Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=O)[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([C:27]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([CH3:30])=[CH:32][CH:33]=3)=[O:29])[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(CN)cc1
Reactant: COc1cc(Nc2ncc(C)c(N3CCCC(C(=O)O)C3)n2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2ncc(C)c(N3CCC[C@H](C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8.2 (380 mg, 0.866 mmol), TEA (0.362 mL, 2.60 mmol) and 4-methylbenzylamine (0.331 mL, 2.60 mmol) in DCM (21.7 mL) was added HATU (494 mg, 1.299 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was then concentrated and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5 to 10% MeOH in DCM to give 8 as a stereomeric mixture. This mixture was brought up in a mixture of MeOH and DCM and purified by supercritical fluid chromatography using an ODH (21×250 mm, 5 um) column. The stereoisomer was then resolved with a mixture of 35% MeOH with 0.2% diethylamine going to 40% MeOH with 0.2% diethylamine at 4 minutes with a flow rate of 65 mL per minute to provide 8. 1H NMR (300 MHz, CDCl3) δ ppm 1.61 (br. s., 1H) 1.66-1.81 (m, 1H) 1.81-2.00 (m, 2H) 2.07 (s, 3H) 2.30 (s, 3H) 2.37-2.72 (m, 1H) 2.76-3.12 (m, 1H) 3.16-3.55 (m, 1H) 3.55-3.88 (m, 10H) 3.99 (d, J=11.98 Hz, 1H) 4.13-4.50 (m, 2H) 6.51 (br. s., 1H) 6.84 (s, 2H) 6.95-7.26 (m, 4H) 7.34 (br. s., 1H) 7.85 (s, 1H); M+H 506.27637.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:28])=[CH:20][CH:21]=2)[CH2:36][CH2:35]1)[CH3:30]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(C(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3C)cc2)CC1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-(piperidin-4-yl)-acetic acid ethyl ester using BOP reagent in tetrahydrofuran to give the title compound as a light brown foam, MS (ESI+): m/z=529.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:15]([NH2:24])=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:25](OCC)(OCC)OCC>C(O)=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=4[N:24]=[CH:25]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CNc3ccc(C(F)(F)F)cc3N)cc2s1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Temperature: 100 °C
Yield: 69 %

Procedure:
A stirred mixture of N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamine (0.32 g, 0.86 mmol) from the previous step, formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.22 g, 69%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 8.08 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.48-7.54 (m, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.26 (m, 1H), 5.49 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH2:17]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH2:16][S:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CCCCCCCCCCCSCCSCCCCCCCCCCCC(=O)O
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCSCCSCCCCCCCCCCCCO
Temperature: 30 °C
Reaction time: 4 h

Procedure:
Ethylenedithio-bislauryl alcohol was prepared as the final intermediate as ethylenedithio-bislauric acid methyl ester (8 g) was dissolved in dry THF at 0° C. (ice bath). Lithium aluminum hydride (1.16 g) was added to the flask slowly. Hydrogen was generated, and the reaction temperature was gradually raised to 30° C. After stirring for 4 hours, the reaction was quenched by pouring the solution thus formed into ice water. The aqueous solution was neutralized by adding concentrated HCl, and the crude product was then extracted with ethyl acetate three times. After evaporating the solvents, the compound (7.0 gm) was dried under vacuum and analyzed by NMR. NMR data agrees with the expected structure of the final product as set forth in the reaction summary below.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([OH:11])=O)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([Cl:15])=[O:11])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCC[C@H]1C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a solution of (S)-1-isopropylpyrrolidine-2-carboxylic acid (4 g, 23.4 mmol) in dry dichloromethane (40 mL) was added oxalyl chloride (4.4 mL, 46.8 mmol) drop wise under nitrogen at ice bath temperature (0-10° C.). After stirring for 5 min, a drop of dry DMF was added to the reaction mixture and was allowed to stir for 2 h at the same temperature. The volatiles were removed on a rotavapor at reduced pressure and the residue was allowed to stay at high vacuum pump for 1 h to afford (S)-1-isopropylpyrrolidine-2-carbonyl chloride.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:16]([O:18][C:19]([CH2:21][N:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][C:24](=O)[C:23]1=[O:34])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([CH2:21][N:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][CH:24]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:23]1=[O:34])=[O:20])[CH3:17]
Reactant: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Reactant: CCOC(=O)C(N)CCc1ccccc1
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CCc2ccccc21

Procedure:
Ethyl 2-amino-4-phenylbutyrate is treated under conditions of reductive alkylation as described in the previous examples with 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine-2,3-dione to give 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one of example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:37][C:36]([F:41])([F:40])[F:35])[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: O=C(O)C(F)(F)F
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N(CC(F)(F)F)C1CCN(c2ccncc2)CC1

