Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.406 g, 2.13 mmol) and 7-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) using ethanol as reaction solvent. Yield 0.325 g (35%) as a colorless powder. mp 186°-189° C. FDMS m/e=423 (M+ of free base). α[D]589 =+8.44 (c=1.09, dimethylsulfoxide).
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7]([C:9](C(OCC)=O)([CH2:24][CH3:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1)=[O:8])C>C(O)C>[C:7]([CH:9]([CH2:24][CH3:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)C(C)c1ccc(CC(CC)(C(=O)OCC)C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(Cc1ccc(C(C)C(=O)O)cc1)C(=O)O

Procedure:
To a mixture of 14g. of potassium hydroxide, 100 ml. of water and 10 ml. of ethanol was added 14g. of ethyl 2-[4-(2,2-diethoxycarbonylbutyl)phenyl]propionate and the mixture was refluxed for 6 hours. The reaction mixture was treated with the same procedure as in Example 1 (2) to give 11.1g. of a pale yellow oil. The oil was heated at 160° - 170° C. for 3 hours and subjected to vacuum distillation to give 7.2g. of the desired product boiling at 230° C./0.05 mmHg. as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:33](O)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:33][CH3:34])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 2.53 g (5.9 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoic acid in 150 mL ethanol is slowly added 1.5 mL (20.5 mmol) thionyl chloride and the reaction mixture is subjected to reflux for 8 hours. The solvent is evaporated and the residue is adjusted to pH 8 using 1N aqueous sodium hydroxide solution. The mixture is then extracted with methylene chloride (2×50 mL). Combined organic extracts are dried (MgSO4) and evaporated to give an oil which is then purified by flash chromatography using ether as the eluent to obtain ethyl 6-(p-chlorophenylsulfonamido)-2-[3-(3pyridyl)propyl]-hexanoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])=[CH:31][CH:30]=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:38][CH2:37][C:36]([O:35][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=3)([CH3:40])[CH3:39])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(CO)Oc1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(COC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.16 g.) in 1,2-dichloroethane (10 ml.) is added, dropwise and below 10° C., to a stirred mixture of 2-(4-chlorophenyloxy)-2-methylpropanol (1.40 g.), pyridine (4.0 ml.), and 1,2-dichloroethane (10 ml.). The mixture is stirred at ambient temperature for 20 hours, then mixed with ice-water and chloroform. The organic phase is separated, and washed with 3N-hydrochloric acid and water. 0.4N-Aqueous potassium hydroxide (5 ml.) and ice are added, the mixture is shaken, and enough ether is added to cause the resulting emulsion to separate into two layers. The organic layer is washed with water, dried and evaporated. The residual oil (3.6 g.) is chromatographed in light petroleum (b.p. 60°-80° C.) on a column of silica gel (45 g.). The column is washed portionwise the solvent (2 l ) until no more material is eluted, and then with a mixture of light petroleum and ether (10:1, 200 ml.). This eluate is evaporated to give 2-(4-chlorophenyloxy)-2-methylpropyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (2.6 g.) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:15])[CH:27]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 97.1%, 454.6 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:45])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:7][C:6]=1[O:42][CH2:43][CH3:44])C.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:18][N:14]2[C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:45])=[O:3])=[C:6]([O:42][CH2:43][CH3:44])[CH:7]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1ccc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid ethyl ester (50.0 mg, 0.076 mmol) in THF/MeOH (1.2 mL/0.4 mL) was added 4 N LiOH (0.4 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid (24.4 mg, 50.9%). HRMS (ES+) m/z Calcd for C33H32Cl2F2N2O4+H [(M+H)+]: 629.1780, found: 629.1782.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.[Pd]>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[C:22]([NH:25][C:33]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[NH:34])[CH:23]=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CSC(=N)c1cccs1
Reactant: CCOc1ccc(Cc2nc3ccc([N+](=O)[O-])cc3n2CCN(CC)CC)cc1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCOc1ccc(Cc2nc3ccc(NC(=N)c4cccs4)cc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-6-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 43 (90 mg, 0.227 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (24 mg, 0.0227 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to 44 3-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-3H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 44 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (129.5 mg, 0.454 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 44 hours. The solvent was evaporated and residue partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 8. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 3% methanol/97% dichloromethane to 5% methanol/95% dichloromethane to afford a yellow solid 45 N-[3-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-3H-benzoimidazol-5-yl]-thiophene-2-carboxamidine. Yield: 38 mg (35.2%). 1H NMR (DMSO) δ: 0.81 (t, 6H, J=7.0), 1.28 (t, 3H, J=7.0), 2.35-2.50 (2×m, 6H), 3.97 (q, 2H, J=7.0), 4.07 (t, 2H, J=6.7), 4.21 (s, 2H), 6.42 (br s, 2H), 6.67-6.70 (m, 1H), 6.85-6.88 (m, 1H), 6.88 (d, 2H, J=8.6), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.7), 7.46 (d, 1H, J=8.5), 7.60 (d, 1H, J=5.2), 7.73 (d, 1H, J=3.6); MS (ESI): 476 (MH+, 100%).
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:33])([F:32])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[N:22][C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[N:20]2)=[CH:15][CH:14]=1>>[F:3][CH:4]([CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:24]([C:21]2[N:22]=[CH:23][N:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][C:11]([F:10])([F:33])[F:32])=[CH:14][CH:15]=3)[N:20]=2)=[CH:25][CH:26]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CF
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(F)C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil immersion, 0.48 g, 12 mmol) was added to a dry, oven-dried round bottomed flask and placed under nitrogen. Diethyl ether (9 mL) was added, followed by absolute ethanol (0.05 mL), and the reaction was cooled in an ice bath. Ethyl 2-fluoroacetate (0.87 mL, 9.0 mmol) was added dropwise. The reaction was stirred for 15 minutes in ice bath (gas evolution ceased). 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (2.2 g, 6.5 mmol) was added in solid portions. The solution slowly turned color to a golden yellow. The ice bath was removed after 1 hour and warmed to room temperature, stirring for an additional 2 hours until the reaction was quenched with saturated aqueous ammonium chloride, diluted with diethyl ether, and stirred at room temperature for 3 days. The biphasic solution was diluted with brine and extracted with ethyl acetate (2×). The organic layers were dried organic over anhydrous sodium sulfate, filtered, and concentrated to give an orange liquid. The crude material was purified by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent to afford the intermediate ethyl 2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate as a crude compound (0.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mmol), aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphere of Nitrogen for 7 h. The mixture was then concentrated in vacuo, and the residue triturated with heptane (30 ml) to give the desired product. 1H NMR (400 MHz, CDCl3) δ=7.11 (d, 1H, J=9.2 Hz), 7.25-7.29 (m, 3H), 7.40-7.45 (m, 3H), 8.35 (d, 1H, J=2.4 Hz) and 9.45 (brs, 1H).
Reaction SMILES: Cl.[CH:2]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:2]2[CH2:3][CH2:4]3)=[CH:11][C:12]=1[C:19]([F:20])([F:21])[F:22])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C1CC2CCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride 7a (4.6 g, 34.43 mmol, obtained from Tyger Scientific Inc., 324 Stokes Avenue, Ewing, N.J., 08638 USA under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene 18 (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 mL, 86.07 mmol) in acetonitrile (50 mL). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 19 (7.2 g, 88% yield) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH2:30][OH:31])=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O=C1CCC(=O)N1[O:39][C:40](=O)[CH2:41][C:42]#[N:43].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>O1CCOCC1.C(O)C.C(OC(=O)C)C>[C:42]([CH2:41][C:40]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:27])[CH3:28])[CH:22]=4)[C:17]3=[O:29])[C:11]=2[CH2:30][OH:31])[CH:3]=1)=[O:39])#[N:43]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(N)c(=O)n(C)c3)c1CO)C2=O
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(NC(=O)CC#N)c(=O)n(C)c3)c1CO)C2=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.095 mmol) was placed in a mixture of 1.5 ml dioxane and 0.5 ml of ethanol. To this mixture was added cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester, at first 1 equivalent (17.4 mg, 0.095 mmol), and then over a period of 3 days 5 more equivalents of this reagent at 2-4 hours intervals. During this time the reaction mixture was heated at 50-60° C. After cooling, the reactin mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by Prep TLC with 5% methanol in dichloromethylene to afford 12 mg (26% yield) of 2-Cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-acetamide.
Reaction SMILES: IC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[I:34])=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccccc1I
Agent: O=C(N=C=S)c1ccccc1I
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4I)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (86 mg, yield 90%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (10 g, 49.9 mmol), N,N-diisopropylethylamine (26 ml, 149 mmol), benzyl chloroformate (8.5 ml, 59.5 mmol) and dichloromethane (dehydrated) (300 ml) were mixed under ice-cooling. The resulting mixture was stirred at room temperature for one hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with dichloromethane three times. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (13.1 g, yield 78.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:3]=12.[CH3:34]I>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:34])[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: CI
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC

