Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32](O)=[O:33])[S:26]1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=4)=[O:23])=[CH:12][N:13]=3)[CH2:22][CH2:21]2)=[O:33])[S:26]1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: O=C(O)CC1SC(=O)NC1=O
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC4SC(=O)NC4=O)CC3)nc2)cc1I

Procedure:
6-{4-[2-(2,4-Dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the ECDI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and 2-(2,4-dioxo-thiazolidin-5-yl)-acetic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C22H22IN5O4S (m/e) 579, obsd 580 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-].C(O)(C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[CH3:25])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1cc2ccccc2n1C
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CC(Cl)Cl
Product: Cc1c(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c2ccccc2n1C

Procedure:
is obtained as described in Example 10 (a) from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 6.53 g 1,2-dimethylindole in dichloro-ethane in the presence of 12 g aluminum chloride. After treatment with isopropanol, crystals having a melting point of 247°-249° C. are obtained.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2csc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2csc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-ethylphenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-ethyl-phenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (d, J=7.1 Hz, 2H), 7.19 (d, J=7.1 Hz, 2H), 6.94 (d, J=6.7 Hz, 1H), 6.62 (d, J=6.7 Hz, 1H), 4.92 (s, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.65 (q, J=7.5 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 2.10 (s, 3H), 1.25 (t, J=8.5 Hz, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][CH2:35][CH2:36][OH:37].[Br:38][C:39]1[O:43][C:42]([C:44]([OH:46])=O)=[CH:41][CH:40]=1>ClCCl>[Br:38][C:39]1[O:43][C:42]([C:44]([NH:34][CH2:35][CH2:36][OH:37])=[O:46])=[CH:41][CH:40]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(Br)o1
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: O=C(NCCO)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol), N,N-diisopropylethylamine (0.82 mL, 4.7 mmol) and 2-aminoethanol (0.14 mL, 2.4 mmol) were added to a solution of 5-bromo-2-furoic acid (0.30 g, 1.6 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, water (5 mL) was added thereto. The whole was extracted with ethyl acetate (10 mL), and the organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.18 g) as a colorless solid (yield 49%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH:5][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=1
Reactant: COc1ccc(N)cc1O
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(NC2=CC(=O)CCC2)cc1O
Yield: 100.2 %

Procedure:
A solution of 1.00 g (7.19 mmole) of 3-hydroxy-4-methoxyaniline, 0.83 g (7.19 mmole) of 1,3-cyclohexanedione, and 50 mg of p-toluenesulfonic acid in 20 ml of benzene were heated reflux for 4.5 hours. The reaction solution was allowed to stand for one night at room temperature and the precipitated brown solid was collected by suction filtration. The crystal was washed with benzene, then was dried in vacuo to obtain 3-(3-hydroxy-4-methoxyanilino)-2-cyclohexen-1-one 1.68 g (yield 100%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]=[C:17]=[S:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].CO>O1CCCC1>[C:19]([NH:22][NH:23][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[S:18])(=[O:21])[CH3:20]
Reactant: CC(=O)NN
Reactant: CCn1c2ccccc2c2cc(N=C=S)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c2ccccc2c2cc(NC(=S)NNC(C)=O)ccc21

Procedure:
3.8 g of 9-ethyl-3-isothiocyanatocarbazole was reacted with 1.1 g of acetylhydrazine in 30 ml of tetrahydrofuran at 60° C. for 2 hours. Then, 10 ml of methanol was added thereto and crystallization was conducted while cooling with ice. Crystals thus precipitated were collected by filtration, and recrystallized from CHCl3 /CH3OH (70 ml/200 ml) to obtain 2.4 g of the desired end compound. m.p. 197°-199° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(=S)=S>[C:1]([C:12]1[CH:13]=[C:8]([CH:5]([CH3:6])[CH3:7])[CH:9]=[CH:10][C:11]=1[CH:14]([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)c1ccc(C(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(C(C)C)ccc1C(C)C
Temperature: -10 °C
Yield: 88.5 %

