Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:44]1[CH2:48][CH2:47][C@@H:46]([OH:49])[CH2:45]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-L-proline (2 g, 9.3 mmol), EDAC (3.5 g, 18 mmol), HOBt (1.35 g, 10 mmol) in DMF (20 mL) was added triethylamine (2 mL, 14 mmol) and (R)-(+)-3-pyrrolidinol (1.5 mL, 18 mmol). After stirring at room temperature for 48 h, the reaction was quenched with water and sodium bicarbonate solution. It was then extracted with 5% of methanol in dichloromethane. The residue was purified on a silica gel column eluting with 10% of methanol in dichloromethane to give 2.2 g (83%) of (S)-2-((R)-3-hydroxy-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=3[C:7]([F:22])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH:1]1([C:4]2[C:14]3[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:7]([F:22])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)ccc(F)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(C2CC2)c2c1CNCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A mixture of tert-butyl 9-cyclopropyl-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (270 mg, 0.878 mmol), ethyl acetate (4 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (144 mg, 67.3%) as a solid.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11](Cl)(=[O:13])=[O:12])#[N:3]>O1CCOCC1.O>[NH2:3][C:2]1[C:4]2[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=2[S:11](=[O:13])(=[O:12])[N:1]=1
Reactant: N#Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: NC1=NS(=O)(=O)c2cccc(Cl)c21

Procedure:
12.5 ml of 25% ammonia were added at approx. 60° C. to a solution of 11,8 g of 2-cyano-3-chlorobenzenesulphonylchloride in 20 ml of dioxane. After heating on a steam bath for 30 minutes the reaction mixture was cooled and diluted with water. The resulting crystalline product was sucked off, washed with water and dried. The desired product was obtained in a yield of 8.9 g. After recrystallization from ethanol, the product melted at 261°-263° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:31])=[N:11][C:12]2[N:13]([CH:23]=[C:24]([C:26]([O:28]CC)=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:31])=[N:11][C:12]2[N:13]([CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CC(=O)OC(C)(C)C)c(C)nc2n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
To a stirred solution of ethyl 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (100 mg, 021 mmol) in THF (2 mL) and H2O (0.5 mL) at room temperature was added LiOH.H2O (18 mg, 0.42 mmol). After 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure gave 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (95 mg, 100%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1>[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][N:28]([C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 2-hydroxyisobutyric acid (49 mg, 0.47 mmol) in THF (3 mL) was added 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol). The resulting mixture was allowed to stir at r.t. for 4 h then quenched with sat. aq. NH4Cl and extracted with DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with MeOH/H2O. The resulting solid was collected by filtration and dried in vacuo affording 800 (111 mg, 63%). LCMS (method G): RT 7.36 min, [M+H]+ 563.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 5.44 (1 H, s), 4.26 (6 H, brd s), 3.92 (3 H, s), 3.78 (4 H, t, J=4.52 Hz), 3.30-3.23 (4 H, m), 3.09 (3 H, s), 2.26-2.16 (2 H, m), 2.19-2.02 (2 H, m), 1.35-1.33 (9 H, m)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:27]O)=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:27][C:31]#[N:33])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CC#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
To a mixture of [3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]methanol (0.74 g), triethylamine (0.36 g) and ethyl acetate (50 mL) was dropwise added methanesulfonyl chloride (0.41 g) at room temperature and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was washed successively with water saturated aqueous sodium hydrogencarbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil. To a mixture of this yellow oil and dimethyl sulfoxide (20 mL) was added an aqueous solution (2 mL) of sodium cyanide (0.18 g) at room temperature and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.60 g, 81%) of 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-brown prism crystals. melting point: 138-139° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:16])[CH3:7])=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([CH:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:16])[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)N1CCCCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)N1CCCCCCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 90 mg of this ester in 0.5 ml ethanol and add 1 ml 1.0 N NaOH. Stir the mixture at room temperature for 3 hours, then dilute with water and extract with ether. Add solid sodium dihydrogen phosphate to the aqueous phase until it is acidic, then extract with ethyl acetate. Dry the ethyl acetate over Na2SO4, filter and concentrate to obtain 1-(1-carboxyethyl)perhydroazocin-2-one, m.p. 166-167 (from acetone-ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCc1cc(CO)cc(Cl)c1O
Reactant: COC(=O)C(Br)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a magnetically stirred solution of 0.600 g (2.99 mmol) of the product of Step B in 6 mL acetone was added 0.869 g (3.30 mmol) of methyl α-bromo-(3-chlorophenyl)acetate, 0.829 g (6.00 mmol) of potassium carbonate and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.925 g (80%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[C:8]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(N3CCCCC3)c(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCCCC3)c(-c3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-phenyl-2-(piperidin-1-yl)quinoxaline-6-carboxylate (170.9 mg, 0.49 mmol, 1.00 equiv) in methanol (12 mL), sodium hydroxide (98.5 mg, 2.46 mmol, 5.00 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 86 mg (52%) of 3-phenyl-2-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH2:35]([C:42]1([OH:48])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([C:42]1([OH:48])[CH2:47][CH2:46][N:45]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])[CH2:44][CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1[nH]c2ccccc2c1C(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a stirred solution of 0.1 g (0.57 mmol) 2-methyl-1H-indole-3-carboxylic acid in 10 ml CH2Cl2 were added 0.14 g (0.73 mmol) EDC, 0.10 g (0.73 mmol) HOBt, 90 μl (0.63 mmol) Et3N and 0.11 g (0.57 mmol) 4-benzyl-piperidin-4-ol. The mixture was stirred overnight at RT and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 0.15 g (75%) of (4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanone as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[C:9]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH:24][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([CH3:8])[CH3:7])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 2-(S)hydroxyl-3-methyl-butyric acid (35.4 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.21 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in 2 ml of methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a light yellow solid (44 mg), LC-MS M+1=357.1
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][C:14]1=[O:22].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>C1COCC1.O>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][CH:15]1[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[O:13][C:14]1=[O:22]
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C1CC2CCCCC2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C1OC2CCCCC2C1Cc1ccc2ccccc2c1
Temperature: -78 °C

