Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[O:9]
Reactant: BrBr
Reactant: O=CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC(Br)c1ccccc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of phenyl-acetaldehyde (1 g, 8.3 mmol) in CH2Cl2 (3 mL) was added dropwise a solution of Br2 (1.3 g, 8.3 mmol) in CH2Cl2 (3 mL) at −10° C. over 30 min. The resulting solution was allowed to warm to rt and then heated to reflux overnight. Aqueous NaHCO3 was added to the cooled mixture and the solution was extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford crude bromo-phenyl-acetaldehyde (1 g, 5.05 mmol, 61%) as a green liquid which was taken to the next step directly. Anal. Calcd. for C8H7BrO m/z 198.0, found: 198.0 GC-MS (M)+.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:11][CH:12]([CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 65.3 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (4.34 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-chlorobenzenesulfonyl chloride (3.87 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.07 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[CH:33][C:34]([O:36][CH3:37])=[O:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCN(Cc2ccccc2)C1
Yield: 61 %

Procedure:
1-benzylpyrrolidin-3-one a43 (8.75 g, 50 mmol, 1 eq) is dissolved in toluene (100 ml). Methyl (triphenylphosphoranylidene)acetate a44 (18.4 g, 55 mmol, 1.1 eq) is added and the mixture is refluxed for 60 h. The cold suspension is then filtered and the filtrate is concentrated to dryness. The crude product is purified by chromatography over silicagel (ethyl acetate/hexane 10/90) to afford 7.2 g of pure methyl (1-benzylpyrrolidin-3-ylidene)acetate a45.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH:9]([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[Cl:8][C:7]1[C:6]([CH:9]([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[N:5][CH:4]=[N:3][CH:2]=1
Reactant: CC(c1ncnc(Cl)c1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ncncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of 3-(4,5-dichloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (see Preparation 6(iii)) (0.58 g, 1.46 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (45 mg) and sodium acetate (122 mg, 1.5 mmol) for 7 hours. The catalyst was then removed by filtration and the filtrate was concentrated under reduced pressure. "Flash" chromatography of the residue on silica using ethyl acetate as the eluant provided, after combination and evaporation of the appropriate fractions, the title compound (0.35 g, 72%), m.p. 128° C. Found: C,51.68; H,3.89; N,18.58; C16H14ClF2N5O.0.03 H2O requires: C,51.76; H,3.94; N,18.87%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>O>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 86.6 %

