[C:7]2=[CH:8][CH:9]=[CH:10][C:11]3=[CH:12][CH:13]=[CH:14][C:5](=[C:6]23)[CH2:4][NH:3]1
Reactant: O=C1NS(=O)(=O)c2cccc3cccc1c23
Solvent: C1CCOC1
Product: O=S1(=O)NCc2cccc3cccc1c23
Temperature: 65 °C
Yield: 60.6 %

Procedure:
A solution of 1,1-dioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-3-one (137 mg, 0.587 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.17 mL, 1.17 mmol). The resulting solution was heated at 65° C. for 5 hours. The reaction mixture was quenched with methanol (5 mL) and evaporated under vacuum. The residue was purified by preparative layer chromatography on two 1 mm×20 cm×20 cm silica gel GF plates, developing with 7:3 ethyl acetate-hexanes, to afford the title compound (78 mg, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:22])=[N:10][C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1>CO.[Pd]>[Cl:22][C:14]1[C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]=2)=[C:18]([NH2:19])[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1-c1nc(-c2ccncc2)c(-c2ccc(Cl)cc2)[nH]1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(Cl)c1-c1nc(-c2ccncc2)c(-c2ccc(Cl)cc2)[nH]1
Yield: 53.9 %

Procedure:
A solution of 0.2 g of 4-[5-(4-chlorophenyl)-2-(2-chloro-6-nitrophenyl) imidazol-4-yl]pyridine in 20 ml of methanol was hydrogenated in the presence of 0.1 g of 10% palladium/charcoal for 2 hours. The catalyst was filtered off and the solution was evaporated to dryness. Recrystallization from ethyl acetate yielded 0.1 g of 3-chloro-2-[5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl]phenylamine, m.p. 220-222° C.
Reaction SMILES: Cl[CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[C:16]1([NH:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)C>[CH3:4][CH:3]([CH3:5])[CH:2]([NH:25][CH2:24][CH2:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1
Reactant: CC(C)C(Cl)c1cncnc1C(F)(F)F
Reactant: NCCNc1ccccc1
Solvent: CC(C)O
Product: CC(C)C(NCCNc1ccccc1)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.05 g (4.2 mol) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine and 0.61 (4.2 mol) of N-phenylethylenediamine were added to 10 ml of isopropyl alcohol, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated, then poured into water and extracted with ethyl acetate, and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.38 g of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine. Then, 0.38 g (1 mmol) of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine and 0.5 g (5 mmol) of triethylamine were added to 10 ml of dichloromethane, and a dichloromethane solution containing 0.2 g (2 mmol) of phosgene was dropwise added under cooling with ice. After the dropwise addition, stirring was further continued at room temperature for 1 hour to terminate the reaction. After termination of the reaction, the product was poured into water, washed with an aqueous sodium hydrogencarbonate solution, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.25 g (yield: 61%) of 1-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-3-phenylimidazolin-2-one as colorless crystals (melting point: 126-128° C.).
Reaction SMILES: Br.[NH2:2][C:3]1[N:7]2[C:8](SC)=[N:9][CH:10]=[C:11]([Cl:12])[C:6]2=[N:5][N:4]=1.[C:15](OCC)(=[O:18])C=C.C[O-].[Na+].C(O)(=O)C>CO>[NH2:2][C:3]1[N:7]=[C:6]2[N:5]([C:8]([O:18][CH3:15])=[N:9][CH:10]=[C:11]2[Cl:12])[N:4]=1
Reactant: CSc1ncc(Cl)c2nnc(N)n12
Reactant: C=CC(=O)OCC
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ncc(Cl)c2nc(N)nn12
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (51 mmol) of 3-amino-8-chloro-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine hydrobromide, 8.2 mL (76 mmol) of ethyl acrylate, and 150 mL of methanol was prepared and cooled in an ice bath. A solution of 17 mL (76 mmol) of 4.5 molar sodium methoxide in methanol was added to this slowly with cooling and stirring. When the addition was complete, the mixture was allowed to warm to ambient temperature and was stirred for 18 hours. It was then neutralized with 2.0 mL of acetic acid. The solids that formed were recovered by filtration, washed with diethyl ether, and dried to obtain 7.7 g (75 percent of theory) of the title compound as a tan powder melting above 250° C. 1H NMR (DMSO-d6): δ 8.0(s, 1H); 6.6 (brs, 2H); 4.1 (s, 3H); 13C: δ 166.40, 151.65, 147.73:, 140.95, 108.57, 56.12. Anal. Calc'd for C6H6N5ClO: C, 36.1; H, 3.03; N, 35.1. Found: C, 36.1; H, 3.19; N, 34.8.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH3:13])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>C1COCC1>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH3:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Add 1 N lithium hydroxide (19.5 mL, 19.5 mmol) to a solution of (S)-2-sec-butylamino-6-(methanesulfonyl-methylamino)-isonicotinic acid methyl ester (2.45 g, 7.77 mmol) in THF (10 mL) at 0° C. After 2 h at room temperature, acidify the mixture to about pH =2 and concentrate. Extract the residue with ethyl acetate (3×40 mL), wash the combined extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a yellow solid (2.23 g, 95%).