Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]([OH:38])[CH3:37])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36](=[O:38])[CH3:37])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a −78° C. solution of oxalyl dichloride (85 mg, 0.665 mmol) in CH2Cl2 (10 mL) was added DMSO (104 mg, 1.33 mmol). After stirred at −78° C. for 10 min, a solution of 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38 (180 mg, 0.443 mmol) in CH2Cl2 was added into the mixture by dropwise. The resultant mixture was stirred at −78° C. for another 30 min, then was added triethyl amine (224 mg, 2.22 mmol). The reaction mixture was warmed up to room temperature and stirred for 2 h. The resultant mixture was quenched with saturated ammonium chloride solution and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (CH2Cl2: MeOH) to provide 45 mg of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 in 25% yield. LCMS showed m/z: 409 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].B([O-])([O-])[O-:27].ClC1C=CC=C(C(OO)=O)C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]1[O:27][CH:8]1[C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Reactant: [O-]B([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC1=C2C3OC3[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To a stirred solution of 4-acetamino-androsta-1,4,6-triene-3,17-dione (3.384 g, 10 mmol) in CH2Cl2 (100 ml) was added borate buffer of pH 8 (50 ml) and then gradually 50% m-chloroperbenzoic acid (6.9 g, 20 mmol) under cooling. The mixture was stirred for 6 h at room temperature until total conversion (TLC monitoring). The mixture was then stirred with 20% sodium metabisulfite solution for 1 h at room temperature. Finally the organic phase was separated, dried and evaporated under vacuum. The residue was submitted to flash chromatography on silica gel with EtOAc thus giving pure title compound in 50% yield (1.772 g).
Reaction SMILES: [CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C(F)(F)F)cc3)C3CCCC3)c2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(CC2(C(=O)O)CC2)c1)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.83 g (9.63 mmol) of (+/−)-tert-butyl 1-[3-({cyclopentyl[4-(trifluoromethyl)phenyl]acetyl}-amino)benzyl]cyclopropanecarboxylate were dissolved in 25 ml of dichloromethane and, after addition of a drop of water, 7.5 ml of TFA were added at RT. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→2:1). This gave 3.89 g (90.8% of theory) of the target compound.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O>[Cl:6][C:7]1[C:8]([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:36](=[O:37])[C:35]3[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:34]=3[Cl:33])=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1
Reactant: Nc1ccc(OCc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OCc2ncc(C(F)(F)F)cc2Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 300 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridylmethyloxy)aniline and 120 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 220 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added thereto, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 380 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridylmethyloxy)phenyl)-2-chloro-5-nitrobenzamide (Compound No. 135) having a melting point of from 193 to 195° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[N:18]=[CH:19][N:20]3[C:26]4[CH:27]=[CH:28][S:29][C:25]=4[C:24](=[O:30])[N:23]4[CH2:31][CH2:32][C@H:22]4[C:21]=23)[N:13]=1>CN(C)C=O>[CH2:1]([N:5]([CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[N:18]=[CH:19][N:20]3[C:26]4[CH:27]=[CH:28][S:29][C:25]=4[C:24](=[O:30])[N:23]4[CH2:31][CH2:32][C@H:22]4[C:21]=23)[N:13]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: O=C1c2sccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
0.6 ml (3.45 mmol) of dibutylamine was added to a suspension of 400 mg (1.15 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e]-[1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried with magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, methyl acetate/methanol 10:1). There were obtained 425 mg (84%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.31 (silica gel, methyl acetate/methanol 10:1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCC3CCCCC3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCC4CCCCC4)CC32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a solution of 3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine (Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over 5 minutes ethanesulfonylchloride (25 μl, 34 mg, 0.26 mmol). The mixture was allowed to warm to room temperature and was stirred for 1.5 h. Further ethanesulfonylchlonide (25 μl, 34 mg, 0.26 mmol) was added and the mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (21 mg, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Cl)cc(Cl)c3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Cl)cc(Cl)c2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5,7-dichlorobenzoxazole (250 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38]O)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[F-:58].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][F:58])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [F-]
Reactant: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@]1(CF)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of the compound from Example 138, Step A (63 mg, 0.1 mmol) in anhydrous dichloromethane (5 mL) under argon, were added 4-dimethylaminopyridine (DMAP) (2 mg, 0.015 mmol) and triethylamine (62 μL, 0.45 mmol). The solution was cooled in an ice bath and p-toluenesulfonyl chloride (30 mg, 0.15 mmol) was added. The reaction was stirred at room temperature overnight, washed with NaHCO3 (2×10 mL), water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to a pink solid in vacuo. The solid was dissolved in anhydrous THF (5 mL) and cooled in an icebath. Tetrabutylammonium fluoride (1M solution in THF, 1 mL, 1 mmol) was added and the mixture stirred at room temperature for 4 h. The solvent was removed in vacuo, the residue taken up in dichloromethane, and washed with NaHCO3 (2×10 mL), water (10 mL) and brine (10 mL). The dichloromethane layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to afford the title compound (20 mg) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.54 g, 1.24 mmol) prepared in Example 14c, triethylsilane (1.98 mL, 12.4 mmol), trifluoroacetic acid (0.96 mL, 12.4 mmol) and dichloromethane (20 mL), to yield the title compound (0.54 g, 99%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9](C(OCC)=O)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C[Si](I)(C)C.CO>ClCCCl>[CH:7]12[NH:9][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2](=[O:1])[CH2:8]2
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCCl
Product: O=C1CC2CCC(C1)N2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a stirred solution of ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.53 mmol) in 1,2-dichloroethane (10 mL) was added 369 μL (2.60 mmol) of trimethylsilyl iodide (TMSI) under a nitrogen atmosphere. The reaction mixture was heated at 60° C. for 4 h and cooled to room temperature. Methanol (10 mL) was added and the mixture was stirred for 30 min at room temperature (rt). The solvent was removed on vacuo and the residue was partitioned between CH2Cl2 and 1M aqueous NaOH solution (5 mL). The mixture was extracted with CH2Cl2 (3×10 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, methylene chloride/EtOH/NEt3 85/10/5) to afford a pale yellow oil (140 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 95.1 %

