Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][C@H:18]([N:20]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:26])[CH3:19]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][C@H:18]([N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[CH3:26])[CH3:19])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: Cc1ccc(C)n1[C@H](C)CBr
Product: Cc1cc(CC[C@@H](C)n2c(C)ccc2C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 76, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (R)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole to give (R)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-(2,5-dimethylpyrrol-1-yl)-3-methylpropyl)pyridine.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C1COC(=O)N1[C:23](=[O:29])[CH:24]([CH3:28])[CH2:25][CH:26]=[CH2:27])C>O1CCCC1.CCCCCC.[Cl-].[NH4+].C(Cl)Cl>[C:2]1([CH2:1][O:8][C:23](=[O:29])[C@@H:24]([CH3:28])[CH2:25][CH:26]=[CH2:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CCC(C)C(=O)N1C(=O)OCC1C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CC[C@H](C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 5.1 g of benzyl alcohol in 50 ml of tetrahydrofuran is added, dropwise, 3.8 ml of 2.5M n-butyl lithium in hexane. To this mixture is added, via cannula, a solution of 3.5 g of S-(R*,R*)]4-(1-methylethyl)-3-(2-methyl-1-oxo-4-pentenyl)-2-oxazolidinone in 100 ml of tetrahydrofuran. The resulting solution is stirred at 0° C. for 2 hours. The reaction is diluted with saturated aqueous ammonium chloride and methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.9 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2](F)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[F:1]/[CH:2]=[CH:3]/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=C(F)F)CC2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/F)CC2)CC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To trans-1-(2,2-difluoro-1-ethenyl)-4-(trans-4-propylcyclohexyl)cyclohexane (44.0 g, 0.16 mol) were added toluene (250 ml) and a 70 wt. % toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (120 ml), followed by reacting the mixture under reflux on heating with stirring for 15 hours, cooling the reaction mixture, pouring it in ice water (300 ml), extracting the resulting product with toluene (300 ml), three times washing with 6N-hydrochloric acid (300 ml), washing with water till the aqueous layer became neutral, drying the toluene solution over anhydrous magnesium sulfate, filtering off the drying agent, distilling off toluene, dissolving the residue in heptane, purifying according to silica gel chromatography, repeating crystallization from hexane solvent and drying to obtain the objective substance (2.1 g, 0.008 mol). This compound exhibited a CS point of -13° C., an SN point of 43° C. and an NI point of 80° C.
Reaction SMILES: [OH:1]O.[ClH:3].[CH3:4][C:5]1([CH3:17])[N:10]([N+:11]2[N-:12][O:13][C:14](=[NH:16])[CH:15]=2)[CH2:9][CH2:8][S:7][CH2:6]1>>[ClH:3].[CH3:4][C:5]1([CH3:17])[N:10]([N+:11]2[N-:12][O:13][C:14](=[NH:16])[CH:15]=2)[CH2:9][CH2:8][S:7](=[O:1])[CH2:6]1
Reactant: CC1(C)CSCCN1[n+]1cc(=N)o[n-]1
Reactant: OO
Agent: Cl
Product: CC1(C)CS(=O)CCN1[n+]1cc(=N)o[n-]1

Procedure:
1.2 g of a 35% strength aqueous hydrogen peroxide solution are added to a solution of 3 g of 3-(3,3-dimethyl-perhydro-1,4-thiazin-4-yl)-sydnone imine hydrochloride (step g of Example 14) at room temperature with stirring, whereupon the temperature rises somewhat. The mixture is stirred for 2 hours and then concentrated in a water jet vacuum and the residue is recrystallized from ethyl acetate. Yield: 2.5 g; m.p.: 192° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C@@:8]1([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[F:25][CH2:26][CH2:27]C1C[C@H]2[C@@H](C=1)[C@](CC(OC(C)(C)C)=O)(C[N+]([O-])=O)C2>>[C:1]([O:5][C:6](=[O:24])[CH2:7][C@@:8]1([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:27][CH2:26][F:25])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@H]2CC=C[C@H]21
Reactant: CC(C)(C)OC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CC(CCF)=C[C@H]21
Product: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@H]2CC(CCF)=C[C@H]21

Procedure:
The compound of interest was obtained as an oil substance (700 mg, 65.8%) in the same way as in paragraph (3-a) using tert-butyl(±)-[(1R,5S,6S)-3-(2-fluoroethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (870 mg, 2.77 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[CH2:18]([Mg]Br)[CH3:19].C(I)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH3:19])#[N:2]
Reactant: CC[Mg]Br
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c[nH]c2ccc(-c3ccccc3C#N)cc12
Yield: 31.6 %

