Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.C(N(CC)CC)C.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=1>C(#N)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:23]1[CH2:24][CH2:25][C:20]2([CH2:26][CH2:27][N:16]([C:14]([C:12]3[N:13]=[C:9]([CH3:8])[S:10][CH:11]=3)=[O:15])[CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)CC2)cs1
Reactant: OCCc1cccc(CBr)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)CC2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of (2-methylthiazol-4-yl)(7-oxa-3,10-diazaspiro[5.6]dodecan-10-yl)methanone trifluoroacetate (example 89, step g) (0.21 g) in acetonitrile (15 mL) was treated with triethylamine (0.214 mL) followed by 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.121 g). The reaction mixture was stirred for 3 hours at 20° C. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was re-extracted twice with DCM and the combined organics were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 6% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NC(CO)CO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC(CO)CO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with 2-amino-1,3-propanediol (34.1 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (50 mg, 69% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].I[CH:28]([CH3:30])[CH3:29]>O>[CH:28]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
A mixture of 5 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 50 ml of dimethylformamide, 5.25 g of sodium carbonate and 2.7 ml of 2-iodopropane were stirred under an inert atmosphere and the mixture was then added dropwise over 20 hours to 400 ml of water. The mixture was stirred for 30 minutes, was allowed to crystallize and was then vacuum filtered. The recovered product was washed and dried at 50° C. under reduced pressure to obtain 5.8 g of 3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 178° C.
Reaction SMILES: [OH-].[K+].C(O)C.[SH:6][CH2:7][CH2:8][OH:9].[CH3:10][C:11]1([CH3:14])[CH2:13][O:12]1>>[OH:9][CH2:8][CH2:7][S:6][CH2:10][C:11]([OH:12])([CH3:14])[CH3:13]
Reactant: OCCS
Reactant: CC1(C)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CSCCO

Procedure:
1 mol of KOH is dissolved in 1 mol of ethanol and 1 mol of 2-mercaptoethanol is added. 1 mol of 2,2-dimethyloxirane is added dropwise to this solution in the course of 60 min and with cooling. The mixture is then neutralized, the precipitate is filtered off, and the filtrate is concentrated and distilled in vacuo. 2-Hydroxy-2-methylpropyl 2-hydroxyethyl sulphide of boiling point 93° C. at 0.199 mbar is obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[C:17]([Cl:18])=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1>CN(C)C=O>[Cl:18][C:17]1[C:13]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:14][O:15][C:16]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1noc(-c2ccccc2)c1Cl
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(OC2CN3CCC2CC3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 1.96 g of 3-quinuclidinol in 30 ml of dimethylformamide was cooled to 5° C. in an atmosphere of nitrogen. 0.67 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was then added to the cooled solution, and then the solution was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was cooled to 5° C., and 3.0 g of 3,4-dichloro-5-phenylisoxazole were added. The resulting mixture was then stirred at room temperature for 5 hours. At the end of this time, it was poured into 100 ml of ice-water and extracted twice, each time with 100 ml of ethyl acetate. The ethyl acetate extracts were combined and washed twice, each time with 100 ml of a 10% w/v aqueous solution of sodium chloride; they were then dried over anhydrous magnesium sulfate, after which the drying agent was removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure. The residue thus obtained was purified by column chromatography through silica gel using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to afford 4.21 g (yield 98.7%) of the title compound as a colorless and transparent oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1.CO>ClCCl.CS(C)=O>[CH3:12][N:4]([CH2:3][CH:2]=[O:1])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CN(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (24.52 g, 140 mmol) in 340 mL dichloromethane and 85 mL DMSO was added 39 mL (279.8 mmol) of triethylamine and the reaction mixture stirred at ambient temperature under N2. To this was added 45 g (280 mmol) of pyridine sulfur trioxide, portionwise. Exotherm was observed and the solution became clear dark yellow. Cooled to 0° C. and stirred for 1 hour 20 minutes. Monitored by TLC (10% methanol in dichloromethane). Concentrated to a total volume of ˜250 mL. Washed with 3×250 mL H2O then 250 mL NaCl (sat). Dried over MgSO4, filtered, and solvent evaporated. Distilled at 75° C. (3 mm Hg) to provide 13.83 g of a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4cc3OC)CC2)c1
Yield: 74.5 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([N+:13]([O-])=O)=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>Cl.O.C(O)C.O1CCCC1.[Zn]>[NH2:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:12])[NH:11][C:2](=[O:1])[N:3]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:22][CH2:21]2)=[CH:8][CH:7]=1
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2cc([N+](=O)[O-])ccc12
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Yield: 68.9 %

