Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28].[BH3-]C#N.[Na+]>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[CH:14][CH:13]=2)[CH:16]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)NC(=O)CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(C)(=O)=O)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(methylsulfonyl)propanamide (239 mg, 1.19 mmol, 1.5 equiv) were dissolved in anhydrous EtOH. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by prep-TLC to give 3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamide as a white solid (65 mg, 14%), (mobile phase:CH3OH/DCM=1:10). ESI-MS (M+1)+: 461.2, HPLC: 96.38%. 1H NMR (400 MHz, DMSO-d6) δ: 7.93 (s, 1H), 7.85˜7.77 (m, 2H), 7.59˜7.49 (m, 1H), 7.43˜7.35 (m, 1H), 7.20˜7.11 (m, 1H), 4.45˜4.33 (m, 1H), 4.20 (s, 2H), 2.98 (t, 2H), 2.77 (s, 3H), 2.35 (t, 2H), 2.26˜2.14 (m, 2H), 1.86˜1.75 (m, 2H), 1.41˜1.30 (m, 2H), 1.27˜1.14 (m, 2H), 1.13˜1.02 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:2][C:3]1([CH3:10])[CH2:9][O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: CC(C)(CO)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CC1(C)CCC(=O)OC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.1 %

Procedure:
To a solution of 5-hydroxy-4,4-dimethyl-pentanoic acid (300 mg, 2.05 mmol) in DMF (5 ml), K2CO3 (369 mg, 2.87 mmol) and iodomethane (154 ul, 2.47 mmol) are added at room temperature. The mixture is stirred at room temperature for 15 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, and brine, and dried over MgSO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 47%); TLC (hexane/AcOEt, 2:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.97 (s, 2H).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-])=O>CO.Cl.[Pd]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([C@@H:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)=[O:19])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)[C@H]1CN2CCC1CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 739 mg (2.10 mmol) of (3R)-N-(4′-nitrobiphenyl-4-yl)quinuclidine-3-carboxamide (Example 6A) in 10 ml of methanol and 5 ml of 2 N hydrochloric acid is hydrogenated under atmospheric pressure in the presence of 448 mg (0.21 mmol) of 5% palladium on carbon for 2 h. Filtration through kieselgur is followed by washing with methanol and concentration of the filtrate and drying under high vacuum. 755 mg (89.2% of theory) of the title compound are obtained.
Reaction SMILES: C(OC([N:8]([C:23]1[CH:35]=[CH:34][C:26]([C:27](N2C=CN=C2)=[O:28])=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O)(C)(C)C.[OH-].[Na+].[NH2:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42]>C(Cl)(Cl)Cl>[CH:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:23]2[CH:35]=[CH:34][C:26]([C:27]([NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCC1CCCCC1)c1ccc(C(=O)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(t-butyloxycarbonyl)-N-(8-cyclohexyloctyl)amino]benzoyl}imidazole, 50 ml. of chloroform and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[C:18]([CH2:22][C:23]#N)[CH:19]=[CH:20][CH:21]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH2:32].[OH-:33].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[C:18]([CH2:22][C:23]([OH:33])=[O:32])[CH:19]=[CH:20][CH:21]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: N#CCc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Reactant: [OH-]
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl}acetonitrile (0.35 g; 0.914 mmol), concentrated sulfuric acid (2 ml) and water (2 ml) was stirred at 80° C. for 2 hours. After air cooling, 5N-aqueous sodium hydroxide was added thereto to be alkaline. Ethyl acetate was added thereto and back-extracted. The water layer became neutral with 2N-aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give 3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl acetic acid as colorless amorphous solid (0.08 g; 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl.C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)ccc1O
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2cc(F)ccc2o1