Procedure:
Similarly to Method B in Example 43 and using 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) and trifluoroacetic acid (5 ml) instead of acetic acid, the title compound (37 mg) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])/[CH:18]=[CH:17]/[CH2:16][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNCCc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of phenethylamine (20 mL, 160 mmol) in anhydrous THF (250 mL) was added NaHCO3 (7 g) followed by methyl 4-bromocrotonate (10 mL, 84 mmol). After stirring for 4 h the reaction was concentrated to approximately half the volume and filtered through a pad of silica gel and eluted with 2% MeOH/CHCl3 to wash off the product. The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3) to give the title compound as a slightly yellow liquid (16.5 g, 81%). TLC Rf 0.53 (5% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.2 (1H, s), 2.8 (4H, br s), 3.35 (2H, dd), 3.7 (3H, s), 5.95 (1H, dt), 7.0 (1H, dt), 7.25 (5H, br s)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.[OH-].[K+].Br[CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C=O)C>[CH2:20]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (0.5 g, 2.2 mmol) in DMF (4 ml) was added 10% aqueous potassium hydroxide (1.23 ml), followed by dropwise addition of 1-bromobutane (0.24 ml, 2.2 mmol). The mixture was stirred at room temperature for 12 h, then water (12 ml) was added. The product was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded the residue which was purified by flash chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to give the title compound (0.41 g, 59%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:22]=1[CH3:37].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:22]=3[CH3:37])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (63.5 mg, 0.24 mmol; described herein), 4-chloro-3-methyl-2-(pyridin-2-yl)quinoline (61.2 mg, 0.24 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (280 μL, 2.9 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, d, J=4.7 Hz), 8.19 (1H, d, J=8.2 Hz), 7.85-7.95 (2H, m), 7.81 (1H, dd, J=8.2, 0.8 Hz), 7.71 (1H, td, J=7.6, 1.2 Hz), 7.59 (1H, d, J=2.7 Hz), 7.47-7.55 (1H, m), 7.34-7.45 (1H, m), 6.78 (1H, s), 6.24 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.73 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.13-3.36 (4H, m), 2.87-3.01 (4H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=483.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC1CCC(C)C1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g.) in methylene chloride (100 ml) was added dicyclohexylcarbodiimide (1.09 g.), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromatography on silica gel, 4:1 hexane:ethyl acetate, eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:57])([F:56])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[F:57][C:31]([F:30])([F:56])[C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH:45][C:13](=[O:15])[C:12]([N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:17][CH3:18])=[CH2:16])[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:53])[F:54])=[CH:48][CH:47]=3)[N:39]=2)=[CH:36][CH:37]=1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 29A (1.1 equiv., 400 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 140 mg of a white solid. Yield=21% 1HNMR (DMSO, 400 MHz) δ 1.25 (3H, t), 3.40 (2H, q), 4.60 (2H, d), 5.18 (1H, s), 6.18 (1H, s), 7.70 (2H, d), 7.82 (2H, d), 7.86 (4H, d), 8.02 (2H, s), 8.40 (4H, d), 8.89 (1H, bt) [M+1] 668.9 (C31H24ClF6N3O3S requires 668.05).
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22]C)=O)[CH:16]=[CH:17][CH:18]=1.[C:26]1([CH2:32][C:33]#[N:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:33]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=1)#[N:34]
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: N#CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1

Procedure:
To a flame-dried flask was added 8.1 g. of sodium methoxide, 125 ml. of toluene and 21 ml. of methanol. The mixture was brought to reflux at 85°-87°, and to it was added dropwise a mixture of 22.8 g. of methyl (3-trifluoromethylphenyl)acetate and 12.9 g. of phenylacetonitrile. The apparatus was then set up for distillation, and the mixture was heated to 110°, removing about 46 ml. of distillate. The mixture was then cooled to about 12°, and to it was added 50 ml. of ice-water. The aqueous layer was removed and washed with 20 ml. of cold toluene. The organics were combined and washed with cold water. The aqueous layers were combined, and the pH was adjusted to 3.5 with cold hydrochloric acid. The oily product was collected by extracting the aqueous portion with three 40 ml. portions of dichloromethane, drying the organic layer over sodium sulfate and evaporating it under vacuum to obtain 30.5 g. of oil, which was 89% pure product by vapor phase chromatography.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (432 mg, 65%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Mg]Br)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ncccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ncccc3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 100 mg (0.248 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide in THF 2 ml, was added 1.09 ml (0.545 mmol) 3,4-dimethoxyphenylmagnesium bromide. The reaction mixture was stirred at room temperature for 30 min, then quenched with saturated solution of NH4Cl, extracted with ethyl acetate and purified with flash chromatography to give the desired product 22 mg. LCMS observed for (M+H)+: 480.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:41](N)(N)(=[O:43])=[O:42]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[NH:38][S:41](=[O:43])(=[O:42])[N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (8.0 mg, 0.014 mmol) and sulfamide (2.0 mg, 0.021 mmol) in pyridine (300 μL) was heated to 120° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature and diluted with 25 mL of EtOAc. The organic solution was washed with 1 N HCl (2×5 mL) and brine (1×5 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC with 25% EtOAc/hexanes afforded 4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine 1,1-dioxide. Rf=0.29 (25% EtOAc/hexanes). LCMS=641.1 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 7.58-7.85 (m, 5H), 7.35-6.86 (m, 4H), 4.82-4.94 (m, 2H), 3.54-4.42 (m, 6H), 2.71-2.91 (m, 2H), 1.11-1.26 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[OH-].[Na+]>ClCCl>[F:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[CH2:5][CH2:6][CH:2]([OH:1])[C:3]2=[O:4])=[CH:11][CH:10]=1
Reactant: O=C1OCCC1O
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1C(O)CCN1c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 3-hydroxydihydrofuran-2(3H)-one (5.00 g, 49.0 mmol) and 4-fluoroaniline (6.53 g, 59.0 mmol) was stirred at 150° C. for 1 day. After completion of the reaction, dichloromethane and 10 M sodium hydroxide aqueous solution were added to the reaction solution and the resultant mixture was filtered. To the filtrate, dichloromethane and concentrated hydrochloric acid were added to adjust pH to 1. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (6.78 g, yield 71%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:22]([CH:23]=[O:24])=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:22]/[CH:23]=[O:24])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1ccc2cccnc2c1
Product: O=C/C=C/c1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 184 (M+H)+.