Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[C:41]([O:69][CH3:70])=CC3[C:49](=[O:50])[N:48]4[CH:51]=[C:52]([C:54]#[C:55][CH2:56][NH:57][CH3:58])[CH2:53][C@H:47]4[C:46](=O)[N:45](COCC[Si](C)(C)C)[C:44]=3[CH:68]=2)=[CH:33][C:6]2[N:7](COCC[Si](C)(C)C)[C:8](=O)[C@@H:9]3[CH2:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1>C1COCC1>[CH3:70][O:69][CH2:41]/[C:40](/[O:39][CH2:38][CH2:37][CH2:36][O:35][C:34]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11](=[O:12])[N:10]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:15][C@H:9]3[CH:8]=[N:7][C:6]=2[CH:33]=1)=[CH:68]\[CH2:44]/[N:45]=[CH:46]\[C@@H:47]1[CH2:53][C:52]([C:54]#[C:55][CH2:56][NH:57][CH3:58])=[CH:51][N:48]1[CH:49]=[O:50]
Reactant: CNCC#CC1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(c6ccc(OC)cc6)C[C@H]4C(=O)N5COCC[Si](C)(C)C)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Solvent: C1CCOC1
Product: CNCC#CC1=CN(C=O)[C@H](/C=N\C/C=C(\COC)OCCCOc2cc3c(cc2OC)C(=O)N2C=C(c4ccc(OC)cc4)C[C@H]2C=N3)C1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Compound 2 (0.041 g, 0.04 mmol) was dissolved in anhydrous THF (3.8 mL) under an argon atmosphere and cooled to −78° C. in an acetone-dry ice bath. LiEt3BH (0.25 mL of a 1M solution in THF, 0.35 mmol, 6 eq) was added to the mixture, and the reaction was stirred at −78° C. for 40 minutes. The reaction was quenched with H2O (3 mL) and after addition of brine (3 mL) the aqueous phase was extracted (DCM, 9 mL-methanol 1 mL), dried (MgSO4) and the solvent was removed by rotary evaporation under reduced pressure. The crude was dissolved in a mixture of ethanol (3 mL), DCM (1.5 mL) and H2O (1.5 mL) and silica gel was added to the mixture. The reaction was stirred for four days at room temperature under an atmosphere of Argon. The mixture was filtered over a sinter funnel washing with a mixture of DMC (140 mL) and methanol (15 mL). The organic phase was washed with brine (200 mL), dried (MgSO4) and the solvent was removed by rotary evaporation under reduced pressure. The resulting brown solid was purified by flash column chromatography (silica gel, gradient 90% DCM-10% methanol). Compound 3 was obtained as a brown solid (0.029 g, 59%); Rf 0.11 [8% methanol in DCM]; LC-MS (5 min) 2.47 min, ES+ 702.28.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[I:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Ic1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 54 %

Procedure:
20.3 g (0.12 mol) of diphenylamine, 60.9 g (0.15 mol) of 4,4'-diiodobiphenyl, 19.3 g (0.14 mol) of anhydrous potassium carbonate, 1.52 g (0.024 mol) of copper powder, and 20 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 21 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 1/3 mixture of toluene and n-hexane) to obtain 29.0 g (yield: 54.1%) of N-(4'-iodo-4-biphenylyl)-N,N-diphenylamine. The melting point of the product was from 139.5° C. to 140.5° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](N)=[O:11])[C:4]=2[NH:3]C=1.NCC(C1C([N+]([O-])=O)=CC=CC=1C(O)=O)=[O:16]>>[NH2:3][C:4]1[C:5]([NH2:1])=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]([OH:11])=[O:16]
Reactant: NC(=O)c1cccc2nc[nH]c12
Reactant: NCC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Nc1cccc(C(=O)O)c1N

