Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:36][CH2:37][N:38]([C:17]([CH:15]2[CH2:16][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:11])=[O:10])[C:13](=[O:26])[N:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:39][CH2:40]1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(C)ccc4C)CC3)N(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (0.040 g) in tetrahydrofuran (2 ml) were added 1-(2,5-dimethylphenyl)-piperazine (0.030 g), (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP reagent, 0.071 g) and N-ethyl-diisopropylamine (0.041 g). The mixture was stirred at room temperature for 4 h. The solvent was evaporated and the product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(3-methoxy-benzenesulfonyl)-3-phenyl-imidazolidin-2-one (0.065 g) as a colorless solid. MS: 549.0 ([M+H]+)
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.O>C(#N)C>[Br:12][C:8]1[C:7]([NH2:10])=[CH:6][CH:5]=[C:4]([O:3][CH:2]([F:1])[F:11])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(OC(F)F)nc1
Solvent: CC#N
Solvent: O
Product: Nc1ccc(OC(F)F)nc1Br

Procedure:
6-Difluoromethoxy-pyridin-3-yl-amine obtained in Step B (1.36 g) was treated with N-bromosuccinimide (1.51 g) in acetonitrile for 10 minutes. The solution was poured into water, extracted with ethyl acetate, the organic layer dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) afforded 2-bromo-6-difluoromethoxy-pyridin-3-yl-amine as a red oil. 1H NMR (400 MHz, CDCl3) 3.95 (br s, 2H), 6.72 (d, 1H), 7.07 (d, 1H), 7.24 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:21])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[H-].[Na+]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([Cl:23])[CH:25]=2)[C:12]1=[O:21])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)[C@@H](C(=O)OC(C)(C)C)N1Cc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)[C@@H](C(=O)OC(C)(C)C)N1Cc2ccccc2N(Cc2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of (2S)-3-methyl-2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-butyric acid tert-butyl ester (633 mg, 2.08 mmol) and 3-chlorobenzyl bromide (470 mg, 2.29 mmol) in DMSO (10 mL) was added sodium hydride (75 mg, 1.87 mmol) and the reaction mixture was stirred at room temperature for 40 hours. To this reaction was then added sat. aq. NH4Cl and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and evaporated.
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:20]>O.CC(C)=O>[Cl:20][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in a mixture solvent of 1.5 ml of water and 10 ml of acetone, and 1.3 ml of concentrated hydrochloric acid was added thereto, followed by dropwise addition of 0.23 g of sodium nitrite dissolved in 1 ml of water under ice-cooling and subsequent stirring for a while. Next, 0.35 g of cuprous chloride was added and the mixture was warmed up to room temperature. After completion of the reaction, insoluble matter was filtered and the resulting residue was mixed with water, extracted with ethyl acetate and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=500:1-40:1) to give 0.56 g of methyl 5-chloro-2,4-dimethoxybenzoate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=C=O)[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH2:22][N:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH3:1])[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27]
Reactant: CNCCc1ccccn1
Reactant: Cc1c(Br)c(=O)c(C=C=O)c(C)n1Cc1c(F)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)c(=O)c(CN(C)CCc2ccccn2)c(C)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylaminoethyl)pyridine (680 mg, 5.00 mmol) was added to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone (430 mg, 1.16 mmol) in CH2Cl2 (15 mL). After 30 min., NaBH(OAc)3 (1.23 g, 5.80 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (15 mL) and the organic layer was separated and washed with sat. NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was used in the next step without any further purification. Crude yield 426 mg (75%). LRMS m/z 490.0 (M+−1), 492.0 (M++1).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>CCCCCC.CCOCC>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
n-Butyllithium (28.5 ml of a 2.54M solution in hexane) was added to a -78° solution of oxazole (5.0 g) in ether (150 ml). The resulting solution was stirred at -78° for 30 min, followed by the addition of trimethylsilyl chloride (7.86 g), and the mixture allowed to warm to room temperature. The reaction mixture was distilled and the fraction with a boiling point of about 130° was collected to afford 2-trimethylsilyl oxazole (5.12 g); MS, m/e=142(M+1), 91, 73.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].[Br-]>>[C:25]1([C:7]2[C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][C:9]=3[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.091 g, 88%) from (1,3-diphenyl-dibenzofuran-2-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp>120° C. (decomp.); 1H NMR (DMSO-d6) δ 3.66 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.09-7.15 (m, 1H), 7.33-7.39 (m, 1H), 7.39-7.47 (m, 3H), 7.48-7.56 (m, 5H), 7.68 (d, J=8.1 Hz, 1H), 7.70-7.74 (m, 3H); IR (KBr) 3420, 3070, 2950, 2910, 1730, 1610, 1500, 1465, 1455, 1405, 1330, 1310, 1240, 1220, 1175, 1155, 1070, 750, and 700 cm−1; mass spectrum [EI], m/z 394 (M)+; Anal. Calcd. for C26H18O4.1.25H2O: C, 74.90; H, 4.96; N, 0.00, Found: C, 75.07; H, 4.89; N, 0.06.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCCCCCCCCCCNCCCN
Reactant: O=C1CCCCC1
Product: CCCCCCCCCCCCNCCCNC1CCCCC1