Procedure:
To a mixture of methyl 4-hydroxybenzoate (4.84 g), potassium carbonate (4.80 g), and N,N-dimethylformamide (50 mL) was added 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (6.00 g) with stirring, and the mixture was stirred at 80° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (8.09 g, yield 87%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). White crystals were obtained by recrystallization from ethyl acetate-diisopropyl ether. melting point: 104-105° C.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:37][CH2:36][C:35]([O:39][CH3:40])([CH3:38])[CH:34]([NH:41]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:32][CH2:33][CH:34]([NH2:41])[C:35]([O:39][CH3:40])([CH3:38])[CH2:36][CH2:37]1)=[O:23]
Reactant: COC1(C)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC1(C)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CCC1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-(1-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl)-5-methoxy-5-methyl-azepan-4-yl]carbamate (0.12 g, 0.17 mmol) in MeOH (10 mL) was added HCl in dioxane (4 M, 10 mL, 0.04 mol). The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Purification via preparative HPLC gave 485 as a pale yellow solid (64 mg, 74%). 1H NMR (400 MHz, d6-DMSO) δ 9.63 (s, 1H), 7.69 (s, 1H), 7.59-7.48 (m, 3H), 7.31-7.22 (m, 2H), 3.61 (s, 3H), 3.31-3.25 (m, 1H), 3.14-3.03 (m, 2H), 3.03 (s, 3H), 2.99-2.89 (m, 1H), 2.11-2.02 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.59 (m, 4H), 1.47 (dd, J=14.5, 6.2 Hz, 1H), 1.19 (s, 3H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH:19]([CH3:25])[C:20](OCC)=[O:21])=[CH:13]2)([O-:9])=[O:8].O.[OH-].[Na+]>C1COCC1>[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH:19]([CH3:25])[CH2:20][OH:21])=[CH:13]2)([O-:9])=[O:8]
Reactant: CCOC(=O)C(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a cooled solution of LiAlH4 (1.0 M in THF, 1.2 mL, 1.2 mmol) in THF (5.3 mL) at 0° C. was added a solution of ethyl 2-(5-nitro-1H-indol-2-yl)propanoate (0.20 g, 0.76 mmol) in THF (3.66 mL) dropwise. After addition, the mixture was allowed to warm up to room temperature and was stirred at room temperature for 3 h. The mixture was cooled to 0° C. Water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at room temperature for 0.5 h and was then filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.14 g, 81%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: COc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 7 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-methoxyphenyl phosphonic dichloride to yield 1-(4-methoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 7% yield) as a white solid having a melting point of 190°-192° C. and the following analysis:
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(NCCCCCCOC2CCCCO2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CC(C)c1ccc(N(CCCCCCOC2CCCCO2)C(=O)C2CCCc3ccccc32)cc1
Yield: 33.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and (4-isopropylphenyl)[6-(tetrahydropyran-2-yloxy)hexyl]amine (2.0 g) as starting materials, N-(4-isopropylphenyl)-N-[6-(tetrahydropyran-2-yloxy)hexyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.0 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 9, N-(6-hydroxyhexyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1nc(CO)cs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCNc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.3 g of 2-octylaminothiazol-4-ylmethanol, 2.6 g of pyrid:ne sulfur trioxide complex, 1.6 g of triethylamine and 20 ml of dimethyl sulfoxide. giving the title compound as pale brown needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 91.1 %

Procedure:
A solution of 4-(3-fluoro-4-methoxy-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (4.7 g, 14.6 mmol) in methanol (400 mL) was allowed to stir under atmospheric pressure of hydrogen at room temperature in the presence of 10% palladium on carbon (0.8 g) for 16 hours. Removal of the catalyst by filtration and evaporation of the filtrate gave a crude oil. Silica gel chromatography eluting with ethyl acetate in hexane (10%) gave the title compound (4.3 g, 99%) as a colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]3[N:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]2[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.Cl.O1CCOCC1>ClCCl.C(OCC)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]3[N:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]2[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([NH2:34])[CH2:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(1,3-thiazol-2-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (302 mg, 0.54 mmol) and 4N HCl/dioxane (1.5 ml) in dichloromethane (10 ml) was stirred at room temperature for 16 hours and diluted with diethyl ether. The precipitate was collected on a filter paper and dried to give a yellow solid (76%). 1HNMR (DMSO-d6) 400 MHz δ: 8.79 (m, 2H), 8.69 (s, 1H), 8.13 (dd, J=4.9, 1.4 Hz, 1H), 7.93 (dd, J=7.7, 1.4 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.72 (d, J=2.9 Hz, 1H), 7.56-7.50 (m, 4H), 7.40 (td, J=7.7, 1.7 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.15 (td, J=7.5, 1.2 Hz, 1H) 6.91 (dd, J=8.0, 1.7 Hz, 1H), 6.76 (dd, J=8.0, 4.6 Hz, 1H), 2.60-2.55 (m, 4H), 2.25-2.15 (m, 1H), 1.86-1.76 (m, 1H); LC/MS [M+H]: 463.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[CH3:15][N:16](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:15]#[N:16])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cc(F)cc2cc[nH]c12
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 7-bromo-5-fluoro-1H-indole (D131) (15 g) in DMF (150 mL) under N2 atmosphere were added Zn(CN)2 (24.0 g) and then Pd(PPh3)4 (15.8 g), the reaction mixture was heated to 120° C. and stirred overnight. After cooling, DCM (300 mL) was added to the resulting mixture which was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to afford 7 g (64% yield) of 5-fluoro-1H-indole-7-carbonitrile (D132) as a white solid. δH (CDCl3, 400 MHz): 6.51 (1H, t), 7.20 (1H, dd), 7.30 (1H, t), 7.52 (1H, dd), 8.82 (1H, br s).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:8]2[CH:7]=[N:6][C:5]([C:3](=[O:4])[N:2]([CH3:12])[CH3:1])=[CH:10][CH:9]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of 5-bromo-pyridine-2-carboxylic acid dimethylamide (161a) (1.14 g, 4.95 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (1.10 g, 4.95 mmol), and K3PO4 (2.10 g, 9.91 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (210 mg, 0.495 mmol), and Pd(OAc)2 (111 mg, 0.495 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 6 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 35-70% EtOAc in hexanes to give a white foam (238 mg, 13% yield). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=2.78 Hz, 1 H) 7.70 (d, J=8.59 Hz, 1 H) 7.31 (dd, J=8.72, 2.91 Hz, 1 H) 7.25 (d, J=1.26 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 3.87 (s, 3 H) 3.15 (d, J=4.29 Hz, 6 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C20H22N2O5 m/z 371.20 (M+H+).
Reaction SMILES: C(OC(N(C)CC(O)=O)=O)(C)(C)C.C(O[C:19](=O)[N:20]([CH2:22][C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH:28]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)C)(C)(C)C.C(OC(=O)NC)(C)(C)C>>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH:28]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:43])[CH2:22][NH:20][CH3:19])=[CH:34][CH:33]=1
Reactant: CN(CC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CNC(=O)OC(C)(C)C
Product: CNCC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-acetamide was prepared in accordance with the methods of Example 12, except that N-tert-butoxycarbonyl-N-methyl-glycine was used instead of N-tert-butoxycarbonyl-N-methyl-L-leucine in Step A, and {[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester was used instead of (S)-1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester in Step B. MS: 333.2 (M+1 for C19H22N2F2O1); an oil;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7].[Cl:14]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:14][CH2:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N2CCCCC2)sc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc(N2CCCCC2)nc1CCl
Reaction time: 15 h
Yield: 14.3 %