Procedure:
2,4-Dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-7-nitro-1,2,3,4-tetrahydroquinazoline (3.00 g) obtained in Example 11 was dissolved in a mixture of concentrated hydrochloric acid (10.0 ml), water (50.0 ml), ethanol (50.0 ml) and tetrahydrofuran (50.0 ml) and an excess of zinc powder was added in portions. After completion of the reaction, the reaction mixture was filtered, and the filtrate was made basic with 25% aqueous ammonia solution and extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure to give the title compound (1.95 g, 69%). Recrystallization from ethyl acetate yielded a yellow crystal having a melting point of 162 to 164° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.[Li]CCCC.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=1.CCOCC>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:21]([O:10][CH:8]2[CH2:9][CH:3]3[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]3)[CH2:7]2)[N:22]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1C2CCC1CC(Oc1nc(Cl)nc(N3CCOCC3)n1)C2
Temperature: -78 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to −78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4,-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>C1COCC1>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:20])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)CCCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Temperature: 70 °C

Procedure:
Dissolve trans-5-chloro-pentanoic acid-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-amide (22.7 g, 65.1 mmol) in anhydrous THF (500 mL), add sodium hydride (60% dispersion in mineral oil, 13.0 g, 0.32 mol) by portions and heat the reaction mixture at 70° C. for 18 hours. Cool the reaction mixture to room temperature, quench with water (200 mL) and extract with DCM (3×100 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a white solid (15.0 g, 74%): MS (ES+) m/z=312 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]([OH:57])=O.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][N:7]([CH3:8])[C:55](=[O:57])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH2:2][CH2:3]1
Reactant: CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Reactant: COCCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1

Procedure:
A mixture of 194 mg of methyl 4-[2-(4-{[(2-{[3-({cyclopropyl[2-(methylamino)ethyl]amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.050 mL of (2-methoxyethoxy)acetic acid, 84 mg of WSC.hydrochloride, and 5.0 mL of DMF was stirred for 15 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 200 mg of methyl 4-[2-(4-{[(2-{[3-(11-cyclopropyl-8-methyl-7-oxo-2,5-dioxa-8,11-diazadodecan-12-yl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1N(COCC[Si](C)(C)C)C=C([Sn](C)(C)C)N=1.C[Sn](C)(C)C1NC=NC=1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][CH:2]=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: C[Sn](C)(C)c1cnc[nH]1
Agent: Cc1nc([Sn](C)(C)C)cn1COCC[Si](C)(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccccc1OCC2

Procedure:
Following the procedure for 265, a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and a mixture of regioisomers 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethyl stannyl)-1H-imidazole and 2-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-5-(trimethyl stannyl)-1H-imidazole were reacted to give 9-(1-(2-(tert-butyldimethylsilyl)ethoxy)methyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine which was dissolved (360 mg, 0.71 mmol) in ethanol (3 mL). To the mixture was added HCl-methanol (3 mL, 4 mol/L) dropwise at 0° C. After 30 minutes, the temperature was allowed to warm up to 70° C. and stirred for over night. Concentrated, the residue was basified with TEA, then purified by per-TLC to give 240 mg of 271. Yield=91%. 1H NMR (MeOD, 400 MHz): δ 8.72 (s, 1H), 8.60 (d, J=4.4 Hz, 1H), 8.19 (s, 1 H), 7.87 (s, 1 H), 7.51 (d, J=2.0 Hz, 1 H), 7.46 (s, 1 H), 5.72-5.72 (m, 1 H), 4.65-4.64 (m, 2 H), 4.60-4.59 (m, 2 H), 2.68 (s, 3 H), 1.63-1.62 (d, J=6.8 Hz, 6 H). LC-MS: m/z=376 [M+H+]
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH2:34][CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:34]([N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]2)[CH:26]=[CH:25][CH:24]=1)[CH3:32])[CH3:35]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(C)Cc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 21.3 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), N-methylethanamine (50.7 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (11.5 mg, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5](C(OC)=O)[C:6]([O:8][CH3:9])=[O:7].[Cl-].[Li+]>CS(C)=O.O>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Cc1ccccc1Br)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1ccccc1Br
Temperature: 160 °C
Reaction time: 7.5 h
Yield: 68.6 %

