Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32].CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 μL, 0.10 mmol). The mixture was stirred at room temperature for 1 h before being filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to yield N-(1-(2-acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.15 (t, J=5.9 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m, 2H), 1.41 (s, 9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99% CH3CN, 3 min run; ESI-MS 516.4 m/z (M+H+).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[O:12]C(C)(C)[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:32](=[O:33])[C:31]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][C:23]=3[C:22]([CH3:35])([CH3:34])[C:21]=2[CH:36]=1)(C)(C)C.CO.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:34][C:22]1([CH3:35])[C:23]2[O:24][C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:30]=3[C:31]=2[C:32](=[O:33])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:9]([OH:10])[C@H:8]([OH:12])[CH2:7][OH:6])=[CH:36][C:21]1=2
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cccnc4c2C3=O)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2cc(OC[C@@H](O)[C@H](O)CO)ccc2C(=O)c2c1oc1cccnc21
Temperature: 57.5 °C
Yield: 28.1 %

Procedure:
To the mixture of 8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one (Compound GT15-6, 27 mg), MeOH (0.1 ml) and THF (0.3 ml), 0.5 N sulfuric acid (0.1 ml) was added, and the mixture was stirred and heated at 55 to 60° C. for 4 hrs. The reaction mixture was neutralized with saturated aqueous solution of sodium bicarbonate. The resulting solid was filtered and washed with diethyl ether. The filtrate was extracted with the mixture solution of DCM and MeOH (DCM:MeOH=10:1). The organic layer was washed with saturated brine, and dried over magnesium sulfate. The filtered solid and the residues obtained after concentration under reduced pressure were combined and purified by silica gel column (DCM/MeOH) to obtain the title compound (5.4 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
The product from Example 193a (1.00 g, 4.9 mmol), and the product from Example 197b (0.90 g, 5.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMF (20 mL) were heated at 100° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with H2O. The resulting solid was collected by filtration, washed with H2O, and dried in vacuum to give brown crystal, which was purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title compound as a dark orange crystal (0.47 g, 30%).
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(=O)(=O)(O)O.[C:23](=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([C:15]([O:17][CH3:23])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid are dissolved in 500 mL of methanol, combined with 5 mL (0.089 mol) of concentrated sulfuric acid and refluxed for 1 hour. After cooling, 100 mL of sodium hydrogen carbonate solution (about pH 8) are added and the methanol is largely evaporated down. The mixture is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The product is purified by recrystallization from ethyl acetate. Yield: 50.0 g of white crystals (93% of theoretical yield).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:11]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:25](Cl)=[O:26])[CH:19]=[CH:18]2)(=[O:13])[CH3:12].O1CCOCC1.N1C=CC=CC=1>O>[C:1]([NH:9][NH:10][C:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][C:11](=[O:13])[CH3:12])[CH:16]=2)[CH:21]=1)=[O:26])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCC(=O)NN
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCC(=O)NNC(=O)c1ccc2cc(OC(C)=O)ccc2c1
Temperature: 80 °C
Yield: 73.8 %

Procedure:
In a 200 ml-three-necked flask, 1.77 g (12.3 mM) of heptanohydrazide, 3,23 g (13.0 mM) of 6-acetoxy-2-naphthoyl chloride prepared in the same manner as in Example 3 and 90 ml of dioxane were placed and heated to about 80° C. To the mixture, 5.0 ml of pyridine was added at about 80° C. under stirring, followed by heating to 90°-92° C. and stirring for 1 hour at 90°-92° C. After the reaction, the reaction mixture was cooled on an iced water bath and poured into 350 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and recrystallization from a mixture solvent (acetoneethyl acetate) to obtain 3.23 g of N-heptanoyl-N'-(6-acetoxy-2-naphthoyl)hydrazine (Yield: 75.4 %) ##STR137##
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S-:33].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([S:33][CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of tert-butyl(6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.24 g, 0.5 mmol), sodium thiomethoxide (0.080 g, 1.1 mmol) and N,N-dimethylformamide (4 mL) was stirred at 85° C. for 1 h, and the reaction mixture was poured into water (50 mL) and extracted twice with ethyl acetate (25 mL). The extracts were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl[2-isobutyl-6-(methylsulfanyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.17 g, 73%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].N1C=CC=CC=1.[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52])([O-:44])=[O:43]>ClCCl>[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35])(=[O:53])=[O:52])([O-:44])=[O:43]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.8 %

