Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[C:17]2[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-nitrobenzyl bromide (1.85 g, 8.56 mmol), 1H-indole-2-carboxylic acid ethyl ester (1.62 g, 8.56 mmol) and potassium carbonate (4.17 g, 30 mmol) in 100 mL of acetone was refluxed for 1 day. After cooling to room temperature the reaction was quenched by addition of water and then partitioned between water and methylene chloride. The organic phase was dried over MgSO4, and concentrated to yield ethyl 1-(4-nitrobenzyl)-1H-indole-2-carboxylate as an off-white solid (2.0 g, 72%): 1H NMR (DMSO-d6) δ 1.27 (t, J=7.1 Hz, 3H), 4.26(q, J=7.1 Hz, 3H), 5.99(s, 2H), 7.18(t, J=7.0 Hz, 1H), 7.22 (d, J=9.0-Hz, 2H), 7.34 (t, J=7.0 Hz, 1H), 7.43 (s, 1H), 7.58 (d, J=13.8 Hz, 1H), 7.76 (d, J=13.8 Hz, 1H), 8.15 (d, J=9.0 Hz, 2H); MS (ESI) m/z 325 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].CN(C)C=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: CS(=O)[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (3.1 g) and sodium methanesulfinate (1.5 g) were added to N,N-dimethylformamide (50 ml), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (2.8 g, melting point: 164° to 166° C., yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:20]1([C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[C:8]2=[O:12])[CH2:22][CH2:21]1
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: Ic1cnccc1C1CC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccc(F)cc2CCN1c1cnccc1C1CC1
Yield: 81.8 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 500 mg, 3.02938 mmol) was reacted with 3-iodo-4-cyclopropyl-pyridine 816 mg, 3.3323 mmol), 1,4-dioxane (10 mL), copper iodide (57.3 mg, 0.3 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.30 mmol) and potassium phosphate (1.92 g, 9.0 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 700 mg of the product (81.9% yield).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]#[C:36][CH2:35][O:34][CH3:33])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: C#CCOC
Product: CCCCCCc1cccc(-c2nc(C#CCOC)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 12, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 3-methoxy-propyne to give the title compound as yellow oil. MS: 491.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CCC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.0 g, 10.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.03 g, 1.07 mmol) and CuI (203 mg, 1.07 mmol) in triethylamine (30 mL), was added 4-methylpent-1-yne (2.23 g, 27.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound (2.2 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.90-3.86 (m, 1H), 3.77-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.33 (d, 2H), 2.05-1.94 (m, 2H), 1.86 (m, 1H), 1.76-1.71 (m, 1H), 1.60-1.54 (m, 2H), 1.02 (d, 6H); LCMS: 283 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:29]([C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[N:4][C:3]([C:2]([F:15])([F:16])[F:1])=[N:5]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)cc2)cc1
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (0.92 g, 3.95 mmol) in 10 mL of dioxane, were added pyridine (0.319 mL, 3.95 mmol) and a solution of 4-methoxybenzoyl chloride (673 mg, 3.95 mmol) in 3 mL of dioxane. The mixture was refluxed with stirring for 12 hours. The solvent was removed under reduced pressure. 50 mL of dichloromethane and 20 mL of 0.1 N hydrochloric acid were added to the residue and the organic layer was separated. The aqueous layer was extracted with 50 mL of dichloromethane. A combined organic layer was washed with 0.1 N hydrochloric acid and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (toluene-ethyl acetate 9:1) and then recrystallized with diisopropyl ether-hexane to give pale brown needle of 1,5-bis(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (0.67 g, 48.6% yield).
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH3:38][CH:39]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:41]=O>>[CH3:38][CH:39]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:41]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)[CH3:13]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(CC=O)CC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCC(C)CC(C)(C)C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.80 g, 5.63 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.5 mL, 5.63 mmol, 1.0 equiv.) and 3,5,5-trimethylhexanal (1.20 g, 8.44 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 0.73 g (46%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:30][CH2:31][C:32]3[N:33]=[C:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[S:35][CH:36]=3)=[C:8]([C:28]#[N:29])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=2)[N:4]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:3]=1[C:49]([O:51][CH3:52])=[O:50].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:30][CH2:31][C:32]3[N:33]=[C:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[S:35][CH:36]=3)=[C:8]([C:28]#[N:29])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[N:4]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:3]=1[C:49]([O:51][CH3:52])=[O:50]
Reactant: COC(=O)Cn1c(C(=O)OC)c(N)c2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C(=O)OC)c(N)c2c(-c3ccc(OCCO)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19 mg (0.024 mmol) of the compound from Example 33A were initially charged in 1 ml of THF, and 0.122 ml (0.122 mmol) of a 1N solution of tetrabutylammonium fluoride in THF were added. The reaction mixture was stirred at RT for 2 h and then diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated, and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile). This gave 15 mg of the product, which were purified by preparative thin-layer chromatography (dichloromethane/methanol=20/1).
Reaction SMILES: COC(=O)[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:14])N)[CH2:7][CH:8]([CH3:10])[CH3:9].[OH-:16].[Na+]>Cl>[CH3:9][CH:8]([CH2:7][C@H:6]([CH2:5][NH2:4])[CH2:11][C:12]([OH:14])=[O:16])[CH3:10]
Reactant: [OH-]
Reactant: COC(=O)NC[C@H](CC(N)=O)CC(C)C
Agent: Cl
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A 0.2 l reactor was loaded with 6N hydrochloric acid (100 ml) containing compound 27 (12 g, 0.055 mole), and was heated to 100°-110° C. for 12-24 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 37 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 21.5% yield. Purity: 99.9% area by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:16])[CH3:15])=[O:5])[CH3:2].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.[NH2-].[Li+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:15])[CH3:16])=[O:5])[CH2:2][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CN1C(C)(C)CCCC1(C)C
Reactant: CCCCCCCCO
Agent: [Li+]
Agent: [NH2-]
Solvent: CCO
Product: CCCCCCCCOC(=O)CN1C(C)(C)CCCC1(C)C