Procedure:
Following the general procedure of Example 33, but starting with N-dodecyl-1,3-propanediamine and cyclohexanone, the title compound is produced; IR nmax (neat) 3292, 2925, 2854, 2810, 1466, 1450, 1367, 1130 and 721 cm-1. (PLA2)
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8].[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)(=[O:17])[CH3:16]>ClCCl>[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:22]=[CH:23][CH:24]=[C:25]1[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:17])[CH3:16]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)OCCn1cccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1cccn1CCOC(C)=O

Procedure:
In the next step, a solution of pyridine in anhydrous dichloromethane is added to a stirred and cooled solution of ethoxalyl chloride in anhydrous dichloromethane so that the reaction temperature remains at about -20° to -25° C. Upon completion of this addition an approximately equimolar amount of 1-(2-acetoxyethyl)pyrrole of Formula (III) in anhydrous dichloromethane is added while the temperature is maintained at temperatures of about 0° to -20° C. Washing with water, drying, removal of the solvent and purification gives ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH2:20][CH3:21]>[Pd]>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:20][CH3:21]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1CC)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], (2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH3:21].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:5]=1[CH2:21][Br:23]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1CBr
Temperature: 80 °C
Reaction time: 22 h
Yield: 124.2 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-6-nitro-benzoic acid methyl ester (8.9 g, 25.1 mmol) and N-bromosuccinimide (5.36 g, 30.1 mmol) in 50 mL of CCl4 is added 2,2′-azobisisobutyronitrile (412 mg, 2.5 mmol) at room temperature. The reaction mixture is stirred at 80° C. for 22 hours and then cooled to room temperature and then quenched by crushed ice. The mixture is extracted with dichloromethane and washed with aqueous NaHCO3 solution followed by brine, dried over Na2SO4, filtered and evaporated in vacuo to afford the 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-6-nitro-benzoic acid methyl ester (12.6 g) as brown oil. 1H-NMR (400 MHz, δ, ppm) CDCl3: 0.37 (s, 6H), 1.07 (s, 9H), 4.0 (s, 3H), 4.49 (s, 2H), 6.94 (d, 1H), 8.09 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCOCC1>[C:16]([NH:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (±)1-Amino-2-phenylethyl phosphonous acid (19) (12.95 g, 70 mmol) in dioxane (200 mL) and aqueous 1M NaOH (75 mL) at 0° C. was added dropwise benzyl chloroformate (20 mL). The pH of the solution during this addition was kept at 8-9 with the simultaneous addition of aqueous 1M NaOH (75 mL). The reaction mixture was stirred at room temperature for a further 16 hours and then was concentrated in vacuo to half volume. Washed with diethyl ether (2×75 mL) and then acidified to pH1 with the addition of concentrated aqueous hydrochloric acid. Extracted with ethyl acetate (3×80 mL) and the combined organic phases were washed with water (1×20 mL), dried over anhydrous MgSO4, filtered and evaporated in vacuo which gave after crystallization from ethyl acetate--light petroleum (±)N-CBZ-1-amino-2-phenylethyl phosphonous acid (20) (15.44 g) (mp 136-137° C.) (Baylis, E. K.; Campbell, C. D.; Dingwall, J. G., J. Chem. Soc., Perkin Trans. 1, 1984, 12, 2845, reports mp 137° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[F:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.7 %

