Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:20]2[NH:21][C:22](=O)[C:23]([OH:31])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:20]2[NH:21][CH2:22][C:23]([O:31][S:34]([CH3:33])(=[O:36])=[O:35])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C2(NC(=O)OCc3ccccc3)CCC(CO)CC2)[nH]c(=O)c1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(COS(C)(=O)=O)CC2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 815.4 %

Procedure:
To a stirred solution of ethyl 2-(1-(benzyloxycarbonylamino)-4-(hydroxymethyl)cyclohexyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.85 g, 4.15 mmol) in THF (40 mL) cooled to 0° C. was added methanesulfonyl chloride (0.96 mmol, 12.45 mmol) and triethylamine (1.79 mL, 12.87 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h. The resulting precipitate was filtered off and washed with THF. The filtrate and washings were concentrated to afford an amber oil. A solution of this oil in methanol (10 mL) was treated with K2CO3 (574 mg, 4.15 mmol) at room temperature for 3 h. The mixture was then concentrated and the residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (100 mL) followed by brine (100 mL), then dried (Na2SO4), filtered and concentrated to give 2.3 g of title compound as a yellow oil. LCMS (M+H)=602.45.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[NH2:14].[OH-].[NH4+]>O.Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]([F:10])[CH:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Sc2ccncc2)c(F)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Sc3ccncc3)c(F)c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
2-Amino-4,6 dichloropyrimidine (A21, 12 mmol) and 3-fluoro-4-(4-pyridinylthio)-aniline (B7,12 mmol) were suspended in water (150 mL) and treated with 10 drops of concentrated hydrochloric acid. The mixture was stirred at 100° C. overnight. The clear solution was then neutralized with ammonium hydroxide. The precipitated yellow product was filtered, washed with water, and purified by column chromatography with 1-3% MeOH in CH2Cl2 to give the desired product as a white solid (1.98 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1

Procedure:
A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone (280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The mixture was stirred for 1/2hour, and then diluted with water. The precipitated product was filtered, washed with water and dried. Yield = 20.5 g (83%), m.p. 188°-190°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and benzoyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH2:18]([N:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:6]=1[C:4]([OH:5])=[O:3])[CH3:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(C)Cc1ccccc1
Reactant: BrCc1cccc2ccccc12
Product: CN(Cc1ccccc1)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-[(benzyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester (Lit. 4) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 433.4 ([M−H]−).
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.C[OH:21].C(Cl)Cl>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:21])=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: CO
Reactant: [O-][n+]1nc(NCCCO)nc2cc3c(cc21)CCC3
Solvent: ClCCl
Product: [O-][n+]1nc(NCCCO)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
TFM (0.44 mL, 2.4 mmol) was added to a stirred solution of 1-oxide 50 (486 mg, 2.2 mmol) in DCM (20 mL) at 0° C. and the solution stirred at 20° C. for 16 h. H2O2 (70%, 1.1 mL, ca. 21.9 mmol) was added dropwise to a stirred solution of TFAA (3.1 mL, 21.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to the solution of 1-oxide 50 prepared above and the resulting solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 4 h, then the mixture extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 50 (254 mg, 52%); and (ii) 1,4-dioxide 51 (166 mg, 27%) as a red solid: mp (MeOH/DCM) 182-184° C.; 1H NMR δ 8.05 (s, 1H, H-9), 8.03 (s, 1H, H-5), 7.61 (br t, J=5.7 Hz, 1H, NH), 3.82 (br t, J=5.7 Hz, 2H, CH2O), 3.78 (br s, 1H, OH), 3.71-3.77 (m, 2H, CH2N), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.04 (br t, J=7.5 Hz, 2H, H-8), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.97 (br p, J=6.0 Hz, 2H, CH2); 13C NMR δ 156.1, 149.5, 145.8, 137.8, 129.7, 115.7, 111.3, 60.2, 39.1, 33.4, 32.3, 31.5, 25.5. Anal. calcd for C13H16N4O3: C, 56.5; H, 5.8; N, 20.3. Found: C, 56.8; H, 5.9; N, 20.2%.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH:19]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[BH4-].[Na+]>CC(N(C)C)=O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[CH:19]=1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium cyanoborohydride (166 mg; 2.64 mmol; 4.0 eq.) was added to a solution of 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and pyrrolidine (1.64 mL; 19.8 mmol; 30 eq.) in DMA (4 mL) and the reaction mixture was stirred at RT. After 12 h, as no product was detected, sodium borohydride was added (100 mg; 2.64 mmol; 4.0 eq.) and the reaction mixture was stirred at RT for 1 hour. Reaction was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.245 (brs, 1H), 9.26 (s, 1H), 8.14-8.13 (m, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.67 (s, 2H), 2.49-2.45 (m, 7H), 1.74-1.70 (m, 4H). HPLC (Condition A): Rt 2.63 min (purity 99.5%). MS (ESI+): 359.2, MS (ESI−): 357.3.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]#[N:19])=[CH:9][CH:8]=1>CS(C)=O.O>[OH:3][N:2]=[C:18]([NH2:19])[CH2:17][C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([Br:6])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: N#CCc1cccc2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(Cc1cccc2ccc(Br)cc12)=NO
Temperature: 60 °C
Yield: 80.8 %