Procedure:
Under argon, a solution of diisopropylamine (3.36 ml, 24 mmol) in 20 ml of dry THF was cooled to 0° C. and admixed with butyllithium (9.6 ml, 24 mmol, 2.5 M in hexane). The solution was stirred with ice-cooling for 15 min, cooled to −78° C. and admixed with a solution of hexahydro-benzofuran-2-one (2.8 g, 20 mmol) in 10 ml of THF. This mixture was stirred at −78° C. for 1 h, and a solution of 2-bromomethylnaphthalene (5.31 g, 24 mmol) in 20 ml of THF was then added. The mixture was stirred at −78° C. for another 2 h and then at room temperature overnight. Water was then added, the organic solvent was removed under reduced pressure and the aqueous phase was extracted with MTBE. The combined ether phases were dried over magnesium sulphate, filtered and concentrated. Purification was carried out by column chromatography. Yield: 2.5 g (44.6%). Rf (cyclohexane/ethyl acetate 3:1)=0.69, Rf (cyclohexane/ethyl acetate 1:1)=0.83 MS (CI): m/e=281 [M+H+]
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:16])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1.C[Si](C)(C)[Si](C)(C)C.[Li]>C1(C)C=CC=CC=1.C1(B(O)O)C2=C3C(=CC=C2)CCCN3C=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]1([C:2]2[C:3](=[O:23])[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:16])[C:6]=2[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1
Reactant: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Reactant: c1cc2c3c(c1)ccn3CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: OB(O)c1cn2c3c(cccc13)CCC2
Solvent: Cc1ccccc1
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:22][CH:21]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Potassium carbonate (4.1 g) and (3-bromopropoxy)-tert-butyldimethylsilane (4.1 g) were added to a solution of 4-bromothiophenol (3.0 g) in N,N-dimethylformamide, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→20:1) to give the title compound as a colorless oil (5.5 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13](Br)=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C[O-].[Na+].[C:26](O)(=[O:28])C>O>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([O:28][CH3:26])=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)c2nc(SCc3ccccc3)nn2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)cn2nc(SCc3ccccc3)nc12

Procedure:
2-Benzylthio-6,8-dibromo[1,2,4]triazolo[1,5-a]pyridine (9.5 g, 23.8 mmol) was mixed with acetonitrile (50 mL) in a round bottom flask. Sodium methoxide (13.1 mL of 25 percent solution in methanol, 57.1 mmol) was added and the mixture was heated at reflux for 2 hours. Glacial acetic acid (10 mL) was added and the entire reaction mixture was poured into a mixture of ice and water (300 mL). The brown precipitate that formed was recovered by filtration and dried. This was chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and hexane. Product-containing fractions were combined and concentrated under reduced pressure to obtain 6.58 g (80 percent of theory) of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: COc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1-isocyanato-3-methoxybenzene as starting materials in 66% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.40 (s, 1H), 9.33 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.10 (m, 5H), 6.87 (d, 1H), 6.79 (d, 1H), 6.48 (d, 1H), 4.20 (d, 2H), 3.68 (s, 3H), 2.87 (m, 6H), 2.66 (m, 1H), 1.89 (m, 2H), 1.61 (m, 2H). LCMS for C32H33ClN7O3 (M+H)+: m/z=598.2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[SH:17][CH2:18][C:19]([OH:21])=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
A solution of 4,4'-dichlorobenzhydrol (Aldrich) (500 mg, 1.97 mmol), mercaptoacetic acid (181 mg, 1.97 mmol) and ρ-toluenesulfonic acid monohydrate (93 mg, 0.49 mmol) in 7 mL of toluene is stirred at room temperature for 2 hours followed by heating at 50°-60° C. for 1 hour. Upon cooling, the mixture is diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The product is concentrated in vacuo to give [[bis-(4-chlorophenyl)methyl]thio]acetic acid as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1)#[N:30].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([CH:32]=3)[C:29]#[N:30])[CH:7]=[CH:6][CH:5]=2)([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=2)[N:9]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N#Cc1cncc(-c2cccc(C3(c4ccnc(C(F)(F)F)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 38 %

Procedure:
The title compound was synthesized as described for Example 12 in 38% yield starting from 1-(3-bromophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (24.2 mg, 0.05 mmol), 5-cyanopyridin-3-ylboronic acid (8.0 mg, 0.05 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.4 mg, 0.005 mmol), and K2CO3 (aq) (0.08 mL, 0.16 mmol).