Procedure:
A mixture of 45.4 parts of 1-ethoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine, 36.5 parts of 1-octanol and 0.5 part of lithium amide was heated at 110°-115°C for 48 hours, the ethyl alcohol formed during the reaction being removed by distillation. Fractional distillation of the reaction mixture gave 1-octoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine having a boiling point of 120°C/0.005 mm Hg.
Reaction SMILES: [N:1]([OH:4])=[N+]=[N-].[C:5]([O:9][C:10](OC([O-])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.[OH-].[OH-].[Pd+2]>[C:10]([NH:1][OH:4])([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: [N-]=[N+]=NO
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NO
Yield: 39.2 %

Procedure:
A solution of 15a (9.85 g, 69.8 mmol) and t-butyldicarbonate (18.3 g, 83.8 mmol) in 50 mL of MeOH was placed in a Parr bottle with 20% Pd(OH)2 (2.0 g) and hydrogenated under 50 psi of H2 overnight. The reaction mixture was filtered through a sintered glass funnel and concentrated on a rotary evaporator. The residue was triturated with ether and the solid was collected and dried to give 3.64 g (24% yield) of Boc-amino alcohol 15b.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc2nc(CO)[nH]c2c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(CO[Si](C)(C)C(C)(C)C)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxybenzimidazole (354 mg) was dissolved in dry DMF (2 mL), tert-butyldimethyl-chlorosilane (270 mg) and imidazole (45 mg) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=12:1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[BH4-].[Na+].[H][H]>CO.C(OCC)(=O)C.[Pd]>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:11])[CH3:10]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)O)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-methyl-3-nitroacetophenone (25 g, 139 mmol) in methanol (200 mL) is added sodium borohydride (6.2 g, 163 mmol) over 15 minutes. The mixture is stirred at room temperature for 1 hour, then is quenched with water. The mixture is rotary evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and rotary evaporated to afford a light brown viscous oil. The oil is diluted with ethyl acetate (200 mL), 5% palladium-on-carbon (5 g) is added and the mixture is treated with hydrogen at 40 psi for 18 hours. The mixture is then filtered on Celite and the filtrate is rotary evaporated to afford 3-(1-hydroxyethyl)-6-methylaniline as a light yellow, pasty solid.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[C@H:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CN[C@@H]2C[C@@H](C(c3ccccc3)c3ccccc3)OC[C@@H]2O)cc1