Procedure:
The method of preparing for benzimidazole-4-amide derivatives of the present invention is as follows: using 2-aminoacetyl-3-nitrobenzoic acid as an initiating raw material, 2-aminoacetyl-3-nitrobenzoic acid in turn is undergoing ammonolysis, Hoffman degradation and reduction, to produce 2,3-diamino benzoic acid; and then condensing 2,3-diamino benzoic acid and aldehydes X—CHO in the presence of catalyst of cupric acetate, to produce benzimidazole-4-carboxylic acid; and then reacting benzimidazole-4-carboxylic acid with thionyl chloride to produce acyl chloride, and then condensing the acyl chloride and an amine NH2—Y, to produce the benzimidazole-4-carboxamide derivative.
Reaction SMILES: [OH:1][C@@H:2]([CH2:33]O)[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=3)=[CH:18][C:17]2=[O:31])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.[CH3:35]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1>ClCCl>[OH:1][C:2]([CH3:33])([CH3:35])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=3)=[CH:18][C:17]2=[O:31])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1
Agent: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 162, 300 mg, 0.90 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (154 mg, 0.99 mmol) and 1-hydroxybenzotriazole (128 mg, 0.95 mmol). The reaction mixture was stirred at 25° C. for 1 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 168 mg, 1.08 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (20% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(3-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (217 mg, 51%) as a yellow powder: HR-ES-MS m/z calculated for C25H34N4O5 [M+H]+ 470, observed 471; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.31 (t, J=6.8 Hz, 3H), 1.38-1.64 (m, 2H), 1.67-1.84 (m, 1H), 3.89 (s, 2H), 4.04 (q, J=6.8 Hz, 2H), 4.16 (d, J=18.1 Hz, 1H), 4.56 (d, J=18.1 Hz, 4.68 (s, 1H), 4.86 (s, 1H), 4.87-4.93 (m, 1H), 6.44 (d, J=1.8 Hz, 1H), 6.78-6.92 (m, 3H), 7.35 (t, J=8.3 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1>>[BrH:12].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][C:13]([Br:12])=[CH:14][CH:15]=3)=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: O=C(CBr)c1ccc(Br)cc1
Product: Br
Product: Cc1nc2n(CC(=O)c3ccc(Br)cc3)cccc-2c1C

Procedure:
This compound was prepared by reacting 2,3-dimethylpyrrolo [2,3-b]pyridine with p-bromophenacyl bromide following the procedure in example 8.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+:23]>C(O)C>[N+:1]([C@@H:4]1[CH2:5][CH2:6][C:7](=[O:9])[NH:23][C@H:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2ccccc2)N1
Yield: 84.7 %

Procedure:
Methyl 4-nitrobutyrate (1) (240 g, 1.63 mol), benzaldehyde (189 g, 1.78 mol), ammonium acetate (164 g, 2.12 mol) and ethanol (1680 ml) were placed in a 3-liter 3-necked flask equipped with a mechanical stirrer, under an atmosphere of nitrogen. The mixture was heated under reflux for four hours to yield an orange solution which crystallised on cooling. The crystalline product was isolated by filtration, washed with ethanol, ether and then dried under vacuum to afford trans-3nitro-6-oxo-2-phenylpiperidine 304 g (85%): m.p. 174°-175° C.; 1H NMR (360 MHz, CDCl3) δ2.28-2.38 (1H, m; CHH), 2.51-2.71 (3H, m, CH2 +CHH), 4.69-4.74 (1H, m, CHNO2), 5.25 (1H, d, J=6.0 Hz, PhCHN), 6.0 (1H, brs, NH), 7.31-7.35 (2H, m, ArH), 7.38-7.45 (3H, m, ArH); 13C NMR (CDCl3 /DMSO), 22.92 (CH2), 27.62 (CH2), 58.58 (PhCHN), 85.01 (CNO2), 126.47 (Ar), 129.02 (Ar), 129.17 (Ar), 137.85 (Ar), 169.55 (C=O); Calculated for C11H12N2O3 ; C, 59.99; H, 5.49; N, 12.72. Found: C, 60.07; H, 5.60; N, 12.76%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][O:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: CI
Reactant: Oc1ccc2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
3 g (18.05 mmol) of the alcohol obtained in Step A are dissolved in 10 ml of DMF in a flask. 2 eq. of NaH (60% in oil) are added slowly and allowed to act for 30 minutes under an inert atmosphere. 2 eq. of iodomethane are then added. The mixture is stirred for 2 hours; the DMF is then evaporated. Washing with ethyl acetate and with water is carried out and the two phases are separated. The combined organic phases are dried over MgSO4 and the solvent is evaporated. The oil obtained is purified on a silica column (eluant: PE/AcOEt 8/2), which allows the pure title product to be obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.[OH-].[Na+]>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([OH:30])=[O:2])[C:12]([CH3:29])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)c(Cl)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(COc2nc(C)n(-c3cc(C(=O)O)ccc3C)c(=O)c2Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[5-chloro-4-(3-methoxy-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (260 mg, 0.6 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for three hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to a yellow oil (230 mg, 92%). MS (M+H): 415
Reaction SMILES: O1C2C=CC=CC=2C(C2C=CC(OCC(O)=O)=C(C)C=2[Cl:22])=N1.C([O:27][C:28](=[O:48])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[O:39][N:38]=2)=[C:33]([CH3:46])[C:32]=1C)CCC.C(NC1C=CC2ON=C(C3C=CC(OCC(O)=O)=C(Cl)C=3Cl)C=2C=1)(=O)C.ClC1C=CC2ON=C(C3C=CC(OCC(O)=O)=C(Cl)C=3Cl)C=2C=1>>[O:39]1[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:28]([OH:27])=[O:48])=[C:32]([Cl:22])[C:33]=2[CH3:46])=[N:38]1
Reactant: Cc1c(OCC(=O)O)ccc(-c2noc3ccccc23)c1Cl
Reactant: CCCCOC(=O)COc1ccc(-c2noc3ccccc23)c(C)c1C
Agent: CC(=O)Nc1ccc2onc(-c3ccc(OCC(=O)O)c(Cl)c3Cl)c2c1
Agent: O=C(O)COc1ccc(-c2noc3ccc(Cl)cc23)c(Cl)c1Cl
Product: Cc1c(-c2noc3ccccc23)ccc(OCC(=O)O)c1Cl

