Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:17][NH2:18]>C(O)C>[C:1]([NH:17][NH2:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NN
Reactant: CCCCCCCCCCCCC(=O)OC
Solvent: CCO
Product: CCCCCCCCCCCCC(=O)NN

Procedure:
A solution of tridecanoic acid, methyl ester (24.63 g, 0.1078 mol), and anhydrous hydrazine (3.40 mL, 0.108 mol) in absolute ethanol (150 mL) was stirred at room temperature for 24 hours, then refluxed 2 days. The solution was allowed to cool, and the solid that crystallized was filtered off, washed, and dried in vacuo; yield 18.6 g (75%); mp 101°-104° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH:26][CH3:27])[C:17]1=[C:16]2[CH3:28].O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([N:26]([CH3:27])[CH:1]=[O:3])[C:17]1=[C:16]2[CH3:28]
Reactant: CNC1CCCn2c1c(C)c1cc(OC)ccc12
Reactant: O=CO
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)c(C)c1n2CCCC1N(C)C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of formic acid (3.05 g, 66.3 mmol) and acetic anhydride (5.4 g, 55 mmol) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-2-methoxy-N,10-dimethylpyrido[1,2-a]indol-9-amine (2 g, 8.2 mmol, described in Example 27) in dry tetrahydrofuran (20 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. overnight, poured into water (40 mL), and extracted with ether (3×40 mL). The combined extracts were washed successively with 5% hydrochloric acid (50 mL), 5% aqueous sodium bicarbonate (60 mL), and water (80 mL). The ethereal solution was dried over MgSO4, filtered, and evaporated to afford 2.1 g (95%) of the title formamide as a yellow oil.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[NH:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([Cl:31])=[CH:26][CH:25]=2)=[O:21])=O)(C)(C)C.Cl.[CH3:33][N:34]1[CH2:39][CH2:38][C:37]2[N:40]=[C:41](C([O-])=O)[S:42][C:36]=2[CH2:35]1.[Li+]>C(O)C>[Cl:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:20]([NH:19][C@H:10]1[CH2:11][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14][C@H:9]1[NH:8][C:6]([C:41]1[S:42][C:36]3[CH2:35][N:34]([CH3:33])[CH2:39][CH2:38][C:37]=3[N:40]=1)=[O:5])=[O:21])=[CH:30]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4S*)-N1-tert-Butoxycarbonyl-N2-[(5-chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:34][C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry THF (30 mL) were added triphenylphosphine (2.0 g, 7.5 mmol) and 5-mercapto-1-methyl-1H-tetrazole (0.70 g, 6.0 mmol). To the mixture was added diisopropyl azodicarboxylate (1.2 mL, 6.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), which was washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively. The solvent was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g, diethyl ether-hexane 1:1) to give the titled compound as a colorless oily substance. (1.11 g, 74%).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[S:14]1[C:18]2=[CH:19][CH:20]=[CH:21][C:22]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[C:17]2[N:16]=[CH:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:13][CH:2]([F:1])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[S:14][CH:15]=[N:16][C:17]=34)(=[O:25])=[O:24])=[CH:35][CH:34]=2)=[O:32])[CH2:9][CH2:10]1
Reactant: CC(CC1(O)CCNCC1)C(F)F
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added 4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (110 mg 0.57 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (190 mg, 0.57 mmol), DIPEA (367 mg, 2.8 mmol), HATU (261 mg, 0.69 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 5.90-5.61 (m, 1H), 4.36 (s, 1H), 3.57-3.42 (m, 1H), 3.21 (s, 2H), 2.24 (d, J=7.6 Hz, 1H), 2.05 (s, 1H), 1.86-1.77 (m, 2H), 1.36 (dd, J=14.8, 6.3 Hz, 4H), 1.10 (d, J=7.0 Hz, 3H). LC-MS: m/z 510.5 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:27]=[N:28]O.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I.C(N(CC)CC)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1[C:27]#[N:28])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2Br)c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2C#N)c(NC(C)=O)c1
Temperature: 90 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2', 4'-dibromo-6'-methylphenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), triethylamine (1.5 parts), and nitrobenzene (100 parts) was heated to 90° C. for 11/2 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 3 gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-methylphenylazo)-N,N-diethylaniline, infra red spectrum identical with that of authentic material.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH:13]([CH3:21])[C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[C:5]([CH:13]([CH3:21])[C:14]([NH:16][CH2:17][C:18]([Cl:3])=[O:19])=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)c1ccccc1)C(=S)NCC(=O)O
Solvent: c1ccccc1
Product: CC(C(=O)c1ccccc1)C(=S)NCC(=O)Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (10 g) is added to N-(α-benzoylthiopropionyl)-glycine (5.4 g) suspended in benzene (25 ml), with stirring. The reaction mixture is maintained at room temperature until all the solid has dissolved. The resulting yellow solution is evaporated in vacuo, taken up into benzene and again evaporated until all the remaining thionyl chloride has been removed. The residual oil is dissolved in 15 ml anhydrous chloroform.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Mg]Br.C(OCC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])([CH3:35])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)=O)cc3)ccc2C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)(C)O)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[(S)-6-(4-Acetyl-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-carbamic acid tert-butyl ester (400 mg, 0.71 mmol) was dissolved in tetrahydrofuran (15 ml) at 0° C. A 3 molar solution of methylmagnesium bromide in diethyl ether (2.82 ml, 7.12 mmol) was added slowly and the reaction mixture was stirred for 3 hours at room temperature. Another portion of a 3 molar solution of methylmagnesium bromide in diethyl ether (0.5 ml, 1.26 mmol) was added. Since no further conversion was observed, the reaction mixture was evaporated to dryness. Water (20 ml) was added to the residue and the aqueous phase was extracted with diethyl ether (50 ml) twice. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude product was purified by MPLC chromatography using dichloromethane/methanol (100:0-70:30) as eluent, yielding the product (300 mg, 47% purity, 39%).
