Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:30]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and benzaldehyde (0.43 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49 g) as oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:7]1[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1.[Cl-].[Na+]>O>[N:1]1([CH:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClC1CCCc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(c1)CCCC2N1CCCC1
Reaction time: 0.12 h

Procedure:
Over a period of 7 minutes with stirring and while allowing it to heat up, 50 ml of pyrrolidine were added to a solution of 20 g of 8-chloro-5,6,7,8-tetrahydroquinoline in 50 ml of water. The temperature reached 57° C. at the end of the introduction and stirring was continued for 1 hour at this temperature. The temperature was then allowed to return to 20° C. and the reaction medium was saturated with sodium chloride and then was extracted with other. The combined organic phases were dried and the solvents were eliminated under reduced pressure to obtain 20.22 g of 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:24][CH:23]=[C:22]([C:25](O)=[O:26])[C:21]=1[CH3:28])/[C:12](=[O:18])[NH:13]2.[NH2:29][CH2:30][CH:31]([OH:41])[CH2:32][N:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.C(#N)C>[O:40]=[S:36]1(=[O:39])[CH2:35][CH2:34][N:33]([CH2:32][CH:31]([OH:41])[CH2:30][NH:29][C:25]([C:22]2[C:21]([CH3:28])=[C:20](/[CH:19]=[C:11]3\[C:12](=[O:18])[NH:13][C:14]4[C:10]\3=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:17]=[CH:16][CH:15]=4)[NH:24][CH:23]=2)=[O:26])[CH2:38][CH2:37]1
Reactant: NCC(O)CN1CCS(=O)(=O)CC1
Reactant: Cc1c(C(=O)O)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)NCC(O)CN2CCS(=O)(=O)CC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Yield: 59.6 %

Procedure:
5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (114 mg, 0.3 mmol) was coupled with 1-amino-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-propan-2-ol (1.8 mmol), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL), acetonitrile (1 mL) at rt for overnight to give 102 mg (60%) of the titled compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[CH2:32][CH2:33][N:29]([CH3:28])[C:30]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CN1CCNC1=O
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C1=O
Yield: 75.5 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (336 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH:32]1(O)[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([O:18][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Reaction time: 18 h

Procedure:
A solution of N-benzyloxycarbonyl-L-isoleucine (10.0 g, 37.7 mmol) in DCM (150 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.94 g, 41.5 mmol), cyclopentanol (3.90 g, 45.2 mmol) and N,N-dimethylaminopyridine (20 mg). The reaction was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with 1M hydrochloric acid, saturated sodium bicarbonate, and brine before drying over magnesium sulphate, filtration and removal of solvent under reduced pressure to leave N-benzyloxycarbonyl-L-isoleucine cyclopentyl ester as a colourless ester as a colourless oil (10.99 g, 87%). 1H-NMR; δ (CDCl3) 7.44-7.30 (5H, m), 5.37-5.34 (1H, m), 5.22-5.18 (1H, m), 5.11 (2H, s), 4.33-4.27 (1H, m), 1.90-1.55 (10H, m), 1.51-1.35 (1H, m), 1.28-1.20 (2H, m), 0.93 (3H, d, J 6.9 Hz) and 0.91 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1.CC1(C)C2C=CC=CC=2I([C:37]([F:40])([F:39])[F:38])O1>C(Cl)(Cl)Cl.[Zn](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>[CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][O:26][C:37]([F:40])([F:39])[F:38])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: O=C1CN=C(n2cnc(CO)c2)C=C2c3cccc(C4CC4)c3CCN12
Agent: O=S(=O)(N([Zn]N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1CN=C(n2cnc(COC(F)(F)F)c2)C=C2c3cccc(C4CC4)c3CCN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.9 %

Procedure:
A solution of 9-cyclopropyl-2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (135 mg, 0.38 mmol) in CHCl3 (50 mL) under Ar, was treated with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). The mixture was stirred at RT for 16 h, and then treated again with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). After 24 h, the mixture was poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 100:0 to 95:5) and by SFC (column: PPU 5 m, 250×30 mm, 60 A, Princeton; eluent: isocratic 20% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (3 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 1.15 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.56-0.71 (m, 2H); 0.93-1.05 (m, 2H); 1.91-2.04 (m, 1H); 3.14-3.20 (m, 2H); 3.89-4.01 (m, 2H); 4.34 (br s, 2H); 5.00 (s, 2H); 7.03 (s, 1H); 7.18-7.26 (m, 1H); 7.26-7.34 (m, 1H); 7.69-7.85 (m, 2H); 8.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:9]=[CH:8][N:7](C(OC(C)(C)C)=O)[C:6]=2[CH:17]=1.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(NCCC(F)(F)F)cc(Br)cc21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CCNc1cc(Br)cc2[nH]cnc12
Reaction time: 2 h