Procedure:
4-(1,2-benzisoxazol-3-yl)-3-chloro-2-methylphenoxyacetic acid; butyl-4-(1,2-benzisoxazol-3-yl)-2,3-dimethylphenoxyacetate; pentyl (4-(1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetate; 4-(6-bromo-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-ethyl-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-nitro-1,2-benzisoxzaol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(6-amino-1,2-benzosoxazol-3-yl)-2,3-dichlorophenoxyacetic acid); 4-(5-acetamido-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid; 4-(5-chloro-1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid;
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[NH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:16][C:2]([F:1])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:19][CH:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 95 %

Procedure:
A reaction similar to that described in Example 70 (70a) was conducted using 4-(4,4,4-trifluorobutoxy)benzoic acid (6.21 g) prepared in Example 81 (81a) and 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (7.20 g) prepared in Reference Example 2 to give 11.4 g of the title compound (white powder).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].C(O[C:20](=O)[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]O)[CH2:24][CH2:23]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][CH2:29][CH2:28][N:25]3[CH2:24][CH2:23][CH:22]([NH:21][CH2:20][C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)[CH2:27][CH2:26]3)[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1cc2cc(O)cnc2cc1F
Product: COc1cc2cc(OCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)cnc2cc1F

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Examples 2 and 9 using 7-fluoro-6-methoxy-quinolin-3-ol, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting materials.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (120 mg, 0.26 mmol), 3-methyltetrahydro-4H-pyran-4-one (75 mg, 0.66 mmol), triethylamine (0.15 mL, 1.0 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (0.17 g, 0.79 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate to EtOAc/Et3N=10:0.1) to yield the desired product (100 mg, 79%). LCMS calculated for C25H38F3N4O2: (M+1) 483.2; found 483.2.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][NH2:9])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C>C1COCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]([S:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][NH:9][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: NCC(Sc1ccccc1)c1ccc(Br)o1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: O=C(NCC(Sc1ccccc1)c1ccc(Br)o1)c1ccccn1