Reaction SMILES: O[C:2]1[C:3](=[O:37])[N:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[CH:28][CH:27]=2)[CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[C:6]=1[C:7]([C:9]1([CH3:17])[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)=O.O.[NH2:39][NH2:40].Cl.CO>C(O)(=O)C>[OH:11][CH2:10][C:9]([C:7]1[C:6]2[CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[N:4]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)=[CH:30][CH:31]=3)[C:3](=[O:37])[C:2]=2[NH:39][N:40]=1)([CH2:14][OH:13])[CH3:17]
Reactant: NN
Reactant: COc1ccccc1C1C(C(=O)C2(C)COC(C)(C)OC2)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccccc1C1c2c(C(C)(CO)CO)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 73.6 %

Procedure:
A mixture of 3-hydroxy-4-(2,2,5-trimethyl-1,3-dioxane5-yl)carbonyl-5-(2-methoxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.15 g, 0.3 mmol), hydrazine hydrate (0.07 mL, 1.4 mmol) and acetic acid (1 mL) was heated at reflux overnight. After the reaction mixture was concentrated in vacuo, to the resulting residue was added 2 mol/L hydrochloric acid/methanol solution (2.89 mL, 5.8 mmol) and the resulting mixture was heated at reflux for 6 hours. After the reaction mixture was concentrated in vacuo, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform). The resulting compound was triturated with ethyl acetate and n-hexane to give 3-(1,1-dihydroxymethylethyl) 4-(2-methoxyphenyl)-5-(4-thiophene-3-ylphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.105 g, yield: 77%) as colorless solid.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].[I-].[K+].CN([CH:21]=[O:22])C>CCOC(C)=O.O>[CH2:6]([O:22][C:21]1[CH:8]=[CH:9][C:2]([CH:10]=[O:13])=[CH:3][CH:4]=1)[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred mixture of 4-hydroxybenzaldehyde (28.2 g, 231 mmol), potassium carbonate (47.9 g, 35 mmol), potassium iodide and DMF(280 mL) benzyl bromide was added slowly at 0° C. The mixture was stirred at rt overnight. The mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 1N aq HCl and dried. The solution was concentrated to give 4-benzyloxybenzaldehyde (46.5 g, 95%). 1H NMR: (CDCl3, 400 MHZ) δ=5.15 (s, 2H), 7.06 (m, 2H), 7.42(m, 5H), 7.84(m, 2H), 9.89(s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])=[O:4].[I-].[Na+].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)(=[O:9])=[O:10])[C:28](=[O:29])[N:27]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: COC(=O)C1CN1S(=O)(=O)c1cccc(OC)c1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester (0.098 g) in tetrahydrofuran (3 ml) were added sodium iodide (0.054 g) and phenylisocyanate (0.043 g). The mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, 1% aqueous Na2S2O3 solution and again with water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 9:1=>1:1) to give (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid methyl ester (0.060 g) as a colorless solid. MS: 391.1 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCC(CO)C2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCN2CCC(COS(=O)(=O)c3ccc(C)cc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 g (0.005 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-hydroxymethyl-pyrrolidine are dissolved in 10 ml of pyridine, 1.05 g (0 0055 mol) of p-toluenesulphonic acid chloride are added and the mixture is stirred for 6 hours at ambient temperature. The excess pyridine is then distilled off in vacuo, the residue obtained is dissolved in methylene chloride and the organic phase is extracted with ice water. After the organic phase has been dried over magnesium sulphate it is concentrated by evaporation in vacuo. Yield: 1.4 g (66.7% of theory), Rf value: 0.40 (aluminium oxide, neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[CH3:15][C:16]1[CH:17]=[C:18]([O:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1>C(Cl)(Cl)Cl>[CH3:15][C:16]1[CH:17]=[C:18]([O:22][C:23]([N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[NH:5][C:3]([O:2][CH3:1])=[O:4])=[NH:24])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: Cc1cccc(OC#N)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1C(=N)Oc1cccc(C)c1
Temperature: 20 °C

Procedure:
To a suspension of 9.56 g. (0.05 mole) 2-(methoxycarbonylamino)-benzimidazole in 300 ml chloroform a solution of 7.19 g (0.054 mole) 3-methylphenyl cyanate in 20 ml chloroform is added in drops while stirring at 20°C. The reaction mixture is stirred for 5 hours at room temperature and then filtered. The clear filtrate is concentrated under vacuum until dry. The colorless crystalline residue is treated with ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21].[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>C(Cl)(Cl)Cl>[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH:29]([NH:32][C:20]([NH:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[S:21])[CH2:28][CH2:27]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C1(c2ccccc2)CCC(NC(=S)NCCc2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
2-(1H-Indol-3-yl)-ethylamine (tryptamine; 320 mg, 2 mmole) was dissolved in dry chloroform (10 ml) and combined with triethylamine (555 μl, 4 mmole). Thiophosgene (153 μl, 2 mmole) was added to this mixture. After a reaction time of 16 h, N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was added and stirring continued for a further 16 h at RT. Working up was performed by extracting the batch with saturated NaHCO3 solution (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers and could be purified by column chromatography [silica gel 60 (50 g); methanol (500 ml)]. The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-[2-(1H-indol-3-yl)-ethyl]-thiourea was obtained as a colorless foam in a yield of 185 mg (22%). The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-[2-(1H-indol-3-yl)-ethyl]-thiourea was obtained as a colorless foam in a yield of 433 mg (52%).
