Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br: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]N(C)C.IC.C[Si]([C:21]#[N:22])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1.C1COCC1.O>[Br: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][C:21]#[N:22]
Reactant: CN(C)Cc1c[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To an ice cooled suspension of (5-bromo-1H-indol-3-ylmethyl)-dimethyl-amine (11.2 g, 44.1 mmol) in benzene (145 mL) was added iodomethane (8.2 mL, 130 mmol). The reaction mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in THF (210 mL). Trimethylsilyl cyanide (11.7 mL, 87.7 mmol) and tetrabutylammonium fluoride (140 mL, 140 mmol of a 1.0 M solution in THF) were added. After stirring for 2.5 hours, at room temperature, water (12 mL) was added. The mixture was partially concentrated. The residue was partitioned in ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash chromatography using 15-35% ethyl acetate in hexane as an eluant afforded (5-bromo-1H-indol-3-yl)-acetonitrile (5.30 g, 51%) as a mauve solid, mp 105-106° C. 1HNMR (300 MHz, DMSO-d6): δ 11.35 (s, 1H), 7.8 (d, 1H, J=2.2 Hz), 7.35-7.45 (m, 2H), 7.2-7.3 (m, 1H), and 4.0 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15].S(=O)(=O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:13]=[CH:14][N:15]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1cc2ccncc2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A reaction mixture of 3-bromo-4-fluorobenzaldehyde (1.70 g, 8.37 mmol) and aminoacetaldehyde dimethyl acetal (0.917 mL, 8.37 mmol) in toluene (17.0 mL) was stirred at r.t. overnight. Then sulfuric acid (10 mL) and phosphorus pentoxide (2.38 g, 8.37 mmol) were added. The mixture was stirred at 160° C. for 1 h. After cooled, the mixture was poured into crushed ice. The acidic mixture was carefully adjusted to pH=8 by the addition of aqueous NaOH solution (1 N) with stirring and external cooling. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with 40% ethyl acetate in hexanes to afford the desired product (0.35 g, 18.5%). LCMS (M+H)+: m/z=225.9/227.9.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][CH:60]([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (183 mg, 0.433 mmol), 1,1′-(azodicarbonyl)dipiperdine (219 mg, 0.868 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.217 mL, 0.869 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.272 mL, 4.30 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 14 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102 mg, 0.21 mmol, 48%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16](=[NH:18])[NH:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(=[O:25])[C:23]#[CH:24].C(O)C>C(O)(C)(C)C>[CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16]4=[N:18][C:22](=[O:25])[CH:23]=[CH:24][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(COc2ccc(C3CCCCC3)cc2)CNC(=N)O1
Reactant: C#CC(=O)OCC
Solvent: CCO
Solvent: CC(C)(C)O
Product: CC1(COc2ccc(C3CCCCC3)cc2)Cn2ccc(=O)nc2O1
Temperature: 80 °C

Procedure:
A suspension of 5-(4-cyclohexyl-phenoxymethyl)-5-methyl-oxazolidin-2-ylideneamine (1.11 g, 3.85 mmol) in 15 ml of t-butanol was heated to 80° C. All of the suspension dissolved. Ethyl propiolate (0.51 ml, 5.0 mmol) was added followed by 5 ml of ethanol. The reaction mixture was heated at reflux for 8 hrs. An off-white precipitate gradually came out of the solution. The reaction was cooled to room temperature and the solid isolated by filtration and washed with ether to provide the title compound as a white solid. Yield 0.75 g.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].[C:33]1(=[O:51])[N:37]([C:38]2[CH:43]=[C:42]([CH2:44]Cl)[CH:41]=[CH:40][N:39]=2)[C:36](=[O:46])[C:35]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:34]12>CN(C=O)C>[O:51]=[C:33]1[C:34]2[C:35](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:36](=[O:46])[N:37]1[C:38]1[CH:43]=[C:42]([CH2:44][N:6]2[C:5]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=3)=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH:41]=[CH:40][N:39]=1
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(CCl)ccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=CC#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccnc(N3C(=O)c4ccccc4C3=O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a mixture of 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (323 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol), and 2-phthalimido-4-chloromethylpyridine, was added anhydrous DMF (5 ml) and the mixture was stirred for overnight at room temperature. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (1:1)) to afford 152 mg (27%) of a white solid. 1H-NMR (200 MHz, DMSO-d6) δ 1.01 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6.8 Hz), 2.12 (1H, m), 2.33 (3H, s), 4.76 (2H, s), 6.57 (1H, d, J=16.6 Hz), 7.25 (1H, d, J=5.2 Hz), 7.31 (1H, s), 7.61 (1H, d, J=16.6 Hz), 7.80 (1H, s), 7.88-8.02 (6H, m), 8.41 (1H, d, J=5.2 Hz), 11.72 (1H, s).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:37])([F:38])[F:39])(=[O:29])=[O:28])([CH3:25])[CH3:26])[N:21]=[C:20]([C:40]2[CH:41]=[CH:42][C:43]([NH:44][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:45][CH:46]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2C(F)(F)F)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl chloroformate (0.542 mL, 4.32 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[2-(trifluoromethyl)phenyl]sulfonylpropan-2-yl]pyrimidin-2-yl]aniline line (1.5 g, 2.88 mmol) and sodium hydrogen carbonate (0.363 g, 4.32 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours then diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.38 g).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH:5]=1.C(N(CC)C(C)C)(C)C.Cl[C:27]1[N:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:28]=1>CN1CCCC1=O.O1CCOCC1.O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C:29]2[N:28]=[C:27]([NH:16][CH:13]3[CH2:14][CH2:15][N:10]([C:6]4[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=4)[CH2:11][CH2:12]3)[N:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=2)=[CH:39][CH:40]=1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)ncn1
Temperature: 160 °C