Procedure:
To a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine (4.00 g) in acetonitrile (100 mL) was added N-chlorosuccinimide (2.72 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl]piperidine as colorless crystals (0.67 g, yield 14%) from a fraction eluted with ethyl acetate-hexane (1:8, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 79-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: Oc1ccc(F)cc1I
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(F)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-Fluoro-2-Iodophenol [2713-29-3] (0.9 g, 3.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, and filtered to give 83 as a solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].FC(F)(F)C(O)=O.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 87.4 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 0.002 ml of trifluoroacetic acid then added. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 95.2% and n-octyltriethoxysilane was produced at a yield of 87.4%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>C(#N)C>[Br:20][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1
Reactant: CS(=O)(=O)c1cc(CO)ccc1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(CBr)ccc1F
Temperature: 85 °C
Reaction time: 20 h

Procedure:
(Step 1) Triphenylphosphine (3.21 g) was suspended in acetonitrile (50 ml), bromine (0.64 ml) was added, and the mixture was stirred for 30 min. [4-Fluoro-3-(methylsulfonyl)phenyl]methanol (2.5 g) was added to the reaction mixture, and the mixture was stirred at 85° C. for 20 hr, treated with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:1) to give 4-(bromomethyl)-1-fluoro-2-(methylsulfonyl)benzene (1.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1CCCN1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A suspension of 1-(3-nitrophenyl)pyrrolidin-2-one (3.0 g, 15 mmol) in ethanol (50 ml) was heated until complete solution was obtained. The solution was cooled to ambient temperature then treated with 10% palladium on charcoal (150 mg) and hydrogenated at 50 psi until hydrogen uptake ceased (ca. 2 hours). The mixture was filtered through a glass microfibre filter paper (Whatman GF/A) and evaporated to dryness to give 1-(3-aminophenyl)pyrrolidin-2-one as a pale green oil (2.6 g, 100%) which was used without purification.