Procedure:
(1R, 4S, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.021 g, 0.079 mmol) was reacted with p-methoxybenzylamine (0.22 g, 1.58 mmol) (Procedure E) to yield (3R, 4R, 6S)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol, (−)-29 g 0.02 g (63%, [α]D=(−)63.75, c=1, MeOH).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([OH:20])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:10]=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:5][CH2:6][CH2:7][CH:8]([C:9]1[CH:10]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[OH:20]
Reactant: O=C(NCCC(O)c1cccc(C#CCCO)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NCCC(O)c1cccc(C#CCCO)c1

Procedure:
A mixture of, 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-hydroxybut-1-ynyl)phenyl)propyl)acetamide, potassium carbonate (1.6 g, 11.5 mmol) and water (3 mL) in MeOH (15 mL) was heated under reflux for 4 h. Reaction mass was concentrated to dryness under reduced pressure to give 4-(3-(3-amino-1-hydroxypropyl)phenyl)but-3-yn-1-ol as pale yellow oil after purification by flash chromatography with 15% MeOH—NH3 (9.5:0.5)-DCM. Yield (0.38 g, 60%). This compound was utilized as such for the next transformation.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:11]=[O:12]>ClCCl>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(CO)cc1

Procedure:
A solution of 3.75 g 4-aminobenzylalcohol and 3.3 ml isocyanato-benzene in 120 ml dichloromethane was stirred at 23° C. for 2 hours. Afterwards, the reaction mixture was filtered. The crystalline product was washed with diethylether. 6.82 g product was obtained which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55]>>[CH3:1][N:2]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Product: CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 364.5 %

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 102 mg 4-(2-chloroacetyl)-morpholine were reacted in the same manner as in Example 746, to give 0.43 g 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methyl-(2-morpholin-4-yl-2-oxoethyl)amide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 63 mg of the title compound as orange crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][CH:29](O)[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:39])CC)C>ClCCl.O>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][CH:29]([F:39])[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(F)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-hydroxycyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide (124 mg) in dichloromethane (4 ml) was added diethylaminosulfur trifluoride (100 μl) under ice-cooling, followed by stirring at room temperature for 15 minutes. The reaction mixture was diluted with dichloromethane, and water was added thereto. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=7:3-1:0) to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-fluorocyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide (78 mg) as a colorless amorphous substance.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:27]2[N:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)([C:6]([O:8]C)=[O:7])=[O:5]>O.O1CCOCC1>[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:27]2[N:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([OH:31])=[O:30])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)([C:6]([OH:8])=[O:7])=[O:5]
Reactant: CCCN(Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1)c1ncccc1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCN(Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)c1ncccc1C(=O)O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A solution of 350 mg of lithium hydroxide monohydrate dissolved in 10 ml of water was added to a solution of 0.70 g of ethyl 2-{N-[(2'-methoxalylbiphenyl-4-yl)methyl]-N-propylamino}nicotinate [prepared as described in step (a) above] dissolved in 5 ml of dioxane, and the resulting mixture was stirred at 70° C. for 4 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and 8.33 ml of 1N aqueous hydrochloric acid were added to the residual aqueous solution. The crystals thus precipitated were collected by filtration, to give 0.57 g of the title compound, melting at 179°-180° C.