Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>CN(C=O)C>[CH:23]1([CH:13]([N:12]2[C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[N:7][C:2]([N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[CH:3][CH:4]=2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(-c2ccc(Cl)nc2)nc2ccccc21
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cn1
Temperature: 120 °C

Procedure:
90 mg of 2-[2-(6-Chloro-pyridin-3-yl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide (example 189) (0.2 mmol, 1 equiv.) were dissolved in DMF (1 ml). 102 ul (1 mmol, 5 equiv.) of diethylamine are added. The mixture was heated to 120° C. for 15 min using microwave heating). The product was isolated via preperative HPLC. MS (ES+): 489 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(O[C:13]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.O.O1CCOCC1>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:13]1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc21
Yield: 43.2 %

Procedure:
A mixture of 1.0 g of N-methyl-1,2-phenylenediamine, 3.8 g of 5-[4-(ethoxycarbonylmethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in step (d) above], 20 ml of concentrated aqueous hydrochloric acid, 10 ml of 1,4-dioxane and 10 ml of water was heated under reflux for 5 hours. At the end of this time, the insoluble materials which had precipitated from the reaction mixture were collected by filtration and the precipitate thus obtained was dissolved in tetrahydrofuran. Water was then added to the solution. The resulting aqueous mixture was neutralized by adding sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using ethyl acetate and then ethanol as the eluent. The product was then recrystallized twice from a mixture of tetrahydrofuran and ethyl acetate, to give 1.3 g of the title compound, melting at 230°-231° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ncn1
Agent: [Pd]
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncn1
Yield: 71.8 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-6-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate obtained in Example (174c) (111 mg, 0.28 mmol) and a 10% palladium-carbon catalyst (130 mg), to obtain 53.5 mg of the title compound as a pale yellow oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:20])[CH2:18]C.Cl>CN(C)P(N(C)C)(N(C)C)=O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([CH:11]([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][O:20][CH2:17][CH3:18]
Reactant: CC(=O)c1cc(C(C)CO)ccc1O
Reactant: CCOC(=O)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCC(=O)c1cc(C(C)CO)ccc1O
Reaction time: 2 h

Procedure:
2-(3-Acetyl-4-hydroxyphenyl)propan-1-ol (15.0g; 0.077 mol) was dissolved in hexamethylphosphoramide (150 ml) and slowly added to a stirred slurry of sodium hydride (10.0g; 0.417 mol) in hexamethylphosphoramide (40 ml) at a rate sufficient to maintain the temperature below 25° C. Ethyl propionate (20.0g; 0.2mol) was added and the mixture stirred for 2 hours before pouring into 2N hydrochloric acid (600 ml). The solution was extracted with ether (2 × 300 ml) and the extracts evaporated to give 2-[4-hydroxy-3-(3-oxapentanoyl)phenyl]propan-1-ol as a yellow oil. This was dissolved in ethanol (100 ml) containing concentrated hydrochloric acid (20 ml) and the solution was refluxed for 30 mins. The ethanol was removed in vacuo and the aqueous phase extracted with chloroform (2 × 150 ml). The combined extracts were washed with saturated sodium bicarbonate solution and dried over magnesium sulphate. The solvent was removed and the resulting oil was chromatographed on a silica gel column using ether as eluent. Recrystallisation of the product using hexane/ether (2:1) furnished a white microcrystalline solid (5.0g) mp 59.5-60.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])([O-:3])=[O:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:14]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:8]([O:10][CH3:11])=[O:9])[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:35][CH:36]=1)#[N:22]
Reactant: CCCCC(=O)Nc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
A mixture of methyl 4-nitro-3-valerylaminobenzoate (1.0 g), 4-(2-cyanophenyl)benzyl bromide (0.97 g) and potassium carbonate (0.55 g) in DMF (10 ml) was stirred for two days at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to afford a pale yellow oil (1.24 g, 73%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([F:25])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:19][C:18](=[O:24])[NH:17]2)[C:5]([F:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1nc(Br)ccc1F)[C@H](O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2nc(Br)ccc2F)[C@@H](c2ccccc2)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(6-bromo-3-fluoropyridin-2-yl)-2-hydroxy-2-phenylethylcarbamate (208 mg, 0.506 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 10 mL). After 2 h at room temperature, the reaction was concentrated. The resulting residue was loaded onto a strong cation exchange cartridge which was flushed with several volumes of methanol and discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (2 mL), cooled to 0° C., and treated with carbonyldiimidazole (123 mg, 0.759 mmol). After 5 min, the ice bath was removed and stirring continued overnight. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was purified by column chromatography (25%→50% EtOAc/Hex) to give 96 mg (28%) as a white foam solid. Mass spec.: 337.0 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:24][O:25][NH:26][CH3:27]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([N:26]([O:25][CH3:24])[CH3:27])=[O:6]
Reactant: CNOC
Reactant: COC(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
A solution of 2-methoxy-2-methyl-propionic acid (1.0 g, 8.46 mmol) in anhydrous dichloromethane (10 ml) was slowly treated with DCC (1M in DCM, 10.16 ml, 10.16 mmol), O,N-Dimethyl-hydroxylamine (991 mg, 10.16 mmol), DMAP (103 mg, 0.843 mmol), and TEA (1.42 ml, 10.16 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between DCM/1N HCl. The organic layers were collected, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography using 5-60% EtOAc in hexanes as eluant providing 200 mg (14.66%) of 2,N-dimethoxy-2,N-dimethyl-propionamide as a colorless oil.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([OH:25])=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C.[Cl-].[Na+].O>[CH3:30][O:29][N:28]([CH3:27])[C:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]=[CH:14][CH:15]=[CH:16]2)=[O:25]
Reactant: CNOC
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CDI (25.8 g, 151 mmol) was added to a solution of 6-quinolinecarboxylic acid (25 g, 141 mmol) in DMF and the mixture stirred at rt for 10 min. N,O-dimethylhydroxylamine hydrochloride (14.1 g, 142 mmol) was added and the mixture stirred for an additional hour. Brine was then added and the mixture extracted with EtOAc. The organic extracts were dried, filtered and concentrated to give the title compound as a yellow oil (tR 0.2 min (conditions 2), MH+=217).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.[Pd]>[CH3:18][N:17]([CH3:19])[CH:14]1[CH2:13][CH2:12][N:11]([C:4]2[CH:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C1CCN(c2ccc(N)c(N)c2)CC1
Reaction time: 6 h