Procedure:
Dimethyl 2-(2-bromobenzyl)malonate (54.25 g) was dissolved in a mixture of dimethylsulfoxide (220 ml) and water (3.24 ml), and lithium chloride (15.27 g) was added. The mixture was stirred at 160° C. of a bath temperature for 7.5 hours. After the reaction mixture was left standing for cooling, the solvent was removed by distillation under reduced pressure. The residual concentrate was poured into water, extracted with toluene. The organic layer obtained was washed twice with water and once with a saturated aqueous saline, dried over sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residual concentrate was distilled under reduced pressure (96°-98° C./0.5 mmHg) to give the title compound (30.05 g).
Reaction SMILES: Br[C:2]1[C:3]([Cl:31])=[CH:4][C:5]([O:29]C)=[C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:31][C:3]1[C:2]([CH:32]2[CH2:34][CH2:33]2)=[CH:7][C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([OH:29])[CH:4]=1
Reactant: OB(O)C1CC1
Reactant: COc1cc(Cl)c(Br)cc1CCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CCc3cc(C4CC4)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixture of tert-butyl 3-(4-(3-(5-bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (280 mg, 0.54 mmol), cyclopropylboronic acid (185 mg, 2.2 mmol), K3PO4.3H2O (444 mg, 1.9 mmol), tricyclohexylphosphine (30 mg, 0.1 mmol), Pd(OAc)2 (24 mg, 0.11 mmol) in toluene (10 mL) and water (1 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (194 mg, 75% yield). ESI-MS m/z: 477.3[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:3]=1[C:30](=[O:32])[CH3:31].[C:33](O)(=[O:37])[C@@H:34]([CH3:36])[OH:35].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:30]([C:3]1[C:4]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:33](=[O:37])[C@H:34]([OH:35])[CH3:36])[CH2:28][CH2:29]2)=[N:5][C:6]2[N:7]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:2]=1[NH2:1])(=[O:32])[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(=O)c1c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)c1c(OC2CCN(C(=O)[C@@H](C)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (211 mg, 0.49 mmoL), D-(−)-lactic acid (53.3 mg, 0.59 mmoL), EDC (189.0 mg, 0.99 mmoL), HOBt (132.0 mg, 0.99 mmoL) and DIEA (514 uL, 2.96 mmoL) in DMF (5 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13]CC#N)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.S(=O)(=O)(O)O.C(OCC)(=O)C.[C:29]([OH:32])(=[O:31])[CH3:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:30][C:29]([OH:32])=[O:31])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: N#CCCOCCc1ccc2sccc2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCOCCc1ccc2sccc2c1

Procedure:
In 0.6 mL of acetic acid was dissolved 200 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiononitrile, followed by adding thereto 0.4 mL of water and 0.184 mL of sulfuric acid, and the resulting mixture was stirred at 90 to 100° C. for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene ethyl acetate=3:1) to obtain 140 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as colorless crystals.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15]3[C:20]([CH:21]=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][CH:5]=1)C.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[CH:16]1[C:15]2[C:20](=[CH:21][C:22]3[C:27]([C:14]=2[C:7]2[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([OH:3])=[CH:5][CH:6]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 175 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
Under the nitrogen atmosphere, 9-(4-ethoxynaphthalen-1-yl)anthracene (87.1 g) as the fourteenth intermediate compound, pyridine hydrochloride (289.0 g) and 1-methyl-2-pyrrolidone (87 ml) were added to a flask, and stirred for 16 hours at 175° C. The reaction solution was cooled to room temperature, added with water, and washed while being heated. After suction filtration, the solid remained after dissolution was collected. The obtained solid was washed with methanol while being heated. It was then dissolved in heated chlorobenzene and subjected to suction filtration by using a Kiriyama funnel layered with silica gel. An appropriate amount of filtrate was distilled off under reduced pressure, and by adding heptane, re-precipitation was performed to give 4-(anthracen-9-yl)naphthalen-1-ol (74.3 g) as a fifteenth intermediate compound. The scheme is shown in the following “Reaction 26”.