Procedure:
To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (327 mg) and pyridine (80.3 mg) in dichloromethane (6 ml) was added dropwise 2-nitrobenzenesulfonyl chloride (150 mg) at ambient temperature and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was diluted with dichloromethane (10 ml) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 2-4% methanol in chloroform) to give 4-(2-nitrobenzenesulfonyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (460 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[C:9]([F:31])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:34][CH2:33][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:9]([F:31])[CH:8]=2)[CH:13]=[C:5]1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (444 μL, 5.8 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (93.7 mg, 82%). ESI-MS m/z calc. 473.19, found 474.5 (M+1)+. Retention time 1.61 minutes.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([I:22])[CH:21]=1)[NH2:18].O>CC(C)=O>[C:5]([NH:3][C:2]([NH:18][C:17]1[CH:19]=[C:20]([I:22])[CH:21]=[C:15]([Br:14])[CH:16]=1)=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cc(Br)cc(I)c1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of ammonium thiocyanate (4.45 g, 0.0585 mol) in anhydrous acetone (48 ml) was treated dropwise with benzoyl chloride (6.47 ml, 0.05583 mol) and stirred at ambient temperature for 1 h. A solution of 3-Bromo-5-iodoaniline (15.85 g, 0.05319 mol) in anhydrous acetone (48 ml) was then added in one portion and the mixture stirred at ambient temperature for 16 h. The resultant suspension was poured into water (300 ml) and stirred for 0.5 h. The precipitated solid was collected by filtration washed with water followed by 40-60° petroleum ether and dried in vacuo to afford 1-Benzoyl-3-(3-bromo-5-iodo-phenyl)-thiourea (20.70 g, 84%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:12]([NH:14][C:15]3[S:16][C:17]([CH3:33])=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[O:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.FC(F)(F)C(O)=O.CCCCCC>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:12]([NH:14][C:15]3[S:16][C:17]([CH3:33])=[C:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:19]=3[C:20]([OH:22])=[O:21])=[O:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: Cc1sc(NC(=O)c2cccc(-c3ccoc3)c2)c(C(=O)OC(C)(C)C)c1-c1ccccc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1sc(NC(=O)c2cccc(-c3ccoc3)c2)c(C(=O)O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
0.5 g (1.2 mmol) of tert-butyl 2-({[3-(furan-3-yl)phenyl]carbonyl}amino)-5-methyl-4-phenylthiophene-3-carboxylate was dissolved in 2 mL of chloroform, and 5 mL of trifluoroacetic acid (TFA) was added thereto at 0° C. The mixture was stirred at room temperature for 5 hours. n-hexane was added to the reaction mixture, and solids were collected by filtration, followed by recrystallization using a mixed solvent of ethyl acetate and n-hexane, thereby giving 0.34 g of the target 2-({[3-(furan-3-yl)phenyl]carbonyl}amino)-5-methyl-4-phenylthiophene-3-carboxylic acid (yield: 70%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][N:18]([CH2:30][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CN(CCc3ccc(Cl)cc3)Cc3ccc(C(=O)OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of {4-[(4-butylphenyl)ethynyl]benzyl}[2-(4-chlorophenyl)ethyl]amine (2.85 g, 7.1 mmol) and methyl 4-formylbenzoate (1.16 g, 7.1 mmol) in DCE (24 mL) was added at once sodium triacetoxyborohydride (2.25 g, 10.6 mmol) and the resulting reaction mixture was stirred 12 hrs at rt. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex (5/95)) gave 2.8 g (73%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.98 (d, J=8.3 Hz, 2H), 7.51-7.43. (m, 4H), 7.36 (d, J=8.3 Hz, 2H), 7.29-7.15 (m, 6H), 7.00 (d, J=8.3 Hz, 2H), 3.94 (s, 3H), 3.68 (s, 2H), 3.64 (s, 2H), 2.83-2.59 (m, 6H), 1.69-1.55 (m, 2H), 1.44-1.30 (m, 2H), 0.95 (J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:39][CH:38]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC(=O)Oc1ccc(CBr)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(OC(C)=O)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-acetoxy-benzyl bromide following a procedure analogous to that described for Intermediate 7.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)[CH2:3][CH2:2]1.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]([OH:27])[CH2:20]2>>[OH:27][CH:21]1[CH2:20][CH:19]2[N:26]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:11]=3)=[O:15])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1
Reactant: O=C(O)c1cccc(OCCC2CCOCC2)c1
Reactant: OC1CC2CCC(C1)N2
Product: O=C(c1cccc(OCCC2CCOCC2)c1)N1C2CCC1CC(O)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yl-ethoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 360 (M).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:30])[C:10]#[C:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[C].[Pd].O1CCCC1.C(O)C>[Si:1]([O:8][C@H:9]([CH3:30])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](C#CC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C