Procedure:
368 mg (corresponding to 1.1 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 15 mL of N,N-dimethylformamide, and 453 mg (corresponding to 3.3 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 280 μL (corresponding to 1.6 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1), and further by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 222 mg (corresponding to 0.580 mmol) of 2-[4′-(2″-fluoroethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-7, Step 3).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15](I)[CH3:16]>O1CCCC1>[CH2:15]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])[CH3:16]
Reactant: CCI
Reactant: O=C1CC(c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC(c2ccccc2)CC1=O
Yield: 57 %

Procedure:
A mixture of 4-phenyl-pyrrolidin-2-one (24.2 g; 0.15 mole) and sodium hydride (80% oil suspension) (5.4 g; 0.18 mole) in tetrahydrofuran (150 ml) is refluxed for 2.5 hrs. After cooling, ethyl iodide (29 g; 0.185 mole) is added thereto, and the resulting material is refluxed for another 5 hrs. The solvent is then evaporated off; the residue is taken up into chloroform, washed with water, dried and distilled. B.p. (0.2 mm Hg)=124°-126° C. Yield: 57%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:7]1>C(OC)(C)(C)C>[C:8]1([C:15]2[C:16](=[O:17])[NH:18][C:5](=[O:1])[C:4]=2[C:3]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:2]=2)[C:9]2=[C:14]3[C:13](=[CH:12][CH:11]=[CH:10]2)[CH2:15][CH2:8][CH2:7][N:6]3[CH:7]=1
Reactant: C1CCOC1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Solvent: COC(C)(C)C
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
In step 1 of scheme I, lilolidine (Compound 4), was treated with oxalylchloride to give the acyl chloride in methyl tert-butyl ether (MTBE) reaction solvent. The addition of methanol was sufficient to afford the intermediate ketoester, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl) oxoacetic acid methyl ester (Compound 5). In Step 2 of the reaction, Compound 5 and indole-3-acetamide (Compound 5a) were combined to produce 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione (Compound 6). As described in detail in the following examples, it is not necessary to isolate intermediate Compound 5 to produce Compound 6. A solvent swap from MTBE into tetrahydrofuran (THF) was necessary prior to conducting Step 2, since both 5 and 5a have very poor solubility in MTBE. Following the addition of Compound 5a to consume Compound 5 in THF in the presence of base, HCl was added to complete the reaction to afford crude Compound 6. Crude Compound 6 was then purified from DCM and heptane to afford Compound 6 of sufficient purity to proceed to the next step. A detailed description of this process is shown in Example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl.[CH:8]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>[Pd].CO>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:1][CH2:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CN
Reactant: O=CC1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CNCC1CCCCC1

Procedure:
In a methanol solution containing 2.0 g of H-Gly-OMe.HCl, 2.12 ml of cyclohexanecarboxaldehyde was added and the resultant mixture was stirred overnight in H2 atomosphere in the presence of 200 mg of 10% palladium-charcoal. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give N-(cyclohexylmethyl)glycine methyl ester [H-(cHexm)Gly-OMe]. The CHCl3 solution of the amino ester obtained above was mixed with 3.32 ml of triethylamine and 4.18 g of Boc2O under ice cooling and the mixture was stirred for 3 hr. The stirred mixture was washed with 5% aqueous citric acid solution, 5N aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was. subjected to a silica gel column chromatography (chloroform) to give oily Boc-(cHexm)Gly-OMe. The oily product was dissolved in methanol and 11.4 ml of 1N-NaOH aqueous solution was added and the resultant solution was stirred for 2 hr at room temperature. The obtained solution was neutralized with citric acid, evaporated and dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was dissolved in methanol and cyclohexylamine was added to the solution, then the resultant solution was evaporated and crystallized from ether to give 1.75 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:25][CH:26]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc(NC(c2cc3ccccc3o2)C2CCCCC2)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cc3ccccc3o2)C2CCCCC2)cc1