Procedure:
5-(2-cyanophenyl)indole (1.26 mmoles,630 mg) was dissolved in THF (20 ml) and treated with ethylmagnesium bromide (1.26 mmoles, 0.630 ml) and ethyl iodide (3.45 mmoles, 0.54 g) as in Example 24 to yield 98 mg of 5-(2-cyanophenyl)-3-ethylindole. (MS)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[NH2:39].C(=O)([O-])O.[Na+].[Cl:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)(Cl)Cl>[Cl:45][CH2:46][C:47]([NH:39][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:7]=[C:6]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)=[O:48]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
400 mg of 6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine synthesized in Production Example 182 was dissolved in 20 ml of chloroform, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 124 μl of chloroacetyl chloride were added thereto at 0° C., and then the resulting mixture was stirred at room temperature overnight. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated, to give 495 mg of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.02 g, 3 mmol) in DCM (30 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (541 mg, 3 mmol), EDC (633 mg, 3.3 mmol), and TEA (1.05 mL, 7.5 mmol). This mixture was stirred at room temperature for 18 h. The reaction mixture was washed with H2O (20 mL), dried over Na2SO4, filtered, concentrated and purified with CombiFlash to afford 0.7052 g (50%) of the title compound. LC-MS m/z 466 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:16][CH:15]=1
Reactant: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 13.8 %

Procedure:
N-((5-Chloro-1H-indol-3-yl)methyl)-4-(3-fluorobenzyl)benzamide was prepared following method B starting from N-((5-Chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide (0.080 g, 0.240 mmol), 3-fluorophenylboronic acid (0.036 g; 0.252 mmol); Tetrakis(triphenylphosphine)palladium(0) (0.014 g; 0.012 mmol), sodium carbonate (0.051 g; 0.480 mmol) and sodium iodide (0.109 g; 0.720 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.013 g (14%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[Li]CCCC.[C:16](=[O:18])=[O:17].Cl>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:16]([OH:18])=[O:17])=[CH:9][N:10]=1
Reactant: O=C=O
Reactant: c1csc(C2OCCO2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C2OCCO2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)thiazole (65 g, 0.41 mol) in THF (900 mL) under nitrogen was slowly added n-BuLi (180 mL, 2.5 M in hexanes) at −78° C. The mixture was stirred at −78° C. for 2 h, and then solid dry ice was added. The solution was then warmed to rt and stirred overnight. Hydrochloric acid (2 N) was added to the solution until pH<4. The mixture was then extracted with ether (5×300 mL). Combined organic phases were washed with water (200 mL), brine (200 mL), dried (Na2SO4), and concentrated to give a yellow solid. This solid was then rinsed with petroleum ether to give 2-(1,3-dioxolan-2-yl)thiazole-5-carboxylic acid (72.5 g, 87%). 1H NMR (dmso-d6, 400 MHz) δ 13.70 (s, 1H), 8.36 (s, 1H), 6.10 (s, 1H), 4.06 (m, 4H).
Reaction SMILES: [Li+].[OH-].[CH:3]1([CH2:6][N:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([O:15]C)=[O:14])[C:8]2=[O:17])[CH2:5][CH2:4]1.Cl>C1COCC1.CO>[CH:3]1([CH2:6][N:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=[O:14])[C:8]2=[O:17])[CH2:5][CH2:4]1
Reactant: COC(=O)c1nccn(CC2CC2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nccn(CC2CC2)c1=O
Reaction time: 2 h

Procedure:
LiOH (0.84 mL, 0.84 mmol, 1.0 M) was added to a solution of methyl 4-(cyclopropylmethyl)-3-oxo-3,4-dihydropyrazine-2-carboxylate (87 mg, 0.42 mmol) in a mixture of THF-MeOH (3:1 ratio, 2 mL) at room temperature. After stirring for 2 hours, the reaction mixture was acidified to pH 1 with aq. 1N HCl solution (0.14 mL) and then concentrated to afford the desired product salt. 1H NMR (400 MHz, CD3OD) δ 7.67 (d, 1H), 7.37 (m, 1H), 3.86 (d, 2H), 1.32 (m, 1H), 0.61 (m, 2H), 0.45 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26](O)[C:25]=2[CH:31]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCCl.O>[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:34])([CH3:35])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26]([C:7]3[C:2]([CH3:1])=[C:3]([CH3:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=3[CH3:8])[C:25]=2[CH:31]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: Cc1cc(C)c(C)c(C)c1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: Cc1c(C)c(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c(C)c1C
Yield: 89.3 %

Procedure:
11.5 g (77.5 mmol) of pentamethylbenzene and 10 ml (85.0 mmol) of tin tetrachloride are added to a solution of 19.7 g (75.0 mmol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example la) in 50 ml of 1,2-dichloroethane and the reaction mixture is refluxed for 1 hour. The reaction mixture is diluted with water and extracted three times with toluene. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 26.3 g (89%) of 5,7-di-tert-butyl-3-(2,3,4,5,6-pentamethylphenyl)-3H-benzofuran-2-one, m.p. 185-190° C. (compound (111), Table 1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1CCl>C1COCC1>[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[N:2]([CH3:3])[CH3:1]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C)C)c(C)c1
Temperature: 25 °C