Procedure:
To [1-(3-amino-4-nitro-phenyl)piperidin-4-yl]-dimethyl-amine (3.8 g, 14.4 mmol) was added Pd/C (300 mg) in EtOH (205 mL). The flask was shaken under H2 atmosphere for 6 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness to give 4-(4-dimethylamino-piperidin-1-yl)benzene-1,2-diamine which was used directly in the next step.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:22][O:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(c2cc([N+](=O)[O-])ccc2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of this ester compound in methanol (10 ml) is added 2M aqueous sodium hydroxide solution (10 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is concentrated, and diluted with water and ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and the resulting precipitates are collected by filtration to give the title compound (0.70 g).
Reaction SMILES: [C:1]([C@H:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:5]([OH:9])[C:6]([OH:8])=[O:7])([OH:3])=[O:2].F[C:15](F)(F)C(OC(=O)C(F)(F)F)=O>>[C:1]([C@H:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:5]([OH:9])[C:6]([O:8][CH3:15])=[O:7])([OH:3])=[O:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](O)C(=O)O
Product: COC(=O)[C@@H](O)[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.48 g of 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoic acid were stirred under nitrogen in 10 ml of trifluoroacetic anhydride for 1.5 hours. The solvent was evaporated and the residue was dissolved in 20 ml of dry methanol and stirred overnight at room temperature. The solvent was evaporated to give 5.3 g of methyl 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoate in the form of an orange oil.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[CH:23]=[C:22](I)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=[CH2:29]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[CH:23]=[C:22]([CH:29]=[CH:28][CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=CCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.30 g, allylbenzene 0.16 mL and triethylamine 0.11 mL was added palladium acetate 9 mg, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added to it, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added, and it was heated and refluxed under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-(3-phenyl-1-propenyl)benzoate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH2:18][C:17](=O)[C:16]=2[CH:21]=1.[Cl-].[NH4+].[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:28]([O:27][C:24](=[O:26])[CH2:25][C:17]1[C:16]2[CH:21]=[C:12]([Br:11])[CH:13]=[CH:14][C:15]=2[O:19][CH:18]=1)[CH3:29]
Reactant: O=C1COc2ccc(Br)cc21
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1coc2ccc(Br)cc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of triethyl phosphonoacetate (6 ml, 30.2 mmol) in dry tetrahydrofuran (200 ml) at -78° C. was added a solution of potassium bis(trimethylsilyl)amide in toluene (58 ml of a 0.5 M solution). After stirring for 2 hours at -78° C., 5-bromobenzofuran-3-one (5.5 g, 26 mmol) was added dropwise. The resulting solution was stirred 1 hour at -78° C. and overnight at room temperature. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated and evaporated to dryness to give the crude title compound which was purified by column chromatography on silica using chloromethane, followed by column chromatography on alumina using dichloromethane. (5-Bromobenzofuran-3-yl)acetic acid ethyl ester was obtained as a low melting solid (4.2 g, 57%), mp 38-40° C. 1H NMR 250 MHz, CDCl3) δ1.28 (3H, t, J=7 Hz), 3.65 (2H, d, J=1 Hz), 4.20 (2H, q, J=7 Hz), 7.36 (1H, s), 7.38 (1H, d, J=2 Hz), 7.63 (1H, s), 7.71 (1H, d, J=2 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:3]1=2.S(Cl)([Cl:22])=O>>[Cl:22][C:17]([C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Heat a solution of 5 gm. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid and 40 ml. of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml. portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17]CC4C=CC=CC=4)=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:25](=[S:28])[CH2:26][CH3:27])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.Cl.CCOCC>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:25](=[S:28])[CH2:26][CH3:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=S)c1cc(-c2ccccc2)c2ccc(OCc3ccccc3)cc2c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(=S)c1cc(-c2ccccc2)c2ccc(O)cc2c1