Procedure:
A solution of 2-amino-4-fluorophenol (4.0 g), carbonyldiimidazole (1.7 g) in DCM (100 ml) and acetonitrile (30 ml) was stirred at RT for 5 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 30% ethylacetate/isohexane, yield 4.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:26][C:27]1([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[CH:17]=[C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=[CH:14][C:13]=2[C:12]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[NH-].[CH3:39][O:40][C:41]1[CH:52]=[CH:51][C:44]([CH2:45][C@@H:46]([C:48](O)=[O:49])[NH2:47])=[CH:43][CH:42]=1.O.O[N:55]1[C:59]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH:8]([NH:26][C:27]1([C:33](=[O:35])[NH:47][CH:46]([C:48](=[O:49])[NH:55][CH3:59])[CH2:45][C:44]2[CH:51]=[CH:52][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH2:9][CH2:10][N:11]1[C:12](=[O:25])[C:13]2[CH:14]=[C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]3=[CH:17][C:18]=2[C:19]1=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2cc3ccccc3cc2C1=O)NC1(C(=O)O)CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: C[NH-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(NC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[1-tert-butoxycarbonyl-3-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)propylamino]cyclohexanecarboxylic acid (298 mg,0.62 mmol) in methylene chloride (10 mL) were added successively L-tyrosine methyl ether N-methylamide hydrochloride (180 mg, 0.74 mmol), 1-hydroxybenztriazole hydrate (95 mg, 0.62 mmol), triethylamine (0.12 mL, 0.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg, 0.74 mmol). The resulting mixture was stirred for 3 days at room temperature. After dilution with methylene chloride, the mixture was washed successively with saturated aqueous sodium bicarbonate, water, 0.5M aqueous hydrochloric acid and brine. The solution was dried over magnesium sulfate. The solvent was removed by evaporation under vacuum leaving an oil which was chromatographed on silica gel eluting with 45% hexane in ethyl acetate to afford 4-(1,3-dioxo-1,3dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)-ethylcarbamoyl]cyclohexylamino}butyric acid tert-butyl ester, diastereomer A (91 mg, 22%) and diastereomer B (85 mg, 20%), in addition to a mixture of diastereomers A and B (169 mg, 41%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)(=O)C>[NH2:12][C:11]1[N:7]2[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=[C:8]2[N:10]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)nn2c1N

Procedure:
A solution of 3-tert-butyl-1H-pyrazol-5-amine (484 mg, 3.48 mmol, 1 eq.) and ethyl 2-cyano-3-ethoxyacrylate (590 mg, 3.49 mmol, 1.00 eq.) in acetic acid (10 mL) was stirred for 16 h at 100° C. under nitrogen. After cooling, the resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried and concentrated under reduced pressure. The residue was applied onto a silica gel column with CH2Cl2/MeOH (30:1) as an eluent to obtain the corresponding product as a white solid: LCMS (m/e) 263 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.40-8.38 (broad, d, J=6.0 Hz, 2H), 6.48 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.37-1.31 (m, 12H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>ClC(Cl)Cl>[ClH:24].[C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10]3[CH:15]=[CH:16][C:17]([C:19]([Cl:24])=[O:21])=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCn1c(-c2ccccc2)nc2cc(C(=O)O)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(-c2ccccc2)nc2cc(C(=O)Cl)ccc21
Product: Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(a-2) To a stirred solution of 112.13 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylic acid in 525 parts of trichloromethane were added 142 parts of thionyl chloride. Stirring was continued for 30 minutes at reflux temperature. The reaction mixture was evaporated, yielding 134 parts (100%) of 2-phenyl-1-propyl-1H-benzimidazole-5-carbonyl chloride monohydrochloride as a residue (int. 58).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cn(-c2cccc3ncccc23)cc1C(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2cccc3ncccc23)cc1C(=O)Cl
Product: Cl
Reaction time: 1.5 h
Yield: 100 %

Procedure:
8 mL (110 mmol) of sulphinyl chloride are added to 0.47 g (1.86 mmol) of 3-carboxy-4-methyl-1-(quinolin-5-yl)-1H-pyrrole dissolved in 25 mL of chloroform at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 1.5 hours at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 25 mL of chloroform and then concentrated to dryness again, giving 0.58 g (1.86 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole hydrochloride in the form of a beige-colored solid, which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:8])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 5-aminoindole in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ 11.04(1H, s),9.96(1H, s),8.52(1H, d, J=5.6 Hz), 8.15(1H, d, J=5.3 Hz), 7.97 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=5.6 Hz), 7.36 (2H, s), 7.33 (1H, t, J=2.8 Hz), 7.27 (1H, dd, J=8.6, 2.3 Hz), 6.64 (1H, d, J=5.3 Hz), 6.41 (1H, t, J=2.5 Hz), 2.69 (3H, s).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C(N(CC)CC)C>C1COCC1>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][C:15](=[O:16])[NH:14][N:13]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccn3c(I)cnc3c2)o1
Reaction time: 3 h
Yield: 115.2 %