Procedure:
2-(5-Bromofuran-2-yl)-2-phenylsulfanylethylamine (0.28 g, 0.0009389 mol), 2-pyridinecarboxylic acid (0.12 g, 0.001005 mol) and EDCI were stirred in dry THF (10 ml). After disappearing of the starting material the solvent was evaporated. Then chloroform was added and the solution was washed with 1 M Na2CO3 and water, dried with Na2SO4 and evaporated. The crude product was purified by flash chromatography using heptane-EtOAc as a gradient eluent (85:15-70:30). 1H NMR (400 MHz, DMSO-d6): 3.75-3.80 (2H, m), 4.78-4.84 (1H, m), 6.33-6.37 (2H, m), 6.44 (1H, d), 7.26-7.40 (4H, m), 7.59-7.62 (1H, m), 7.97-8.04 (2H, m), 8.62-8.64 (1H, m), 9.08 (1H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>C1COCC1.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Reaction time: 4 h
Yield: 27.9 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was added potassium carbonate (295 mg, 2.13 mmol) and 2-chloro-N,N-dimethyl-acetamide (82 mg, 0.67 mmol). The reaction was stirred for 4 hours before being diluted with DCM and the mixture washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-5% MeOH in DCM). The resultant material was triturated with diethyl ether then petroleum ether to give 278 as a white solid (85 mg, 0.17 mmol, 29%). LCMS: RT=2.72 min, [M+H]+=464. 1H NMR δ (ppm) (DMSO-d): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.64 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.35, 1.78 Hz), 6.86 (1 H, d, J=1.73 Hz), 5.89-5.79 (1 H, m), 4.48-4.41 (4 H, m), 3.10 (2 H, s), 3.00 (3 H, s), 2.89 (2 H, d, J=10.79 Hz), 2.77 (3 H, s), 2.11 (2 H, dd, J=12.35, 10.20 Hz), 1.71 (2 H, d, J=12.52 Hz), 1.61 (2 H, td, J=12.15, 3.73 Hz), 1.44 (6 H, d, J=6.60 Hz). 1H obscured by solvent.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[K+].Cl>C1COCC1>[CH:11]1([S:17][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: SC1CCCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: c1nc(SC2CCCCC2)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a solution of 100 mg (0.651 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine dissolved in 3.0 mL of THF was added 0.10 mL (0.818 mmol) of cyclohexylmercaptan and 100 mg (0.847 mmol) of 95% potassium tert-butoxide and the resulting mixture heated at reflux for 3.5 hr. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2 N HCl and concentrated in vacuo. The residue was then partitioned between ethylacetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The cude product was purified by silica-gel chromatography (1:3 ethylacetate/hexanes) providing 34 mg (22%) of the title compound as a white solid. Mp 162-163° C. 1H NMR (400 MHz) d: 1.22-1.36 (m, 1H), 1.45-1.64 (m, 5H), 1.75-1.79 (m, 2H), 2.12-2.14 (m, 2H), 4.18-4.20 (m, 1H), 6.50 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.5 Hz), 8.61 (s, 1H), 10.0 (br s, 1H). LRMS: 234 (M+1).
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-:26].[K+].[K+]>C(#N)C>[OH2:26].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]([N:23]2[CH:22]=[N:21][N:20]=[CH:24]2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)=[CH:14][CH:15]=1.[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[N:23]2[CH:22]=[N:21][N:20]=[CH:24]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(C(Cl)c2ccc3ncccc3c2)cc1
Reactant: c1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(C(c2ccc3ncccc3c2)n2cnnc2)cc1
Product: O
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A mixture of 5.34 parts of 6-[chloro(4-chlorophenyl)methyl]quinoline, 6.4 parts of 1H-1,2,4-triazole, 1.26 parts of potassium carbonate and 79 parts of acetonitrile was stirred for 8 hours at reflux temperature. After evaporation to dry, the residue was taken up in water and was further purified according to similar procedures as described in example 12, yielding 3 parts (49.2%) of 6-[(4-chlorophenyl)(4-H-1,2,4-triazol-4-yl)methyl]quinoline hemihydrate; mp. 87.8° C. (compound 35).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][CH:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>CS(C)=O.O>[O:16]=[C:3]1[C:2]([NH:20][CH:18]([CH3:19])[CH3:17])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(NC(C)C)nc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, 2.1 mmol) in DMSO (2 mL) was added propan-2-amine (186 mg, 3.15 mmol) and DIEA (540 mg, 3.15 mmol). After stirring for overnight at 50° C., the reaction mixture was dissolved in water (20 mL), then filtered to afford methyl 2-oxo-3-[(propan-2-yl)amino]-1,2-dihydroquinoxaline-6-carboxylate as a white solid (430 mg, 78%).