Procedure:
To a mixture of THF (20 mL) and dimethylamine (20 mL, 40% wt in water) at 0° C. was added 2,4,6-trimethylbenzyl chloride (5 g, 29.64 mmol). The mixture was allowed to warm up to room temperature and stirred for 4 h before THF was evaporated and the aqueous residue was extracted with ether. The organic layer was worked up and concentrated as usual to give 2,4,6-trimethylphenyl-dimethylamine in quantitative yleld. This compound was then nitrated and the resulted nitro compound reduced to the corresponding aniline as demonstrated in Example 14.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-])=O>[Ni].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C(=O)c2ccccc2)cc1N

Procedure:
To a solution of 14 g. (44.7 mmoles) of ethyl 2-nitro-4-benzoylphenylacetate in 225 ml. of ethanol was added 15 g. of wet Raney nickel and the mixture heated to reflux for 1.5 hours. The mixture was filtered and the filtrate concentrated to give a residual oil which was induced to crystallize by trituration with diethyl ether, 7.9 g., m.p. 150°-152° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:21]1[C:25](B(O)O)=[CH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCCCC1>[S:21]1[C:25]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)=[CH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc(CCNc2cc(-c3cc4ccccc4s3)nc(OC)n2)cc1
Yield: 42.5 %

Procedure:
By proceeding in a similar manner as above in Example 10(a) but using (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (150 mg), benzo[b]thiophene-2-boronic acid (182 mg), Cs2CO3 (590 mg) and tetrakis(triphenylphosphine)palladium (0) (58 mg), and subjecting the crude reaction product to flash column chromatography on silica gel eluting with a mixtures of 20 to 100% EtOAc and cyclohexane, there is prepared (6-benzo[b]thiophen-2-yl-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [85 mg, 42% yield, Example 10(g)]. LCMS: RT=10.39 minutes, MS: 392 (M+H). IC50=5.1 nM
Reaction SMILES: Cl.[C:2]([CH:4]([C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH3:22])[CH2:17][CH2:16]1)[CH2:5][CH2:6][CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])#N.[O:23]1CCCOC1>O>[CH3:22][O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH:4]2[CH2:5][CH2:6][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:14][C:2]2=[O:23])[CH2:16][CH2:17]1
Reactant: C1COCOC1
Reactant: CCCCCCC(O)CCC(C#N)[C@H]1CC[C@H](OC)CC1
Agent: Cl
Solvent: O
Product: CCCCCCC1CCC([C@H]2CC[C@H](OC)CC2)C(=O)O1
Temperature: 25 °C

Procedure:
20 mL of concentrated hydrochloric acid was added to a solution of 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanol (49) (5.1 g, 17.4 mmol) obtained in the third step dissolved in 200 mL of 1,3-dioxane, and refluxed under heating for 20 hours. The reaction mixture was cooled to room temperature and then put in 100 mL of water, and then extracted with 100 mL of ethyl acetate. The resulting organic layer was washed with water (100 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=20/1, column packing: silica gel) and then recrystallized from heptane to obtain 3-(trans-4-methoxycyclohexyl)-6-hexyl-tetrahydro-2-pyranone (Compound No. 25) (2.1 g, 6.9 mmol). The resulting compound was in the form of a colorless liquid, and the yield based on the compound (49) was 40%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:32][Mg]Br>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]([OH:31])[CH3:32])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-4-carbaldehyde (210 mg) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (3M diethyl ether solution, 0.5 mL) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (165 mg, yield 76%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 455 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(N(CC)C(C)C)(C)C.ClCCl>O.C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(Cc2cccc(F)c2)c1
Yield: 49.8 %

Procedure:
A mixture of methyl 3-(bromomethyl)benzoate (0.500 g; 2.18 mmol), 3-fluorophenylboronic acid (0.334 g; 2.40 mmol), N,N-diisopropylethylamine (0.752 mL; 4.37 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.178 g; 0.218 mmol) in water (1 mL) and dimethoxyethane (3 mL) was irradiated in a microwave oven at 130° C. for 15 minutes. The resulting mixture was partitioned between water and ethyl acetate and the phases were separated. The organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to yield 0.265 g (50%) of methyl 3-(3-fluorobenzyl)benzoate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:28]2([CH3:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:11][C@@H:10]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:9]1.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:28]2([CH3:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][O:22][S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:11][C@@H:10]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](OC6CCCCO6)C[C@H](OC6CCCCO6)[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 72.6 %

Procedure:
To a stirred solution of 3.7 g of (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methylpregn-5-en-21-ol in 5 ml of pyridine at 0° was added a solution of 1.77 g of p-toluenesulfonyl chloride in 3 ml of pyridine dropwise over 10 min. After 165 min. at 0°, the mixture was poured into ice water and extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was dissolved in 100 ml of toluene, concentrated in a 50° bath at 11 mm and applied to 80 g of silica gel containing 1% pyridine. Elution with hexane--ether, 7:3, afforded 3.49 g (73%) of (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methyl-21-(p-toluenesulfonyloxy)pregn-5-ene as a white amorphous solid.