Procedure:
Using 4-{[1-benzofuran-2-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above and ethyl 3-(methylamino)propanoate (113 mg) and in the same manner as in Example A1(4), the title object compound (226 mg, 73%) was obtained as a pale-red solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21]C)=[O:20])=[CH:11]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)(C)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([OH:21])=[O:20])=[CH:11]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cn(-c2ccccc2C(C)C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)c1ccccc1-n1cc(C(=O)O)c2ccccc21
Temperature: 50 °C

Procedure:
To a screw capped vial was added methyl 1H-indole-3-carboxylate (17 mg, 0.1 mmol), 2-isopropylbenzene boronic acid (33 mg, 0.20 mmol), and activated 3 Å molecular sieves (100 mg). Anhydrous dichloromethane (1.0 mL), anhydrous pyridine (16 μL, 0.2 mmol) and anhydrous triethylamine (28 μL, 0.2 mmol) were added, the vial capped and the reaction was stirred under air for 15 min. Anhydrous copper(II) acetate was added, the vial capped, and the reaction was stirred overnight under air at 45° C. The reaction was quenched with 20 drops of methanolic ammonium hydroxide (concentrated aqueous ammonia and methanol 1:1), filtered with the aid of additional dichloromethane in order to remove the molecular sieves and the solution applied to a silica gel column for chromatography. Elution with a gradient of ethyl acetate and hexanes furnished methyl 1-(2-isopropylphenyl)-1H-indole-3-carboxylate (10 mg, 35%) as a colorless solid. To methyl 1-(2-isopropylphenyl)-1H-indole-3-carboxylate (43 mg, 0.15 mmol) was added isopropanol (2 mL) and 1 N sodium hydroxide (1 mL) and heated to 50° C. for 2 days. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and 1 N hydrochloric acid (1:1), the phases were separated and the aqueous was extracted twice more with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and evaporated to give 1-(2-isopropylphenyl)-1H-indole-3-carboxylic acid as a straw colored solid of sufficient purity for the next step (>95% LC purity). To 1-(2-isopropylphenyl)-1H-indole-3-carboxylic acid in anhydrous dimethylformamide (2.0 mL) was added anhydrous triethylamine (104 μL, 0.75 mmol), N,N-dimethylaminopyridine (9 mg, 0.075 mmol), 4-(trifluoromethoxy)aniline (32 mg, 0.18 mmol) and stirred for 5 min followed by the addition of PyBroP® (bromotris(pyrrolidino)phosphonium hexafluorophosphate) (105 mg, 0.225 mmol). The reaction was stirred for 14 h at 40° C. The reaction was quenched into water and ethyl acetate, the phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organics were washed successively five times with water, once with brine, dried over sodium sulfate and evaporated to yield a residue which was purified by silica gel column chromatography eluting with a gradient of ethyl acetate and hexanes to furnish Example 50 (14 mg, 20%) as a colorless solid. LC/MS (ESI+) 439.1 (M+H)+; (ESI−) 437.2 (M−H)−. 1H NMR (400 MHz, CD3OD) δ ppm 1.08 (d, J=7.03 Hz, 3H) 1.16 (d, J=6.59 Hz, 3H) 2.51-2.63 (m, 1H) 6.93-6.97 (m, 1H) 7.19-7.32 (m, 5H) 7.37-7.42 (m, 1H) 7.53-7.62 (m, 2H) 7.78-7.82 (m, 2H) 8.12 (s, 1H) 8.28-8.32 (m, 1H).