Procedure:
Using the method of Example 3, Step A, 3-methoxybenzenethiol (884 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(3-methoxyphenylthio)pyridine (1.51 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.12 (d, 1H), 7.39 (t, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 6.93 (s, 1H), 6.88 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)C(=O)OC(C)(C)C.[ClH:17].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:17].[CH3:1][NH:2][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CN(CC1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCC1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of tert-butyl N-methyl-N-(4-tetrahydropyranylmethyl)carbamate (600 mg, 2.6 mmol) in 4.0 mL of ethyl acetate was added 4 M HCl-ethyl acetate (4 mL). After being stirred at room temperature for 1.5 h, the reaction mixture was concentrated in vacuo, and the residue was rinsed with hexane to obtain the title compound (356 mg, 82%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2-ylamine (28.1 g, 148 mmoL) described in Manufacturing Example 1-2-2 in tetrahydrofuran (300 mL) was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred for 15 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 4 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g, 93.7%).
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].[Cl-].[Na+]>CO>[NH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)CC1

Procedure:
A solution of 7.35 g (24.8 mM) of tert-butyl 4-trifluoroacetamido-1-piperidinecarboxylate and 5.71 g (41.3 mM) of potassium carbonate in 50 ml of methanol was stirred at 60° C. for 8 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and the mixture was saturated with sodium chloride and extracted with 10 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to recover the title compound as light-yellow liquid. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:13](OC=C)(=O)[CH3:14]>>[CH3:1][O:2][C:3]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13]1)=[O:4]
Reactant: C=COC(C)=O
Reactant: COC(=O)N(O)c1ccccc1
Product: COC(=O)n1ccc2ccccc21

Procedure:
A solution of 12.0 g of N-methoxycarbonyl-N-hydroxyaniline in 120 ml of vinyl acetate is stirred with 200 mg of Li2PdCl4 for 7 hours at 60° C.; it is then washed with brine, dried over magnesium sulfate and concentrated by evaporation. Chromatography through silica gel (toluene/ethyl acetate 4:1) yields 7.3 g of N-methoxycarbonylindole as colourless oil; IR spectrum (CHCl3): 1730 (CO): NMR spectrum (60 MHz, CDCl3): 1.47 (t, J=7, CH3); 4.47 (q, J=7, CH2); 6.53 (d, J=3.5, CH); 7.1-7.7 (m, 4H); 8.13 (m, 1H) ppm. 1.4 g of an O-acetylated educt in the form of yellow oil are obtained as a second fraction of chromatography.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn](CC)CC.CN([C@@H](C1C=CC=CC=1)C1C2C(=CC=CC=2)C=CC=1O)[C@H](C1C=CC=CC=1)C.[Cl:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=[O:47]>C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C@@H:46]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:47]
Reactant: O=Cc1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: CC[Zn]CC
Agent: C[C@@H](c1ccccc1)N(C)[C@@H](c1ccccc1)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: O[C@H](c1ccccc1)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.3 %