Procedure:
A solution of 142 ml (157 g, 2.0 mol) of acetyl chloride in 362 ml (310 g, 1.91 mol) of 1,4-diisopropylbenzene was added dropwise during the course of 2 hours to a suspension of 200 g (1.5 mol) of aluminum trichloride in 260 ml of carbon disulfide cooled to -10° C. The mixture was stirred for a further 1.5 hours at -100° C., in the course of which the evolution of hydrogen chloride greatly decreased, and a further 100 g (0.75 mol) of aluminum trichloride were then added in portions and the mixture was stirred for a further hour. The reaction mixture was cautiously poured onto I kg of ice/100 ml of 2N hydrochloric acid (strongly exothermic? ). The oily organic phase was separated off and the aqueous phase was extracted twice using ether. The combined organic phases were washed with dilute sodium carbonate solution, then with water and dried over calcium chloride. The solvents were stripped off and the residue was distilled through a 30 cm Vigreux column in a pump vacuum. After a forerun (b.p. 70°-91° C./ 0.6 torr, colorless oil, 10.9 g), the title compound (b.p. 92°-95° C./0.6 torr, colorless oil, 344.3 g, 1.69 mol), was obtained, yield 88.4%. The afterrun (b.p. 97°-104° C./1.0 torr, 10.25 g) is a colorless oil which immediately solidifies.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:11][C:6]1[CH:5]=[CH:4][C:3]([O:12][CH3:13])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(Cl)ccc(O)c1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 2,4-dichloro-3-nitro-phenol (600 mg, 2.9 mmol, 1.0 eq) in acetone (30 mL), was added K2CO3 (1.2 g, 8.7 mmol, 3.0 eq) and the solution was stirred at room temperature for 30 min. Methyl iodide (1.2 g, 8.7 mmol, 3.0 eq) was added and the reaction was stirred at room temperature overnight. The reaction was filtered to remove the inorganic salts and the organic phase was evaporated in vacuo to give the title compound (550 mg, 86%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]C(C)(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.CCOC(C)=O>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[OH:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCCCCCc1ccccc1
Reactant: c1cscn1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Thiazole (21 μL, 0.29 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated dropwise with 1.4 M t-BuLi (273 μL, 0.38 mmol). The reaction mixture was stirred at −78° C. for 0.5 h before a solution of 7-phenylheptanal (73 mg, 0.38 mmol) in THF (1.3 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h before being warmed to room temperature. The reaction mixture was diluted with EtOAc, and washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl before the organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 1.5×6.5 cm, 15-25% EtOAc-hexanes) afforded the title compound (50 mg, 62%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, 1H, J=3.2 Hz), 7.24 (m, 3H), 7.14 (m, 3H), 4.96 (dd, 1H, J=4.8, 7.6 Hz), 3.09 (br s, 1H), 2.56 (t, 2H, J=7.8 Hz), 1.87 (m, 2H), 1.58 (m, 2H), 1.44 (m, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC1C=CC(S(O[CH2:18][C@@H:19]([C@@H:33]2[C@:50]3([CH3:51])[C@H:36]([C@H:37]4[C@H:47]([CH2:48][CH2:49]3)[C@:45]3([CH3:46])[C:40]([CH2:41][C@@H:42]([O:59][CH:60]5[CH2:65][CH2:64][CH2:63][CH2:62][O:61]5)[CH2:43][C@@H:44]3[O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:20][CH2:21][C@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])(=O)=O)=CC=1>O1CCCC1>[O:54]1[CH2:55][CH2:56][CH2:57][CH2:58][CH:53]1[O:52][C@@H:44]1[C@@:45]2([CH3:46])[C:40](=[CH:39][CH2:38][C@@H:37]3[C@@H:47]2[CH2:48][CH2:49][C@@:50]2([CH3:51])[C@H:36]3[CH2:35][CH2:34][C@@H:33]2[C@H:19]([CH3:18])[CH2:20][CH2:21][C@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])[CH2:41][C@@H:42]([O:59][CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][O:61]2)[CH2:43]1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 0.033 g. (0.00088 mole) of lithium aluminum hydride, 4 ml. of tetrahydrofuran, and 0.223 g. (0.00026 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4methylbenzenesulfonate) was heated at reflux (60° C.) for 1 hr and cooled to 0° C. The mixture was diluted with 12 ml. of ether and quenched with the dropwise addition of 0.07 ml. of water and 0.05 ml. of 10% aqueous sodium hydroxide solution. The mixture was then stirred for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene.
Reaction SMILES: [NH2:1][CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[NH2:15])[CH2:7][S:8][C@H:3]12.[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41](N2C(=S)N(C)N=N2)=[O:42])[N:39]=1>C1COCC1>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41]([NH:1][CH:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[NH2:15])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Reactant: Nc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1