Procedure:
100 mg of 10% palladium-carbon catalyst was added to a solution of 513 mg of N-(4-((4R)-4-((tert-butyl(dimethyl)silyl)oxy)-2-pentynoyl)-3-fluorophenyl)pyrazine-2-carboxamide in 5 ml of tetrahydrofuran and 20 ml of ethanol, and the reaction liquid was stirred in a hydrogen atmosphere for 1.5 hours. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([CH3:6])([CH3:5])[CH:3]1[NH:7][C:8]([NH2:10])=[S:9].C([O:14][C:15](=O)[CH:16](Br)[CH:17]([CH3:19])[CH3:18])C>>[CH:17]([CH:16]1[S:9][C:8]([NH:7][CH:3]2[C:4]([CH3:5])([CH3:6])[C:2]2([CH3:11])[CH3:1])=[N:10][C:15]1=[O:14])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: CC1(C)C(NC(N)=S)C1(C)C
Product: CC(C)C1SC(NC2C(C)(C)C2(C)C)=NC1=O

Procedure:
Synthesis was performed from N-(2,2,3,3-tetramethylcyclopropyl)thiourea and ethyl-2-bromoisovalerate according to Method C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Cl>C(O)C>[CH3:3][O:4][C:5]([CH:7]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:6]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in ethanol (210 mL), and trimethyl phosphonoacetate (11.4 g, 0.062 mol) added with stirring. The mixture was stirred for 30 min at room temperature. Tert-butyl 4-oxopiperidine-1-carboxylate (11.35 g, 0.057 mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidified with diluted hydrochloric acid until the pH was 4, filtered, concentrated, and partitioned into water and chloroform. Phases were separated. The aqueous phase was extracted once with chloroform. Chloroform phases were combined, washed once with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccc(F)nc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 6-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 4 hours, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 4 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2) to afford, after trituration with diethyl ether, the compound (28) as a yellow powder (45 mg, 6%). IR νmax (cm-1): 2215 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.36 (1H, dd, J5″-4″=8.5 Hz, J5″-F=2.1 Hz, H5″), 7.41 (1H, d, J7′-6′=8.9 Hz, H7′), 7.49 (1H, d, J4′-6′=2.4 Hz, H4′), 7.76 (1H, s, H3), 7.78 (1H, s, H2′), 8.52 (1H, td, J5″-4″=J5″-F=10.1 Hz, J4″-2″=1.8 Hz, H4″), 8.67 (1H, d, J2″-4″=1.8 Hz, H2″), 11.66 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (5′-methoxy), 102.0 (C4′), 108.2 (C2), 109.7 (1C, d, 2JC—F=37 Hz, C5″), 110.0 (C3′), 112.4 (C6′), 113.2 (C7′), 118.0 (C1), 124.0 (C3a′), 127.7 (C2′), 129.5 (1C, d, 4JC—F=4 Hz, C3″), 130.7 (C3), 132.3 (C7a′), 140.7 (1C, d, 3JC—F=8 Hz, C4″), 148.2 (1C, d, 3JC—F=15 Hz, C2″), 154.6 (C5′), 162.6 (1C, d, 1JC—F=237 Hz, C6″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+ MeOH]+); HRESI-MS: m/z 294.1052 (calcd for C17H13N3OF, 294.1043).