Reaction SMILES: C([Li])CCC.CCCCCC.CN(C)CCN(C)C.[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[CH:27]1.[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)([C:27]2[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:35])[CH3:20])[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)[OH:44])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Reactant: O=C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1c(C(O)(CC2CCCC2)c2ccc(Cl)c(Cl)c2)cc2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
A solution of n-butyl lithium in hexane (2.5 M, 4.5 mL, 11.2 mmol) was treated with N,N,N′,N′-tetramethylethylenediamine (1.69 mL, 11.2 mmol) dropwise, which resulted in a slight exotherm. The resulting yellow mixture was then stirred at room temperature for 15 min. After this time, the mixture was treated with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 138, 3.48 g, 14.0 mmol) dropwise. The resulting mixture was then stirred at room temperature for 30 min and then treated with a solution of 2-cyclopentyl-1-(3,4-dichloro-phenyl)-ethanone (1.8 g, 7.0 mmol) in tetrahydrofuran (8 mL) and then stirred at room temperature for 6 h. After this time, the reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution (25 mL) and it was then stirred over the weekend. The reaction mixture was then extracted with ethyl acetate (2×100 mL) and the combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10% ethyl acetate/hexanes) afforded 2-cyclopentyl-1-(3,4-dichloro-phenyl)-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-ethanol (1.13 g, 32%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromophenyl)methanamine (670 mg, 3.6 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (600 mg, 3 mmol) and sodium triacetoxyborohydride (1.27 g, 6 mmol) in 10 mL of dichloromethane was added acetic acid (360 mg, 6 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluting with petroleum ether:EtOAc=3:1) to give tert-butyl 4-(3-bromobenzylamino)piperidine-1-carboxylate (0.9 g, 68%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.48-7.47 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.17 (m, 2H), 4.10 (brs, 1H), 3.79 (s, 2H), 2.85-2.76 (m, 2H), 2.67-2.61 (m, 1H), 1.87-1.82 (m, 2H), 1.45 (s, 9H), 1.37-1.29 (m, 2H).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9]([O:11][CH:12]([O:14][C:15](=[O:55])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@H:25]3[C@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[F:37])[C@:28]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=4[F:47])([C:38]#[N:39])[C@H:27]([CH2:48][C:49]([CH3:52])([CH3:51])[CH3:50])[NH:26]3)=[O:24])=[C:18]([O:53][CH3:54])[CH:17]=2)[CH3:13])=[O:10])[CH2:4][O:3]1.Cl.CCOCC>C(#N)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([O:11][CH:12]([O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@H:25]2[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[F:37])[C@:28]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[F:47])([C:38]#[N:39])[C@H:27]([CH2:48][C:49]([CH3:51])([CH3:50])[CH3:52])[NH:26]2)=[O:24])=[C:18]([O:53][CH3:54])[CH:17]=1)[CH3:13])=[O:10]
Reactant: COc1cc(C(=O)OC(C)OC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 1.17 h
Yield: 51.2 %

Procedure:
A solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 15, 75.7 mg, 0.092 mmol) in acetonitrile (4 mL) was treated with a 2M solution of hydrochloric acid in ether (Sigma Aldrich, 0.5 mL, 1.00 mmol) and stirred for 70 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, brine, dried and concentrated. The crude material was then purified by flash chromatography (methylene chloride/methanol) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-(2,3-dihydroxy-propylcarbamoyloxy)-ethyl ester as a white solid (36.6 mg, 50% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N4O8: [(M+H)+]: 777 found: 777