Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]>[OH-].[Na+]>[CH2:4]([O:3][C:1]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
In a 2 L three-necked flask, L-alanine (54.0 g) is dissolved in 2N NaOH (305 mL) and cooled to 0° C. in an ice-bath. To this solution, carbobenzoxychloride (90 mL) and 2N NaOH (305 mL) are simultaneously added dropwise so that the reaction temperature does not exceed 5° C. After complete addition, the ice-bath is removed and the reaction mixture stirred for 2 hours at room temperature. Diethylether is added (100 mL) and the organic phase is separated. The aqueous phase is washed once more with Et2O (100 mL), and acidified to pH 1 with HCl (2N). Ethylacetate (150 mL) is added, and the organic phase is separated. The aqueous phase is extracted with AcOEt (3×150 mL), and the combined organic phases are washed with H2O (3×100 mL). After drying (MgSO4), the solvent is removed (20 Torr/30° C.) to leave a colorless oil, which crystallizes upon standing (110 g). Recrystallization (AcOEt/hexane) affords 100 mg (73%) of benzyloxycarbonyl-L-alanine, m.p. 85° C.; [α]23 =-14.3 (c=2 in AcOH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[NH:11]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:11]2[C@H:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C@@H:10]2[CH3:9])[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@@H]1CCC[C@H](C)N1
Product: C[C@@H]1CCC[C@H](C)N1c1cc(Cl)ncn1
Temperature: 90 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
0.5 g of 4,6-dichloropyrimidine and 0.76 g of cis-2,6-dimethylpiperidine were mixed and stirred for 10 hours at 90° C. The reaction mixture was subjected to silica gel column chromatography to obtain 0.21 g of 4-chloro-6-(cis-2,6-dimethylpiperidino)pyrimidine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2(/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])[CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2([CH:26]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH2:27][N+:28]([O-:30])=[O:29])[CH2:23][CH2:24][CH2:25]2)=[CH:20][CH:21]=1
Reactant: N#Cc1cccc(I)c1
Reactant: O=[N+]([O-])/C=C/C1(c2ccc(Cl)cc2)CCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(C(C[N+](=O)[O-])C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: -30 °C

Procedure:
3-Iodobenzonitrile (3.76 g, 16.41 mmol) dissolved in tetrahydrofuran (1.5 ml) was cooled to −30° C. A solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 8.84 ml, 17.67 mmol) was added dropwise at −30° C. over 25 min. The reaction mixture was cooled to −78° C. A solution of (E)-1-chloro-4(1-(2-nitrovinyl)cyclobutyl)benzene (3.0 g, 12.62 mmol) in tetrahydrofuran (0.5 ml) was added dropwise. Aqueous work-up yielded the desired product which was used without further purification for the next step. Yield: 3.3 g (8.71 mmol, 69%, purity: 90% by HPLC)
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:30][CH3:31])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C.CO>[CH2:30]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1)[CH3:31]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCC1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 13 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(diethylamino)ethyl]pyrrolidine in a yield of 13% of theory. Colourless crystals, m.p. 137°-138° C. (from ethyl acetate/methanol 98/2 v/v).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([CH3:21])([CH3:20])[CH2:18]O.N1C(C)=CC=CC=1C>ClCCl>[F:16][C:17]([CH3:21])([CH3:20])[CH2:18][O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:9])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(F)CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(F)COS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Add trifluoromethanesulphonic anhydride (4.3 mL, 26.0 mmol) to a solution of 2-fluoro-2-methylpropan-1-ol (2.0 g, 21.7 mmol) and 2,6-lutidine (3.0 mL, 26.0 mmol) in dichloromethane (25 mL) at −78° C. Warm slowly to room temperature and stir at room temperature for 1 hour. Add water to quench the reaction, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with dichloromethane), to give the desired compound as an oil (3.4 g, 70% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8]1)=[O:6].[CH:32](O)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:23]([O:25][CH:26]([CH3:32])[CH3:27])=[O:24])=[CH:8]1)=[O:6]
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21
Reactant: CC(C)O
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
Ethyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding isopropyl ester using CU and isopropanol, and then oxidized as described previously in Step D of Example 63 to give the title compound; 1H-NMR (DMSO-d6): δ 10.83 (1H, s), 7.76 (1H, d), 7.71 (1H, app t), 7.64 (1H, s), 7.52-7.61 (2H, m), 7.40 (1H, m), 7.08 (1H, app t), 6.98 (1H, app t), 5.05 (1H, sept), 1.52 (6H, s), 1.18 (6H, d); MS (ESI): 439 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1.C([N:19](CC)CC)C>ClCCl>[O:1]=[C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]c1=O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Reaction time: 2 h