Procedure:
To a solution of 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride (53 mg, 0.2 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in N-methyl-pyrrolidinone (0.5 mL) was added a solution of 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (65.4 mg, 0.22 mmol)) in dioxane (1.5 mL). The reaction was heated at 160° C. in a microwave oven for 5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from AcOEt to AcOEt/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a white solid (27 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16](OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:8]2[CH2:9][CH:10]3[N:15]([CH3:16])[CH:13]([CH2:12][CH2:11]3)[CH2:14]2)[CH:7]=1
Reactant: COc1ccc(N)cc1C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N)cc1C1CC2CCC(C1)N2C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
3-(5-Amino-2-methoxyphenyl)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane (D4, 0.385 g, 1.16 mmol) was dissolved in dry THF (30 ml) with stirring and was treated with lithium aluminium hydride (0.088 g, 2.32 mmol) under argon. The reaction mixture was then heated to reflux. After 2 h and 4 h, further amounts of lithium aluminium hydride (0.132 g, 3.48 mmol) were added. Reflux was then maintained for a further 4 h, before the reaction mixture was allowed to cool. Water (0.352 ml) was then added, followed by 10% NaOH (0.528 ml) and water (0.880 ml). The mixture was then stirred for 0.5 h before being filtered through kieselguhr. The filter pad was then washed with THF (20 ml) and the filtrate evaporated under reduced pressure to give the title compound as a brown solid (0.242 g, 85%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][CH2:30][CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:33]3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.ClCCl.C(OCC)C>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:33]3)=[CH:26][CH:27]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1CC[C@H](CCCC(=O)c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1.3 g of lithium aluminium hydride and 100 ml of absolute diethyl ether was placed at 0° C. and while gassing with nitrogen and treated with a solution 10 g of aluminium chloride and 200 ml of absolute diethyl ether. After completion of the addition the mixture was stirred at room temperature for a further 20 minutes and treated within 30 minutes with a solution of 9 g of 1-(trans-4-pentylcyclohexyl)-4-[4-(trans-4-pentylcyclohexyl)butanoyl]benzene and 100 ml of absolute dichloromethane. After completion of the addition the reaction mixture was heated overnight under slight reflux, then cooled to 0° C. and treated with 50 ml of water and 500 ml of 25% hydrochloric acid. The organic phase was separated and the aqueous phase was back-extracted three times witch 100 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, 250 ml of concentrated potassium carbonate solution and again with 500 ml of water, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from acetone gave 5.7 g of 1-(trans-4-pentylcyclohexyl)-4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzene with m.p. (C-SB) 50° C. and cl.p. (SB -I) 111° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)c(C)c1

Procedure:
The title compound was prepared by reacting 4-bromo-3-methylanisole (10 g, 0.050 mol) with n-butyl lithium (24 mL of 2.5 M solution in hexane, 0.055 mol) followed by triisopropyl borate (57.7 mL, 47.02 g, 0.25 mol) according to method F to yield 5.7 g (69%) of a white solid: MS (ESI) m/z 313 (2M−H2O—H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CCCC)CCCC)CCC.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:2]1(/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: C(=C/c1ccccc1)\c1ccccc1
Yield: 87 %

Procedure:
Table 1, Entry 3. In the reaction tube were mixed iodobenzene (0.204 g, 1.0 mmol), styrene (0.130 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-n-butylamine (0.185 g, 1.0 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 2.50 min with an effect of 90 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane as the eluent. The yield was 87% (white crystals, terminal/internal arylation 19/1).
Reaction SMILES: FC1C=C([C@H]2CC[C@H](CCCCC)CC2)C=C(F)C=1O.C([O-])([O-])=O.[K+].[K+].C(I)CCCCC.[F:34][C:35]1[CH:40]=[C:39]([C@H:41]2[CH2:46][CH2:45][C@H:44]([CH2:47][CH2:48][CH2:49]CC)[CH2:43][CH2:42]2)[CH:38]=[C:37]([F:52])[C:36]=1[O:53][CH2:54]CCCCC>CN(C)C=O>[F:34][C:35]1[CH:40]=[C:39]([C@H:41]2[CH2:42][CH2:43][C@H:44]([CH2:47][CH2:48][CH3:49])[CH2:45][CH2:46]2)[CH:38]=[C:37]([F:52])[C:36]=1[O:53][CH3:54]
Reactant: CCCCCCOc1c(F)cc([C@H]2CC[C@H](CCCCC)CC2)cc1F
Agent: CCCCC[C@H]1CC[C@H](c2cc(F)c(O)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCI
Product: CCC[C@H]1CC[C@H](c2cc(F)c(OC)c(F)c2)CC1

