Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)=[O:10].O=[C:20]([CH3:37])[CH2:21][CH:22]([NH:29][C:30]([CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH2:16][N:15]([CH:20]([CH3:37])[CH2:21][C@H:22]([NH:29][C:30]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:14][CH:13]2[CH2:12]1)=[O:10]
Reactant: CC(=O)CC(NC(=O)C1CCCC1)c1ccccc1
Reactant: Cc1cccc(C)c1C(=O)N1CC2CNCC2C1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1C(=O)N1CC2CN(C(C)C[C@H](NC(=O)C3CCCC3)c3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
step 5—To a solution of (2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone (66, 0.12 g, 0.52 mmol) in DCM (7 mL) and THF (7 mL) was added cyclopentanecarboxylic acid (3-oxo-1-phenyl-butyl)-amide (85d, 0.15 g, 0.57 mmol). Titanium tetraisopropoxide (0.34 mL, 1.15 mmol) was added to the mixture. After 30 min NaBH(OAc)3 (0.16 g, 0.78 mmol) was added and the mixture stirred at RT for 4 h. Saturated NaHCO3 was added to the mixture and it was stirred for 10 min. The mixture was extracted with DCM and the organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by SiO2 chromatography on silica gel eluting with DCM:MeOH:NH4OH (150:10:1) to afford I-75: ms (ES+) m/z 488 (M+H); Anal. (C31H41N3O2.0.3M H2O) C; calcd, 75.51; found, 75.53; H; calcd, 8.50; found, 8.29; N; calcd, 8.52; found, 8.53.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(C=O)C.[OH-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCC1COCCN1Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1COCCN1Cc1ccccc1)C(=O)OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Diethyl malonate (1.78 g, 11.1 mmol), DMF (25 mL), sodium hydroxide (0.22 g, 5.55 mmol) and 4-benzyl-3-(bromomethyl)morpholine (1 g, 3.7 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004) were added to a dried flask in turn. The mixture was stirred at 80° C. for 4 hours under N2, and cooled to 25° C. The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed with brine (100 mL×6), dried over unhydrous Na2SO4. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=15/1) to give the title compound as colorless oil (1.15 g, 89%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].C(NC1C=CC(C2C([C:50]([C:52]3[C:53]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65](=[O:67])[CH3:66])=[CH:60][CH:59]=4)=[N:54][CH:55]=[CH:56][CH:57]=3)=O)=CC=CN=2)=CC=1)(=O)C>O1CCCC1>[C:65]([NH:64][C:61]1[CH:60]=[CH:59][C:58]([C:53]([C:52]2[CH:50]=[N:54][CH:55]=[CH:56][CH:57]=2)=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:63][CH:62]=1)(=[O:67])[CH3:66]
Reactant: CC(=O)Nc1ccc(-c2ncccc2C(=O)c2cccnc2-c2ccc(NC(C)=O)cc2)cc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Temperature: 0 °C

Procedure:
To a suspension of 307 g of 4-carboxybutyltriphenylphosphonium bromide and 233 g of potassium tert.butoxide in 2.8 liters of tetrahydrofuran are added, at -40° C., 140 g of 4-acetylaminophenyl-3-pyridyl-ketone and this mixture is stirred for 2 hours. The reaction mixture is decomposed by the addition of ice water and evaporated down. The residue is taken up in water and washed with ethyl acetate. The aqueous phase is acidified to pH 5 to 6 and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][C@@H](C2C=CC=CC=2)C)[CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])[CH3:2]>[OH-].[Pd+2].[OH-].C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reaction time: 20.5 h
Yield: 98.9 %