Procedure:
A mixture of 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxylic acid (1.92 g) ethyl chloroformate (1.1 g) and triethylamine (2.0 ml) in 50 ml of dichloromethane is allowed to stir at 25°-30° C. for 2 hours. Ammonia gas is then bubbled into the mixture for 15 minutes. Water (50 ml) is added and the dichloromethane is separated and concentrated on the rotary evaporator. The residue is chromatographed on silica gel with 2% methanol and chloroform to give 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxamide.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:22]=[O:23].O>C1COCC1>[OH:23][CH2:22][C:12]1([C:14]([OH:16])=[O:15])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CO)c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
9-fluorene carboxylic acid (4.98 g, 23.7 mmol) and anhydrous THF (300 ml) were introduced into a flame-dried reaction vessel in which the atmosphere had been replaced by nitrogen, the reaction solution was cooled to −78° C., and n-butyl lithium (41.0 ml of 1.6M hexane solution, 71.0 mmol) was added. After stirring the reaction solution at −78° C. for 30 minutes, paraformaldehyde (2.30 g, 75.0 mmol) dissolved in anhydrous THF (100 ml) was added at −78° C., and stirred at room temperature for 13 hours. Distilled water was added, the solution was extracted with ether, and the pH of the aqueous layer was adjusted to 2 using 1N hydrochloric acid. It was then extracted again with chloroform, and the organic layer was dried by anhydrous magnesium sulfate. The low-boiling fraction was distilled under reduced pressure with the rotary evaporator, and 4.21 g of crude product was thus obtained. The methylene chloride-insoluble fraction of this crude product was collected, and the target compound (4.60 g, 19.3 mmol, 80.5%) was thus obtained. 1H-NMR (500 MHz, CDCl3) d: 7.78 (d, J=7.5, 2H), 7.67 (d, J=7.5, 2H), 7.46 (dd, J=7.0, 2H), 7.54 (dd, J=8.0, 2H), 4.02(s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[CH:5][N:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A solution of methyl 2-methoxypyridine-5-carboxylate (8.4 g, 50 mmol) in dixoane (70 mL) was treated with sodium borohydride (8.1 g, 244 mmol) at 0° C. The reaction mixture was warmed to 100° C. and heating continued overnight. After this time, the mixture was cooled, diluted with methanol, filtered through a fritted funnel with methanol washes, and the filtrate was concentrated. The residue was redissolved in water, 0.5 M sodium hydroxide was added dropwise, and the mixture extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (2.9 g, 35%) as a colorless oil. MW=139.15. 1H NMR (CD3OD; 300 MHz) δ 8.11-8.05 (m, 1H), 7.67 (dd, J1=10.9 Hz, J2=2.43 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 4.89 (s, 1H), 4.54 (s, 2H), 3.89 (s, 3H); APCI MS m/z 140 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnn(C(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cc(CBr)cn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
To a solution of 4-methylpyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) provided 4-bromomethylpyrazole-1-carboxylic acid tert-butyl ester as a light yellow oil (0.42 g, 30%): 1NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([O:8][C@H:9]2[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@@H:11]([S:12][CH3:13])[C@@H:10]2[NH:20][C:21](=[C:23]2[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]2=[O:32])[CH3:22])=[O:7])=[CH:4][CH:3]=1.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[Si:35]([O:19][CH2:18][C@H:15]1[O:14][C@@H:11]([S:12][CH3:13])[C@H:10]([NH:20][C:21](=[C:23]2[C:24](=[O:32])[CH2:25][C:26]([CH3:31])([CH3:30])[CH2:27][C:28]2=[O:29])[CH3:22])[C@@H:9]([O:8][C:6](=[O:7])[C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:16]1[OH:17])([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of methyl 3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-1-thio-β-D-glucopyranoside (3) (1.00 g, 1.95 mmol), t-butyldiphenylsilylchloride (536 mg, 1.95) and 4-dimethylaminopyridine (238 mg, 1.95 mmol), in 1,2-dichloroethane (30 mL), was stirred under reflux for 6 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (60 mL) and washed with diluted brine (3×50 mL, brine/water, 1:2), dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOAc 1:1 as the mobile phase to give a white solid, methyl 6-O(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β-D-glucopyranoside (4) (1.1 g, 75%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[C:20]([O:19][C:18]([NH:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][NH:10][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCCC1CN
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of tert-butyl (2-(aminomethyl)cyclopentyl)carbamate (300 mg) and ethyl 2-chloro-2-oxoacetate (191 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-((tert-butoxycarbonyl)amino)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9].[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH:33]=O)=[N:31][CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH2:33][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[N:31][CH:32]=1