Procedure:
PhB(OH)2 (122 mg, 1.0 mmol) and ZnEt2 (334 μL, 3.25 mmol) in toluene (1 mL) is charged to a 10 mL flask under a nitrogin atmosphere. This mixture is heated to 60° C. and stirred for 10 h with a magnetic stirrer. Then the mixture is cooled to 0° C. and 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-phenyl-methyl}-naphthalen-2-ol (prepared as described by Chan et al., J. Org. Chemistry 2003, 68, 1589-1590; 14.7 mg, 0.04 mmol) in toluene (0.5 mL) and DiMPEG (100 mg, 0.05 mmol) in toluene (0.5 mL) is added. After stirring for additional 15 min, the solution is cooled to −15° C. and 2-chlorobenzaldehyde (70.0 mg, 0.5 mmol) in toluene (1 mL) is added. After stirring 15 h at −15° C., the reaction is quenched with 1 N HCl (2 mL) and the mixture is extracted with EtOAc (5 mL), dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The purification of the residue by flash chromatography (EtOAc/hexane, 1:10) gives (R)-(2-chlorophenyl)-phenylmethanol in about 94.3% ee and about 91.3% yield (the ee value is determined by HPLC using a Chiralcel OD-H column).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].C(O)C>C1C=CC=CC=1.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(C(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Agent: O=[Pt]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 1-(4-acetylphenyl) propan-2-one (10.9 g) and 2-hydroxy-2-phenylethanamine (8.5 g) in benzene (200 ml) was refluxed for 4 hours under Dean and Stark conditions. The solvent was replaced with ethanol (200 ml), platinum oxide (200 mg) was added and the mixture was hydrogenated at ambient temperature and pressure for 6 hours. The solution was filtered and the filtrate was evaporated and chromatographed on silica gel 60 (400 g) eluting with 1% methanol/chloroform. The first fraction (9.0 g) was crystallised from ether to give the title compound as a 9:91 mixture of diasteroisomers m.p. 120°-135°.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([NH2:36])=N)=[O:30].[OH2:37]>C(#N)C.[OH-].[Na+]>[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:37])=[O:30]
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3C)cn2C)cc1C(=O)NCCC(=N)N
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3C)cn2C)cc1C(=O)NCCC(N)=O
Temperature: 60 °C

Procedure:
To a solution of 200 mg of 3-(1-methyl-4 (1-methyl-4-(1-methyl-3-nitropyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidine hydrochloride (prepared as described in WO 96/05196) in 10 ml of acetonitrile and 10 ml of water, 2 ml of NaOH 1N were added. The solution was heated at 60° C. for 4 hours then the solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (methylene chloride/methanol: 10/1) affording 175 mg of 3-(1-methyl-4(1-methyl-4-(1-methyl-3-nitropyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[C:3]#[CH:4]>[N+]([O-])([O-])=O.[Ag+].C(OCCCC)(=O)C>[CH3:5][C:2]1([CH3:1])[C:3](=[CH2:4])[O:14][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6]1
Reactant: C#CC(C)(C)NC(=O)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Product: C=C1OC(c2ccccc2)=NC1(C)C
Temperature: 95 °C
Yield: 93.4 %

Procedure:
A round bottom flask was charged with N-(3-methylbutyn-3-yl)benzamide (5.0 g, 26.7 mmol), silver nitrate (9.1 mg, 0.2 mol %), and n-butyl acetate (20 mL). The resulting mixture was heated to 95° C. for 0.5 h, then cooled to room temperature. The reaction was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried in a vacuum oven to give 4,4-dimethyl-5-methylene-2-phenyloxazoline (4.67 g 93% yield) as a pale yellow oil (bp 70-75° C., 0.6 mm Hg).