Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[CH:15]=[CH:16][C:6]3=[CH:5][C:4]=2[N:3]=1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[C@H:15]4[O:30][C@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)C=C3
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H]1O[C@@H]31
Yield: 94 %

Procedure:
To a solution of 7-chloro-2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (200 mg, 0.77 mmol) in ethyl acetate (3.0 mL), N-methyl imidazole (0.012 mL, 0.154 mmol) and ent-Ph,Ph salen manganese complex (8.0 mg, 0.0077 mmol) were added at room temperature and sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 40 minutes. In water bath, sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was further stirred in water bath for 30 minutes. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=10/1) to obtain (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (yield: 94%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:23]([O:43][CH3:44])[C:24]2[N:28](COCC[Si](C)(C)C)[C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(OC)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C.CC#N.C([O-])(O)=O.[Na+]>O>[CH2:1]([C:3]1[C:4]([CH:23]([O:43][CH3:44])[C:24]2[NH:28][C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2cc(C#N)ccc2[nH]1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
A mixture of (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (mixture, 650 mg, 1.03 mmol) and LiBF4 in CH3CN (1M, 10 mL, 10 mmol)/H2O (1 mL) was stirred at 75° C. for 14 h. The mixture was cooled to room temperature and poured into 5% NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was successively washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptanes/EtOAc=55/45) to give the title compound. MS (ESI+) m/z 499.2 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
344 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] were subjected to N-alkylation with 406 mg of ethyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride as eluent, which separated the compound into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). Isomer A (in which the carbon attached to the phenethyl group had the R-configuration) was eluted first as an oily compound in a yield of 0.17 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 67 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)-ethyl]-1-piperazinyl}aniline (Example 143, step C) (64 mg, 0.194 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (98 mg, 0.13 mmol, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.36 (s, 1H), 8.34 (d, J=13.00 Hz, 2H), 8.21 (d, J=4.94 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (s, 1H), 7.36-7.48 (m, 3H), 7.19 (t, J=7.97 Hz, 2H), 6.96 (s, 1H), 6.66 (s, 1H), 6.41-6.52 (m, 2H), 4.05 (q, J=6.59 Hz, 2H), 3.30-3.37 (m, 2H), 3.07-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.32 Hz, 2H), 2.54-2.61 (m, 4H), 1.22 (t, J=6.68 Hz, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[S:9][C:10](Cl)=[N:11][N:12]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:14]([SH:16])[CH3:15]>O1CCOCC1>[CH2:14]([S:16][C:10]1[S:9][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[N:12][N:11]=1)[CH3:15]
Reactant: CCS
Reactant: CCCCS(=O)(=O)c1nnc(Cl)s1
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)c1nnc(SCC)s1
Temperature: 0 °C

Procedure:
114.5 g 2-butylsulfonyl-5-chloro-1,3,4-thiadiazole and 36 ml ethylmercaptan are dissolved in 400 ml dioxane. Then under agitation 70 ml triethylamine are added to this drop by drop and the solution is heated to boiling under reflux for about one hour. After cooling the reaction mixture is introduced into ice water, the separating oil is extracted with dichloromethane, the methylenechloride phase is dried with magnesiumsulfate and the solvent is completely distilled off, finally in vacuo. 125.3 g of a colorless oil, that is 99 percent of theory, are obtained with an index of refraction of nD20 =1.5552.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH:50]1[C:59]([OH:61])=O>>[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH:50]1[C:59]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:61]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C2CCc3ccccc3C2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 1,2,3,4-tetrahydro-2-naphthoic acid, mp 137°-139° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38].O>CN(C)C=O>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([O:23][C:32]4[CH:33]=[CH:28][C:29]([N+:37]([O-:39])=[O:38])=[CH:30][C:31]=4[N+:34]([O-:36])=[O:35])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 270 mg, 6.75 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (2.0 g, 6.16 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 1-chloro-2,4-dinitrobenzene (1.37 g, 6.78 mmol) and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was poured into water (50 mL), and extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (1.5 g, yield 50%).
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:14][CH2:15]CC)([CH2:10][CH2:11]CC)[CH2:7][CH2:8][OH:9])[CH2:3]CC.COC1C=CC(O)=CC=1.[C:27]([Cl:32])(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(#N)C>[Cl-:32].[CH2:14]([P+:6]([CH2:2][CH3:3])([CH2:10][CH3:11])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH3:15]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CC)(CC)CC
Reaction time: 2 h

Procedure:
A distillation line was installed instead of the condenser and the obtained tri-n-butyl(2-hydroxyethyl)phosphonium chloride was dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 85.9 g (0.822 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:6])=[O:5])[CH3:3].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(=O)C1C=CC=CC=1>[CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:5])=[O:6])[CH3:3]
Reactant: CCOS(=O)(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOS(=O)(=O)C(C)(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 105.4 %