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CC(=O)NCc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncc(Cl)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of N-{3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzyl}-acetamide in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave N-(4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-acetamide as a white foam. 1H NMR (CDCl3) δ 1.58 (m, 1H), 2.03 (s, 3H), 2.04 (m, 1H), 2.18 (m, 1H), 2.24 (s, 3H), 2.65 (m, 1H), 2.79 (m, 1H), 3.69 (dd, 2H, J=12.0, 3.0 Hz), 3.79 (d, 1H, J=12.0 Hz), 3.89 (t, 1H, J=9.0 Hz), 4.12 (d, 1H, J=12.0 Hz), 4.21 (m, 1H), 4.39 (d, 2H, J=6.0 Hz), 4.41 (m, 1H), 5.67 (br s, 1H), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.14 (d, 1H, J=6.0), 7.24-7.30 (m, 3H), 7.39 (s, 1H), 8.28 (s, 1H), 8.36 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.2, 20.8, 21.7, 23.3, 29.3, 43.4, 53.0, 54.0, 54.3, 57.7, 62.6, 65.9, 121.7, 127.1, 130.6, 131.1, 131.3, 134.6, 135.4, 136.1, 136.7, 137.6, 138.1, 142.4, 144.5, 146.6, 154.6, 156.7, 169.8. HPLC: 97%. ES-MS m/z 479 [M+H]+, 501 [M+Na]+. Anal. Calcd. for C27H31N4O2Cl.0.5 CH2Cl2: C, 62.69; H, 6.24; N, 10.63; Cl, 13.46. Found: C, 62.52; H, 6.18; N, 10.47; Cl, 13.59.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)=[CH:22]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[ClH:43]>C1COCC1.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[NH:11]1[CH2:12][CH2:13][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:21]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]5[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22]3)[CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3ccc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)c3)C2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.3 g, 5.6 mmol) in THF (17 mL) was added a 4 N solution of HCl in dioxane (17 mL). The mixture was stirred at room temperature for 2 hours and concentrated to afford {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used for the next reaction. Yield: 99%; LC-MS: [M+H]+=492.3.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[NH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH:16]([CH2:21][CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:14]1
Reactant: COC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A 4N hydrogen chloride in ethyl acetate (1.0 ml; 4.0 mmol) was added to a solution in ethyl acetate (0.5 ml) of methyl 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl]acetate (210 mg; 0.45 mmol) synthesized by the above process, and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The concentrated residue was suspended in diethyl ether and collected by filtration to obtain 116 mg (yield: 76%) of the title compound as a colorless crystalline powder (melting point: 269-271° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:35]([CH3:34])(=[O:37])=[O:36])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCNS(C)(=O)=O
Yield: 20.6 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 74 mg methanesulfonylchloride to give 24 mg 4-tert.-butyl-N-{6-[2-(methanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.11 min, [M−1]−=549.45.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH3:15])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-butoxycarbonyl)-4-piperidinone (5.00 g) and p-phenetidine (3.28 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:21]([C:18]1([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]1)=[O:22])[CH2:7][CH2:6][CH2:5]2
Reactant: NC1CCCc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)NC2CCCc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-6-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light brown oil. MS: 453.2 (MH+).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 73.9 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and isopropanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 10.8 g of p-cyanobenzamide (yield 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Yield: 55.3 %

Procedure:
To a solution of 838 mg of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid in 5 ml of dimethylformamide was added 120 mg of sodium hydride (60% oil) while stirring under ice-cooling. To the mixture was then added 648 mg of 4-nitrobenzyl bromide, followed by stirring at room temperature for 2.5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and then dried (MgSO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography, eluting with hexane ethyl acetate (1:1). Fractions containing the end product were combined and concentrated under reduced pressure to give 687 mg of 4-nitrobenzyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate as colorless crystals, m.p.127°-127.5° C. IRνmaxKBr cm-1 : 3310, 1780, 1759, 1728, 1520, 1345, 1185, 1042