Procedure:
Hydroxylamine hydrochloride (1.14 g, 16.5 mmol) was dissolved in aqueous sodium hydroxide (1N, 16.5 mL, 16.5 mmol) and the solution diluted with DMSO (50 mL). 7-Bromo-2-naphthalenylacetonitrile (1.35 g, 5.5 mmol) was added in one portion and the resulting mixture heated to 60° C. After a total of 18 hours, the mixture was cooled to room temperature and diluted with water (100 mL) to give a precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give a tan solid (1.24 g, 81%) which was of sufficient purity for use in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29].C(N(C(C)C)C(C)C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(piperidin-4-yl)cinnoline-3-carboxamide (Example 51, 0.1 g, 0.24 mmol) in CH2Cl2 (2.5 ml) and DMF (2.5 ml) was added N-ethyldiisopropylamine (0.127 ml, 0.73 mmol) and methanesulphonyl chloride (0.021 ml, 0.27 mmol). The reaction mixture was stirred at for 1 hour, diluted with CH2Cl2 and washed with water. The organic layer was concentrated under reduced pressure and the residue purified by reverse phase chromatography using 0.1% formic acid in water and methanol (50-70%) to give 28 mg (24%) off-white solid. 1H NMR: 11.56 (s, 1H), 8.78 (s, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 7.11 (m, 2H), 4.01 (s, 3H), 3.51 (m, 2H), 2.91 (m, 1H), 2.84 (s, 3H), 2.74 (m, 2H), 2.35 (s, 3H), 1.63 (m, 2H), 0.97 (m, 2H); m/z 488.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[NH3:14].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:14][CH2:12]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N NH3 in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCCc1ccccc1
Yield: 52.4 %

Procedure:
By the method of part A of Example 1 N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) was condensed with 3-phenylpropylamine (2.7 g.) and the product was purified by high pressure liquid chromatography on silica gel using hexaneethyl acetate (7:3) as the eluant, affording 1-(tert-butyloxycarbonyl)-N-(3-phenylpropyl)-L-prolinamide (3.48 g.).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[CH3:33])[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:5]3[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:13][C:14]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:25][CH2:24]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 24.4 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (130 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:19])=[CH:16][CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)c1cccnc1
Reaction time: 0.42 h
Yield: 39.5 %