Procedure:
To a stirred solution of intermediate tert-butyl 6-bromo-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazole-1-carboxylate (7.63 g, 18.69 mmol) in DCM (200 mL) at -rt was added water (20 mL) and TFA (200 mL). After stirring for 2 h, the solution was concentrated, ethyl acetate was added and the organic phase was washed with sodium carbonate solution and water. Evaporation of the yielded 5.17 g 6-bromo-N-(3,3,3-trifluoropropyl)-1H-benzimidazol-4-amine (89.8%).
Reaction SMILES: [N:1]([Sn](CCCC)(CCCC)CCCC)=[N+:2]=[N-:3].[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20]>O1CCOCC1>[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[NH:3][N:2]=[N:1][N:28]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)C1CCC(C#N)CC1
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2nnn[nH]2)CC1
Temperature: 145 °C
Yield: 52.8 %

Procedure:
A mixture of azidotributyltin (1.51 mL, 5.48 mmol), and 4-cyano-cyclohexanecarboxylic acid methyl ester (458 mg, 2.74 mmol) in 1,4 dioxane were sealed in a vial and heated in an oil bath at 145° C. for 4 days. The reaction was concentrated, diluted with aqueous sodium bicarbonate (saturated, 200 mL), washed with ethyl acetate (200 mL), acidified to pH 1 with concentrated HCl, and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, concentrated, and tritrated with mixtures of hexanes and ethyl acetate to give 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid methyl ester (304 mg, 52%) as an off white solid. LCMS calcd for C9H14N4O2 (m/e) 210, obsd 211 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].CN(C=O)C.[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O>[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=4[C:10]=3[CH3:16])=[O:15])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: CCOc1cccc2oc(C(=O)O)c(C)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 115 mg (0.46 mmol) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid in 2 mL of oxalyl chloride was refluxed for 4 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 201 mg (0.56 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were then removed under vacuum. Column chromatography with silica gel gave 237 mg (93% yield) of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off white solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([C:7]2C3C(=CC=CC=3)C(=O)O[C:8]=2[CH:18]([NH:20][C:21]2C3SC=CC=3N=C[N:26]=2)C)C=N1.Cl.[NH2:31][CH:32]([C:34]1[O:35][C:36](=[O:50])[C:37]2[C:42]([C:43]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:33]>>[ClH:1].[NH2:31][CH:32]([C:34]1[O:35][C:36](=[O:50])[C:37]2[C:42]([C:43]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:33].[Cl:1][C:18]1[C:8]2=[CH:7][CH:5]=[CH:6][N:2]2[N:26]=[CH:21][N:20]=1.[C:44]1([C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](=[O:50])[O:35][C:34]=2[CH:32]([NH:31][C:18]2[C:8]3=[CH:7][CH:5]=[CH:6][N:2]3[N:26]=[CH:21][N:20]=2)[CH3:33])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Agent: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: Cl
Product: CC(Nc1ncnn2cccc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Product: Clc1ncnn2cccc12
Yield: 79 %

Procedure:
The title compound was made in a similar way as that of the compound of example 80, from 3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Intermediate E2, 50 mg, 0.166 mmol) and 4-chloropyrrolo[2,1-f][1,2,4]triazine (35.6 mg, 0.232 mmol) to give the title compound (50.3 mg, 79%) as whitish solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28]C[CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.N[C@H]1CCCC[C@@H]1[OH:38]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][O:38][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12
Product: COc1c(C(=O)N[C@H]2CCOC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide in Example 3, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol. The resultant solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 426.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24-8.19 (m, 2H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.62-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.38 (s, 2H), 4.15-4.10 (m, 2H), 4.09-4.00 (m, 1H), 4.03 (s, 3H), 3.70-3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.12-2.04 (m, 1H), 1.84-1.74 (m, 1H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][C:26]#[N:27].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:27][CH2:26][C:25]#[N:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC#N)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (310 mg, 1 mmol), 2-aminoacetonitrile (112 mg, 2 mmol, 2.0 eq) and acetic acid (180 mg, 3 mmol, 3.0 eq) in DCE (10 mL) was stirred at rt for 10 min. Then NaBH(OAc)3 (636 mg, 3 mmol, 3.0 eq) was added to the mixture and the mixture was stirred at rt for 15 h. Then saturated NaHCO3 was added to the mixture until pH=8. The mixture was extracted with DCM (20 mL×3). The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with DCM/CH3OH (20/1) to give product the title compound as a colorless oil (240 mg, yield: 69%). ESI-MS (M+H+): 351.2. 1H NMR (400 MHz, CDCl3) δ: 7.70 (dd, 2H), 7.68 (s, 1H), 7.41 (dd, 1H), 7.13 (d, 2H), 4.30-4.23 (m, 1H), 4.05 (s, 2H), 3.57 (s, 2H), 2.26 (d, 2H), 1.90 (d, 2H), 1.48-1.42 (m, 2H), 1.20-1.09 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1CCC[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[CH:23]([Li])([CH2:25][CH3:26])[CH3:24].CN(C)C=[O:31]>>[CH:24]([C@@H:23]1[CH2:25][CH2:26][CH2:10][C@@H:9]([CH3:14])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:31]
Reactant: [Li]C(C)CC
Reactant: C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Product: C[C@@H]1CCC[C@@H](C=O)N1C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
Similarly to Referential example 2, 2.10 g(10.5 mmol) of (R)-N-tert-butoxycarbonyl-2-methylpiperidine were reacted with 1.59 ml(1 equivalent) of N,N,N′,N′-tetramethylethylenediamine, 111.1 ml (1.1 equivalent) of sec-butyllithium(1.04M) and 1.22 ml(1.5 equivalents) of N,N-dimethylformamide to obtain 1.67 g of (2S,6R)-tert-butyl 2-formyl-6-methyl-1-piperidinecarboxylate(yield 70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.O.[NH4+:21]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:21])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3ccncc3)oc12
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccncc3)oc12
Yield: 33 %