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (196 mg, 0.5 mmol) (prepared as described in Example 329 steps a-c) in THF (10 ml) was added carbonyldiimidazole (243 mg, 1.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) and the reaction mixture left to stir for 3 h. The precipitate formed in the reaction was filtered off, washed with Et2O and dried to afford the desired product (189 mg). MS: [M+H]+=329.
Reaction SMILES: N1C2C(=CC=CC=2)C=N1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:20][CH:19]=3)[CH:15]=[N:16]2)=[CH:32][CH:31]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:16]2[CH:15]=[C:14]3[C:18]([CH:19]=[CH:20][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:13]3)=[N:17]2)=[CH:32][CH:31]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: FC(F)(F)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2[nH]ncc2c1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(cnn2Cc2ccc(Cl)cc2)c1
Product: FC(F)(F)c1ccc2nn(Cc3ccc(Cl)cc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.7 %
Yield: 15 %

Procedure:
Indazole compounds can be synthesized according to methods disclosed in the literature, e.g., Lukin et al. J. Org. Chem. 2006, 71, 8166-8172 and Souers et al. J. Med. Chem. 2005, 48, 1318-1321. A mixture of 5-(trifluoromethyl)-1H-indazole 3a (0.46 g, 2.5 mmol), K2CO3 (1.04 g, 7.5 mmol) in DMF (8 mL) was stirred at room temperature for 30 min. To the mixture was added p-chlorobenzyl bromide (0.77 g, 3.75 mmol). The resulting mixture was heated at 60° C. for 6 h. After cooling, the mixture was poured into water (30 mL). The precipitate was filtered and washed with water and dried. The crude product was purified by chromatography (hexane/dichloromethane, 1:1 to 1:3) to give 1-(4-chlorobenzyl)-5-(trifluoromethyl)-1H-indazole 3b (120 mg, 15%) and 2-(4-chlorobenzyl)-5-(trifluoromethyl)-2H-indazole 3c (60 mg, 7.7%).
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)[NH:3]1.C([Li])CCC.CCCCCC.[CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)/[C:30](=[N:34]/[OH:35])/[CH2:29][CH2:28][CH2:27]2)=[CH2:23].CCN(C(C)C)C(C)C.[Si](Cl)(C)(C)C.[Li]N1C(C)(C)CCCC1(C)C.N1C=CC=CC=1C1[C:71]([C:72]([F:75])([F:74])[F:73])=[C:70]([C:76](OCC)=[O:77])[O:69][N:68]=1>C1COCC1>[N:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:71]([C:72]([F:75])([F:74])[F:73])=[C:70]([C:76]2([OH:77])[O:35][N:34]=[C:30]3[C:31]4[C:26]([CH2:27][CH2:28][CH:29]23)=[CH:25][C:24]([CH:22]=[CH2:23])=[CH:33][CH:32]=4)[O:69][N:68]=1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (Preparation 63D, 0.354 mL, 2.096 mmol) in anhydrous THF (1 mL) in a flame-dried flask at 0° C. was added a 2.5 M solution of butyl lithium in hexane (0.839 mL, 2.10 mmol) dropwise. The resulting dark yellowish reaction mixture was stirred for 30 min. at 0° C. To a solution of (E)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate I-1, 0.131 g, 0.699 mmol) and Hunig's Base (0.220 mL, 1.258 mmol) in anhydrous THF (2.0 mL) at 0° C. was added TMS-Cl (0.089 mL, 0.699 mmol) dropwise. The resulting off-white suspension was stirred for 60 min. at 0° C. The reaction mixture was cooled to −78° C., the above LiTMP solution was added dropwise, and the mixture was stirred for 30 min. at −78° C. To the reaction mixture was added ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.69 M in THF) (1.01 mL, 0.699 mmol), and the resulting orange mixture was then stirred at −78° C. for 30 min. The dry-ice bath was removed, and the reaction mixture was slowly warmed to 0° C. over 25 min. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (˜4.0 mL), and the mixture was diluted with dichloromethane (40 mL), washed with a 1:1 mixture of saturated aqueous solution of ammonium chloride and water, dried over anhydrous sodium sulfate, and concentrated to give a dark red residue, which was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (0.080 g, 0.187 mmol, 26.8% yield) as a yellow oil. The product had an HPLC ret. time=2.76 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=427.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:34][CH:33]=4)=[O:37])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reaction time: 2 h