Procedure:
To a solution of ethyl 1-methyl-1-(4-methylphenyl)ethanesulfonate (0.458 g, 1.89 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (0.370 g, 2.08 mmol) and benzoyl chloride (0.009 g). The mixture was heated under reflux for 1.5 hours, cooled to rt, and filtered. The filtrate was washed with aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give crude ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 100%) which was used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44]([NH2:46])=[S:45])[CH:38]=1>>[ClH:36].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44]2[S:45][C:23]3[CH2:22][CH2:21][N:20]([C:18]([C:15]4[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=5[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:13][CH:14]=4)=[O:19])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]=3[N:46]=2)[CH:38]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: NC(=S)Cc1cccnc1
Agent: Cl
Product: O=C(Nc1ccc(C(=O)N2CCc3sc(Cc4cccnc4)nc3-c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 18.3 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide and 400 mg of 3-pyridylthioacetamide hydrochloride, the procedure of Example 5 was repeated to obtain 100 mg of 4'-[[2-(3-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrochloride as an amorphous solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][OH:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][OH:13])[C:9]=2[CH:14]=1
Reactant: COc1cc2c(cc1Br)C(CO)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(CO)CNCC2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 1 hour at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.006 g clear oil. 1H NMR (400 MHz, CD3OD) d 7.28 (s, 1 H), 6.79 (s, 1 H), 3.84 (m, 2 H), 3.0−2.8 (m, 7 H). MS calculated for C12H16BrNO2+H: 286, observed: 286.
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:12])=[O:11].[CH2:23]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29](=O)[CH2:30]2)[CH2:24][CH3:25].[OH-].[Na+]>CO>[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][CH:29]3[CH2:28][CH:27]4[N:26]([CH2:23][CH2:24][CH3:25])[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:11])=[O:12]
Reactant: CCCN1C2CCC1CC(=O)C2
Reactant: CS(=O)(=O)n1ncc2cc(N)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1C2CCC1CC(Nc1ccc3c(cnn3S(C)(=O)=O)c1)C2
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.9 %

Procedure:
Sodium cyanoborohydride (242 mg, 3.85 mmol) and then acetic acid (220 μl, 3.84 mmol) were added to a solution of 1-(methylsulfonyl)-1H-indazol-5-amine (163 mg, 0.772 mmol) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (150 mg, 0.924 mmol) in methanol (3 ml), and the resulting mixture was stirred at room temperature for 4 days. A 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified successively by a silica gel column chromatography (chloroform/methanol=4/1), a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=4/1) and partition by LC/MS (water containing 0.05% trifluoroacetic acid-acetonitrile containing 0.035% trifluoroacetic acid, 10%–100% gradient, the extraction of the organic layer with aqueous ammonia/ethyl acetate after the partition) to obtain 1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (8 mg, 3%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 105 %

Procedure:
The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 92 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C16H18FN3, 271.15; found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.47 (m, 2H), 7.31-7.27 (m, 2H), 3.55-3.51 (m, 1H), 3.41-3.39 (m, 2H), 3.23-3.14 (m, 2H), 3.00-2.83 (m, 2H), 0.93-0.084 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:13]([C:7]1([C:5]2[O:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH3:15])[CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCC1(c2cc(N)no2)CCCCC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC1(c2cc(NC(=O)c3c(OC)cccc3OC)no2)CCCCC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole and 14.4 g of 2,6-dimethoxybenzoyl chloride in 100 ml of toluene was heated to reflux and stirred for eighteen hours. The reaction mixture then was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid was dissolved in 200 ml of dichloromethane, washed with dilute sodium hyroxide and with brine, dried, and the solvent was removed by evaporation. The product was crystallized from dichloromethane and diethyl ether to provide 15.5 g of N-[5-(1-ethylcyclohexyl)-3-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 179°-181° C. Yield 60%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].[O-][CH2:26][CH3:27].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH2:26][CH3:27])[C:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:5]2[C:21]([F:23])([F:22])[F:24]
Reactant: CC[O-]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Agent: [Na+]
Product: CCOc1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2 except only one equivalent of sodium ethoxide was used.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[CH:12][N:13]=[CH:14][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:10]2[CH:9]=[CH:8]1.[H-].[Na+].[CH3:29]C1C=CC(S(OC)(=O)=O)=CC=1>C1COCC1>[CH3:29][N:17]([CH2:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:25])[CH3:26])[CH:8]=[CH:9][C:10]=12)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCc1cncc2c1ccn2COCC[Si](C)(C)C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methylcarbamate (300 mg, 0.796 mmol) in anhydrous THF (30 mL) at 0° C. was slowly added NaH (60% in mineral oil, 48 mg, 1.194 mmol) and stirred at 0° C. for 30 min. To the mixture was added methyl 4-methylbenzenesulfonate (178 mg, 0.955 mmol) followed by stirring at RT for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (2:1) to afford 232 mg (74.6%) of tert-butyl methyl((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)carbamate as a yellow solid. MS (ESI): m/z=392.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11].[Br:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.CO>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:26]=[C:25]2[NH:24][C:23](=[O:27])[C:22]3([CH:28]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:21]2=[CH:20][CH:19]=1
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Temperature: 135 °C

Procedure:
To a solution of 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 17a in toluene (20 mL) was added E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole prepared in example 157a (0.3 g, 0.83 mmol). The reaction mixture was stirred and heated under microwave irradiation in a sealed tube at 135° C. for 0.5 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield 0.22 g, 53%).