Procedure:
Methyl 2-(pyridin-4-yl)benzo[d]oxazole-7-carboxylate (130 mg, 0.51 mmol) in ammonium water (15 mL) was stirred at 25° C. overnight. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(pyridin-4-yl)benzo[d]oxazole-7-carboxamide as a solid (41 mg, yield 33%). 1H-NMR (400 MHz, DMSO-d6) δ 7.56-7.60 (t, J=8 Hz, 3H), 7.66-7.69 (q, 3H), 7.99-8.05 (q, 3H), 8.45 (s, 1H), 8.65-8.67 (d, J=8 Hz, 1H), 8.83-8.84 (d, J=4 Hz, 1H), 9.47 (s, 1H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [C:1]([Si:5]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:6][CH2:7][CH:8]([CH3:33])[O:9][C:10]1[CH:11]=[C:12]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2].Cl.C[N:46](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>CCCCCC.C(OCC)(=O)C>[C:1]([Si:5]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:6][CH2:7][CH:8]([CH3:33])[O:9][C:10]1[CH:11]=[C:12]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:46])=[O:21])=[CH:15]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.6 %

Procedure:
A mixture of 7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (2.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.19 g), 1-hydroxybenzotriazole ammonium salt (943 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 9 hr. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (1.37 g, yield 69%) as an orange oil. MS 643 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)c1ccc(CC#N)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1ccnc1)c1ccc(CC#N)cc1

Procedure:
A mixture of N-{1-[4-(cyanomethyl)phenyl]-1-methylethyl}acrylamide (20.5 g), imidazole (6.11 g), benzyltrimethylammonium hydroxide (74 mg) and 1,4-dioxane (300 ml) gave N-{1-[4-(cyanomethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propionamide as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=O)[C:6]([NH2:8])=[O:7])[CH3:2].Cl.[NH2:16][OH:17]>>[CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=[N:16][OH:17])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: CCC(CC(=O)C(N)=O)C(C)[N+](=O)[O-]
Reactant: NO
Agent: Cl
Product: CCC(CC(=NO)C(N)=O)C(C)[N+](=O)[O-]
Yield: 69.8 %

Procedure:
4-Ethyl2-hydroxyimino-5-nitro-hexanamide (15 mg) was prepared in the substantially same manner as that of Example 24 from 4-ethyl-5-nitro-2-oxo-hexanamide (20 mg) and hydroxylamine hydrochloride (14 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[N:15]([C:18]1[N:23]=[C:22]([Cl:24])N=[C:20]([Cl:25])[N:19]=1)=[C:16]=[O:17].O1CCC[CH2:27]1>>[Cl:25][C:20]1[CH:27]=[C:22]([Cl:24])[N:23]=[C:18]([NH:15][C:16]([NH:14][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])=[O:17])[N:19]=1
Reactant: C1CCOC1
Reactant: NS(=O)(=O)c1cccc2cccnc12
Reactant: O=C=Nc1nc(Cl)nc(Cl)n1
Product: O=C(Nc1nc(Cl)cc(Cl)n1)NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
To a stirred mixture of 1.8 g of 8-quinoline-sulfonamide in 15 ml tetrahydrofuran is added 2.3 g of 2-isocyanato-4,6-dichloro-1,3,5-triazine. This mixture is then heated to reflux temperature for 21/2 hours, then cooled to room temperature, filtered and the resultant filtrate triturated with hexanes and filtered to give 1.8 g solid, m.p. 198°-200°.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]Cl.[C-:19]#[N:20].[Na+].CC(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(C)c(OCc2ccccc2CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Yield: 97.9 %

Procedure:
2-(2,5-Dimethylphenoxymethyl)benzyl chloride (Purity: 86.8%, 1.50 g, 5 mmol), 95% sodium cyanide (0.31 g, 6 mmol), triethylbenzylammonium chloride (0.06 g, 0.25 mmol), acetone (4 ml) and water (2 ml) were added. The mixture was heated under reflux for 5 hours. After completion of the reaction, water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 97.84).