Procedure:
A solution of methylthioacetyl derivative from Step 4 (140 mg) in AcOH (1 mL) and conc. HCl (1 mL) was stirred at r.t. 18 hr. The reaction mixture was diluted with Et2O, washed with H2O (2×), saturated NaHCO3 solution, brine, dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc:CH2Cl2 (85:15:50) to afford the title compound as a foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of tert-butyl(3-hydroxycyclopentyl)carbamate (800 mg, 3.98 mmol) and Dess-martin reagent (3.6 g, 8.15 mmol) in DCM (20 mL) was stirred at RT overnight. And then, the reaction was quenched by addition of sat. aqueous solution of NaHCO3 and sat. aqueous solution of Na2SO3. The resulting mixture was extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, and then concentrated in vacuo. The residue was purified by silica-gel chromatography to afford tert-butyl(3-oxocyclopentyl)carbamate as a white solid (730 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[CH2:18])[C:14](OC)=[O:15])[C:7]([CH3:19])=[CH:6]2)#[N:2].[Li+].[BH4-]>C1COCC1>[OH:15][CH2:14][CH:13]([CH3:18])[CH2:12][N:8]1[C:9]2[C:5](=[C:4]([C:20]([F:23])([F:21])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:19]
Reactant: C=C(Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)CO
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A solution of methyl 2-{[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-2-propenoate (Example 350) (0.3 g, 0.93 mmol) in THF (10 mL) was cooled to 0° C. and treated with LiBH4 (0.93 mL, 2M in THF). After overnight, the reaction was quenched and partitioned between EtOAc and water. Drying (MgSO4), filtration, and concentration was followed by radial chromatography (0-90% EtOAc-hexanes gradient) to afford the title compound (0.13 g, 47% yield): 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 4.33 (dd, J=14.6, 7.3 Hz, 1H), 3.92 (dd, J=14.6, 7.3 Hz, 1H), 3.52 (br, 2H), 2.50 (s, 3H), 2.19 (m, 1H), 1.56 (br, 1H), 0.97 (d, J=6.8 Hz, 3H); MS (ES) m/z 297 (M+1).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22].N(OC(C)(C)C)=O.[I:32]I>C(Cl)(Cl)Cl>[I:32][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: II
Reactant: COC(=O)c1cc2c(cc1N)CN(C(=O)OCc1ccccc1)C2
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-benzyl 5-methyl 6-amino-1,3-dihydro-2H-isoindole-2,5-dicarboxylate (149 mg, 0.456 mmol) in CHCl3 (5 mL) was added t-butyl nitrite (108 uL, 0.912 mmol). The mixture was stirred for 20 min. I2 (34.7 mg, 1.37 mmol) was added and the resulting mixture was stirred at room temperature for 15 min. The mixture was then heated at 80° C. overnight. The reaction was quenched with sat. aq. NaHSO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide 2-benzyl 5-methyl 6-iodo-1,3-dihydro-2H-isoindole-2,5-dicarboxylate. LCMS calc.=438.0; found=437.8 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.94-7.88 (2 s, 1H); 7.77-7.71 (2 s, 1H); 7.44-7.32 (m, 5H); 5.25 (s, 2-H); 4.76 (t, J=11.6 Hz, 4H); 3.98-3.94 (2 s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1CCNCC1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
In a 100 mL volume glass vessel equipped with a stirrer and a thermometer were placed 15.0 g (55.8 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 13.85 g (163 mmol) of piperidine, and 27.4 mL (113.6 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 55° C. for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and placed under reduced pressure to distill unreacted piperidine off. To the residue was added 18.9 mL (113.4 mmol) of hydrochloric acid (6.0 mol/L), and the mixture was cooled to 0° C. The precipitated crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 13.5 g (isolated yield: 76.3%) of 6-methoxy-7-(3-piperidino-propoxy)quinazolin-4-one.