Procedure:
4-Chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89c, but using 7.1 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1.10 ml of methyl iodide. After purification by flash chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents, argon), 5.69 g of 4-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: C1(C)C=CC=CC=1.Cl.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:14][CH:13]=1.O1CCN([CH2:36][CH:37]([N+:45]([O-:47])=[O:46])[CH2:38]N2CCOCC2)CC1>CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[CH2:38][CH:37]([N+:45]([O-:47])=[O:46])[CH2:36][N:19]2[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])C(CN1CCOCC1)CN1CCOCC1
Reactant: COc1ccc(CNNCc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC([N+](=O)[O-])CN2Cc2ccc(OC)cc2)cc1
Yield: 85.9 %

Procedure:
To a mixed solution of toluene (8 ml) and methanol (12 ml) were added 1,2-bis(4- methoxyphenylmethyl)hydrazine dihydrochloride (0.99 g) and 1,3- dimorpholino-2-nitropropane (0.75 g). The mixture was refluxed with heating for 3 hours. The reaction solution was concentrated under a vacuum, purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby yielding 0.88 g (86%) of 1,2-bis (4-methoxyphenylmethyl)-4-nitropyrazolidine.
Reaction SMILES: [Na+].C(OC([NH:9][C@@H:10]1[C@@H:13](/[CH:14]=[CH:15]/[C:16](=[O:18])[NH2:17])[N:12]([S:19]([O-:22])(=[O:21])=[O:20])[C:11]1=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.CCOCC.CCCCCC.O>[NH2:9][C@H:10]1[C@H:13](/[CH:14]=[CH:15]/[C:16](=[O:18])[NH2:17])[N:12]([S:19]([OH:22])(=[O:20])=[O:21])[C:11]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1/C=C/C(N)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: NC(=O)/C=C/[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
1.55 g (4.34 mmol) of (3R,4R)-3-(1-t-butoxyformamido)-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 5 ml of anisole, the solution is cooled to 0° C. and then treated with 5 ml of trifluoroacetic acid. The suspension obtained is stirred at 0° C. for 1 hour and subsequently at room temperature for 2 hours. The mixture is diluted with 100 ml of ether and 20 ml of n-hexane. The crystals obtained are filtered off and dried. The thus-obtained crude material is dissolved in 10 ml of water and chromatographed on MCI gel using water for the elution. 1.04 g (100%) of (3S,4S)-3-amino-4-[(E)-2-carbamoylvinyl]-2-oxo-1-azetidinesulphonic acid are obtained.