Procedure:
Acylation of diphenylmethyl 7-amino-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (25 mg, 0.054 mmol) with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (19.5 mg, 0.066 mmol) in THF (0.25 mL), according to the procedure described in Example 13, afforded the title compound as a granular yellow solid.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:1]1([C:7]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCc1ccccc1Cl)C1CCCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc2c1CCN=C2C1CCCCC1

Procedure:
1-Cyclohexylcarbonylamino-2-(2-chlorophenyl)-ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same was as in step (b) of Example 13 to afford 1-cyclohexyl-5-chloro-3,4-dihydroisoquinoline as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccs1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-thiophenyl acetic acid (150 mg in 2.5 mL dry methylene chloride) at 0° C. was added 0.004 mL N,N-dimethylformamide followed by the dropwise addition of 0.097 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stirred for an additional 2.5 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].O.[CH:32]([O-:34])=[O:33].[Li+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[Cl-].[Li+].C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.CN(C)C=O>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([C:32]([OH:34])=[O:33])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 77.2 %

Procedure:
Under nitrogen atmosphere, to the dimethyl formamide (3 ml) solution comprising trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 150 mg, 0.345 mmol), lithium formate monohydrate (90 mg, 5.0 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (20 mg, 0.1 eq.), Pd2(dba)3 (32 mg, 0.1 eq.), lithium chloride (88 mg, 6.0 eq.), N,N-diisopropylethylamine (241 μl, 4.0 eq.), and acetic anhydride (131 μl, 4.0 eq.) were added, and the mixture was stirred at 80° C. for 15 hr. Upon the completion of the reaction, ethyl acetate was added to the reaction solution. The organic layer was washed in order with 1 M hydrochloric acid, distilled water, and brine. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (88 mg, 76%).
Reaction SMILES: O1CCOC1C([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(=CC(=O)[C@@H:18]4[O:27][C@@H:19]42)C=C3)CC1)C.CC1(C)CO[CH:33]([CH:36]([C@@H:38]2[C@:55]3([CH3:56])[C@H:41]([C@H:42]4[C@H:52]([CH2:53][CH2:54]3)[C@:50]3([CH3:51])[C:45](=[CH:46][C:47](=[O:58])[C@@H:48]5[O:57][C@@H:49]53)C=C4)[CH2:40][CH2:39]2)C)OC1>>[O:57]1[C:48]2=[C:49]3[C@:50]([CH3:51])([CH2:45][CH2:46][C:47]2=[O:58])[C@@H:52]2[C@H:42]([C@H:41]4[C@:55]([CH3:56])([CH2:54][CH2:53]2)[C@@H:38]([CH2:36][CH3:33])[CH2:39][CH2:40]4)[C@@H:18]2[O:27][C@:19]123
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Yield: 75 %

Procedure:
The procedure of Example 7 was repeated except that 0.295 g (0.769 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one was used in lieu of 0.328 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one to give 0.231 g of 20-(1,3-dioxolan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one (yield: 75%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccnc1C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccnc1C(=O)Nc1ccccc1
Yield: 73 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a, from 1.12 g (5.54 mmol) of 1-amino-N-phenyl-1H-imidazole-2-carboxamide, 1.26 g (6.65 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid and 1.03 g (6.65 mmol) of EDC.HCl. The solid obtained was triturated in diisopropylether to give 1.51 g (67% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(O)C)C>CCOCC>[C:20]1([S:26][C:2]2[C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Cl)S1
Agent: CCOC(C)O
Solvent: CCOCC
Product: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Sc2ccccc2)S1
Temperature: 25 °C
Yield: 36 %

Procedure:
2-Chloro-3-(2,4-dioxothiazolidin-5-ylidene-methyl)quinoline and thiophenol (1.2 eq) were mixed with ethoxyethanol and heated to reflux under N2 for 2 hours. The reaction mixture was allowed to cool to RT, ether was added and bright-yellow precipitate was filtered off, washed several times with ether, air dried for 24 hrs at RT to give pure product (Yield-36%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:12])[CH3:11].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][C@@H:27]1[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:28]1[NH:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:25])=[CH:18]2>C1COCC1>[C:10]([N:36]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][C@H:27]1[NH:26][C:24]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][C:15]([Cl:14])=[CH:23][CH:22]=2)=[O:25])(=[O:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
DIPEA (80 μL, 0.5 mmol) and acetyl chloride (30 μL, 0.5 mmol) were added to a solution of 1,1-dimethylethyl [((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 8, 200 mg, 0.5 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for approximately 1 h. The volatiles were removed by evaporation under reduced pressure the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:1) to afford the title compound (168 mg, 76%) as a white solid.