Procedure:
A mixture of 28.2 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol, 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of dimethylformamide is heated at 80° for 16 hours, while stirring, and is then cooled and worked up in the usual manner. This gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-1-hexoxybenzene.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:21]1[CH2:23][CH2:22]1)#[N:6].Cl.C(N(CC)CC)C.Cl>C(OCC)(=O)C.CN(C=O)C>[CH:21]1([N:11]2[C:12]3[C:8](=[C:7]([C:5]4[NH:6][N:3]=[N:2][N:1]=4)[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:22][CH2:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(C#N)c2ccn(C3CC3)c2c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
In a 100-mL egg plant-type flask, sodium azide (486 mg, 7.48 mmol) was added to a DMF (10 mL) solution of ethyl 4-cyano-1-cyclopropyl-1H-indole-6-carboxylate (475 mg, 1.87 mmol) and triethylamine hydrochloride (1.03 g, 7.48 mmol), and stirred overnight at 110° C. The reaction solution was diluted with ethyl acetate, made acidic with aqueous hydrochloric acid solution added thereto, and the separated organic layer was washed with water and saturated saline water in that order, dried with sodium sulfate, filtered and concentrated. The crude product was washed with hexane to obtain the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of valinol (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0° C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1 N HCl (2×), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-valinol as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: CC(=O)N1c2ccccc2[C@@H](Nc2ccccc2)C[C@@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2[C@@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 50 °C
Yield: 34 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with (±)-trans-1-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.110 g, 0.39 mmol, 1.0 equiv) and 2-furoyl chloride (0.193 mL, 1.9 mmol, 5.0 equ), pyridine (1.0 equ.) and dry toluene (5 mL). The solution was heated to 50° C. for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (30% hexane/70% ethyl acetate to 50% hexane/50% ethyl acetate) to yield the trans isomer 34% yield.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl[CH2:28][CH:29]=[CH:30][CH2:31][OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:28]/[CH:29]=[CH:30]\[CH2:31][OH:32])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCC=CCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OC/C=C\CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 57.5 °C
Reaction time: 5 h

Procedure:
A solution containing 1-benzhydrylpiperazine (3 g, 0.0119 mol), toluene (20 ml), 4-chloro-2-butene-1-ol (1.65 g, 0.0155 mol), diisopropylethylamine (3.81 g, 0.0295 mol), and DMF (3 ml) is stirred at 55-60° C. for 5 hrs. The reaction mass is quenched with water (20 ml), organic layer separated and the aqueous layer extracted with dichloromethane (2×20 ml). The organic extract is washed with water (10 ml), and concentrated to obtain crude product, which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.3:0.7) as mobile phase to obtain pure product.
Reaction SMILES: [O:1]([CH2:9][CH2:10]/[CH:11]=[CH:12]/B1OC(C)(C)C(C)(C)O1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:45]1[CH:46]=[CH:47][C:48](/[C:53](/[C:72]2[CH:77]=[CH:76][C:75]([C:78]([CH3:81])([CH3:80])[CH3:79])=[CH:74][CH:73]=2)=[CH:54]/[C@@H:55]2[N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=3[O:69][CH3:70])[C:58](=[O:71])[CH2:57][CH2:56]2)=[N:49][C:50]=1[O:51][CH3:52]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Si:2]([O:1][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:45]1[CH:46]=[CH:47][C:48](/[C:53](/[C:72]2[CH:73]=[CH:74][C:75]([C:78]([CH3:81])([CH3:80])[CH3:79])=[CH:76][CH:77]=2)=[CH:54]/[C@@H:55]2[N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=3[O:69][CH3:70])[C:58](=[O:71])[CH2:57][CH2:56]2)=[N:49][C:50]=1[O:51][CH3:52])([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(/C=C/CCO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
trans-4-(tert-Butyldimethylsiloxy)-1-buten-1-ylboronic acid pinacol ester (296 mg), tris(dibenzylideneacetone)dipalladium(0) (48 mg), tri(2-furyl)phosphine (73 mg) and cesium carbonate (354 mg) were added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (300 mg) in 1,4-dioxane (3 mL)-water (1 mL), and the mixture was stirred at an external temperature of 65° C. for three hours. The reaction solution was left to cool, diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-6-methoxypyridin-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (399 mg, 100%).