Procedure:
At room temp. under nitrogen, to a solution of 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol) and diisopropyl(ethyl)amine (209 mg, 1.62 mmol) in acetonitrile (5 mL) is added 4-trifluoromethylphenyl isocyanate (197 mg, 0.97 mmol). The reaction mixture is stirred at room temp. for 2 h, concentrated, and the residue is purified by flash chromatography with CH2Cl2-MeOH to afford the title product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[S:6]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH3:1][N:2]([CH2:11][C:8]1[CH:9]=[CH:10][S:6][CH:7]=1)[CH2:3][CH2:4][OH:5]
Reactant: O=Cc1ccsc1
Reactant: CNCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCO)Cc1ccsc1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
2-(Methylamino)-ethanol (0.047 mol, 3.5 g) and 3-thiophenecarboxaldehyde (0.047 mol, 5.3 g) were dissolved in 50 mL of MeOH and 10 mL of AcOH. NaCNBH3 (0.023 mol, 1.5 g) was added portionwise, and the resulting mixture was stirred for 18 h. The solvent was removed in vacuo, and the residue was taken up in 1N KOH and extracted with EtOAc. The organics were dried and concentrated to give an oil which was filtered through a six inch silica gel plug using 1:1 hexanes:ethyl acetate to give 7.6 g of product. 1H NMR (300 MHz) CDCl3: 7.3 (m, 1H), 7.12 (s, 1H), 7.05 (d, 1H), 3.6 (m, 4H), 2.57 (t, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:12]=2)=[C:8]([CH3:24])[CH:7]=[C:6]([OH:25])[C:3]=1[CH2:4]O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]2[C:8]([CH3:24])=[CH:7][C:6]([OH:25])=[C:3]([CH3:4])[C:2]=2[CH3:1])=[CH:12][C:13]=1[CH:21]([CH3:23])[CH3:22]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(CO)c2C)cc1C(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cc2c(C)cc(O)c(C)c2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzyl alcohol ((0.20 g, 0.58 mmol) and Pd—C (0.08 g, 10%) in ethyl acetate-acetic acid (3.5 mL, 95:5) was stirred at room temperature under a H2 atmosphere for 6 h. The reaction mixture was filtered through a Celite plug and the solvent was removed under reduced pressure to afford 4-(4′-methoxymethoxy-3′-iso-propylbenzyl)-2,3,5-trimethylphenol (0.19 g, 100%) as colorless oil: 1H NMR (300 MHz, CD3OD): δ 6.94 (m, 1H), 6.91 (d, J=13.2 Hz, 1 H), 6.68 (dd, J=13.2, 2.4 Hz, 1 H), 6.55 (s, 1 H), 5.17 (s, 2 H), 3.95 (s, 2 H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.17 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=acetone-hexanes (3:7); Rf=0.60.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:21][C@H:22]1[C@@H:26]([N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH2:25][NH:24][CH2:23]1>N1C=CC=CC=1>[NH2:21][C@H:22]1[C@@H:26]([N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH2:25][N:24]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:23]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: N[C@@H]1CNC[C@@H]1n1ccnn1
Solvent: c1ccncc1
Product: N[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@@H]1n1ccnn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (44 mg, 0.156 mmol) and cis-3-amino-4-(1,2,3-triazol-1-yl)pyrrolidine (60 mg, 0.39 mmol) in pyridine (5 ml) was heated at 110° C. for 2-3 h under nitrogen and then stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was washed with water and acetonitrile. The solid was dried under vacuum at 40° C. Yield: 43 mg (66%), m.p. 245°-47° C. 1H NMR (TFA) δ: 1.3-1.8 (m, 4H), 4.4-5.25 (m, 6H), 6.40 (m, 1H), 8.15 (d, 1H), 8.62 (s, 1H), 8.90 (s, 1H), 9.40 (s, 1H).