Procedure:
3-Bromopyridine (0.4 ml, 4.0 mmol) was dissolved in 15 ml of tetrahydrofuran in an argon atmosphere. n-Butyllithium (1.58 M n-hexane solution, 2.4 ml, 3.8 mmol) was added to the solution at −78° C., and the mixture was stirred for 25 min. Subsequently, a solution of 502 mg (2.7 mmol) of 4-bromobenzaldehyde in tetrahydrofuran (2 ml) was added dropwise thereto at −78° C., and the mixture was stirred at −78° C. for one hr, was stirred under ice cooling for one hr, and was then stirred at room temperature for one hr. The reaction solution was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 282 mg (yield 40%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]P(=O)(OCC)OCC)=[O:5])[CH3:2].[H-].[Na+].O1CCCC1.O=[C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:6]=[C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)=[O:5])[CH3:2]
Reactant: O=C1CCCc2sccc21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1CCCc2sccc21
Reaction time: 0.5 h

Procedure:
Diethyl ethoxycarbonylmethylphosphonate (8.47 ml) was dropwise added to a mixture of sodium hydride (60%, 1.71 g) and tetrahydrofuran (THF) (50 ml) at room temperature (r.t.) under nitrogen atmosphere, and the mixture was stirred under the same condition for 30 minutes. To the reaction mixture was added 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene (5.00 g) in a portion, and the whole mixture was stirred at r.t. for 3 hours. The reaction mixture was poured into a mixture of water and ethyl acetate (AcOEt). The separated organic layer was washed with water and brine, and dried over magnesium sulfate (MgSO4), and dried in vacuo to precipitate. The resulting precipitate was washed with isopropyl ether (iPE) to give 4-ethoxycarbonylmethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (5.91 g).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4].[CH3:28][NH2:29]>C(O)CCC>[CH3:28][NH:29][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Solvent: CCCCO
Product: CNC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
A solution of 4 g of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized from ethyl-ether to yield the 1-[7-(N-methylcarbamoyl)heptyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:14])=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1)#[N:2]
Reactant: COc1ccc(N)cc1
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CCCC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(C3(C#N)CCCC3)cc2)cc1

Procedure:
5.8 g. (27 mMol) 4-(1-cyanocyclopentyl)-benzoic acid are reacted with thionyl chloride and subsequently with 4-methoxyaniline as described in Example 1 to give 5.1 g. of the title compound; m.p. 163°-168° C.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]1([NH:15][CH:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.ClCCl.CO>ClCCl>[CH:12]1([N:15]([CH:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:14][CH2:13]1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CCC(NC1CC1)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(c1ccncc1)N(C(=O)c1c(C)nn(C)c1F)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
At ambient temperature a solution of 0.16 g (0.93 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 2 ml of dichloromethane was added dropwise to a solution of 0.15 g (0.85 mmol) of N-cyclopropyl-1-pyridin-4-yl-propylamine and 0.14 ml of triethylamine in 5 ml of dichloromethane. The reaction mixture was stirred for 12 hrs at ambient temperature and then at 40° C. for 8 hrs and washed with water. The organic layers were filtrated over basic alumina and dried. Column chromatography (gradient dichloromethane/Methanol) yielded 0.18 mg (44% yield) of N-cyclopropyl-N-[1-pyridin-4-yl-propyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide (M+H=317).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:47][CH:48]=3)=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 74.1 %

Procedure:
Prepared according to Preparation 22 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 175 mg, 0.379 mmol) and 3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-ol (Preparation 8, 120 mg, 0.379 mmol) to afford the title compound as a solid (213 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}acetamide (77.6 mg, 0.134 mmol) in THF (4.4 mL) was added BH3 (1.34 mL of a 1M solution in THF, 1.34 mmol). The reaction was stirred overnight at room temperature and then 1 N HCl (10 mL) was added. The mixture was stirred for 5 minutes and then adjusted to a slightly basic pH with 1 N NaOH. The mixture was then extracted with CH2Cl2 (4×20 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25 to 40% EtOAc/hexanes gave {2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine. Rf=0.17 (25% EtOAc/hexanes). LCMS=564.3 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.75 (s, 1H), 7.73 (s, 1H), 7.64 (s, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.24 (dd, J=8.2, 2.0 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 3.58-3.73 (m, 5H), 2.88 (m, 1H), 2.74-2.81 (m, 4H), 1.22 (d, J=6.9 Hz, 6H).