Procedure:
In a dry 500-mL Paar flask charged with Palladium hydroxide (20 wt % Pd, dry basis, on carbon, 1.50 g) was added ethanol (75 mL) and (3R,4R)-4-[(R)-1-phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (4.30 g, 11.4 mmol). The reaction mixture was hydrogenated at 53 psi for 20.5 hours with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of ethanol and the combined filtrates were concentrated in vacuo to give a colorless oil (3.07 g, 99%). 1H NMR (300 MHz, CDCl3), δ: 4.32 (bs, 1H), 4.19 (q, 2H, J=7), 4.19 (bs, 1H), 3.08 (td, 1H, J=11, J′=3), 2.75 (bt, 2H, J=14), 2.29 (td, 1H, J=11, J′=4), 1.89 (m, 1H), 1.46 (s, 9H), 1.38 (td, 1H, J=12, J′=5), 1.28 (t, 3H, J=7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:15]=3[CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:21]([O-])=O.Cl.O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.O1CCOCC1>[NH2:21][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[CH:16][C:15]1[CH2:18][CH2:19][CH2:20][C:14]=1[CH:13]=2
Reactant: O=[N+]([O-])c1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-chlorophenyl)-7,8-dihydro-3-nitro-6H-cyclopenta[g]quinoline (4.50 g), dioxane (45 ml) and concentrated hydrochloric acid (15 ml) was added tin(II) chloride dihydrate (9.5 g) followed by stirring at room temperature for one hour. The reaction mixture was then diluted with water, made strongly alkaline with 6N NaOH and extracted with chloroform. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline. The crystals were collected by filtration and washed with isopropyl ether (3.45 g, 83.3%). Recrystallization from ether gave colorless needles, mp 179°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([O:16][CH2:17][C:18]([O:20]C)=O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CC(C)([O-])C.[K+]>O1CCCC1>[NH:1]1[C:2]2=[C:3]3[C:8](=[N:9][C:10]4[CH2:11][CH2:12][CH2:13][CH:14]([C:15]=42)[O:16][CH2:17][C:18]1=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4]3
Reactant: COC(=O)COC1CCCc2nc3ccccc3c(N)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COC2CCCc3nc4ccccc4c(c32)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.3 %

Procedure:
To a solution of methyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)oxy]acetate (13.7 g) in tetrahydrofuran (200 ml) was added potassium t-butoxide (6.7 g). The reaction mixture was stirred at ambient temperature for 2.5 hrs and evaporated. The residue was stirred in dilute potassium carbonate solution/ethyl ether. The precipitate was collected and dried. A 3.5 g sample was recrystallized twice from methanol/water, passed through a column of basic alumina (5% methanol/ethyl acetate) and recrystallized from methanol to give 1.37 g (39%) of product, mp 173°-175° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12][CH2:11]3.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12][CH2:11]3
Reactant: CCCN1CCC[C@@H]2Cc3c(cccc3OC)C[C@H]21
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCN1CCC[C@@H]2Cc3c(O)cccc3C[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.6 g of trans-1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-N-n-propylbenzo[g]quinoline are dissolved in 100 ml of methylene chloride. 1.5 ml of boron tribromide, dissolved in 20 ml of methylene chloride are added dropwise and the mixture is stirred for 1.5 hours at room temperature. An excess of methanol is added to the mixture which is then concentrated in vacuum. This is repeated twice.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[NH:25][C:24](=[O:26])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[NH:25][C:24](=[O:26])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(C3CCC(=O)N3)cc2)cc1
Product: O=C1CCC(c2ccc(CCCCN3CCN(c4cccc(Cl)c4)CC3)cc2)N1

Procedure:
5-[4-(4-(p-Toluenesulfonyloxy)butyl)phenyl]pyrrolidin-2-one and 1-(3-chlorophenyl)piperazine are reacted together to give 5-[4-(4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)phenyl]-pyrrolidin-2-one.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.C1COCC1.O.Cl>C(OCC)(=O)C.O>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]([OH:23])=[O:4])=[CH:15]1
Reactant: COC(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
LiOH (1.6 g, 67.3 mmol) is added to [2-(1H-indol-3-ylsulfanyl)-phenyl]-acetic acid methyl ester (2 g, 6.73 mmol) in 27 mL mixture of THF/water (20:7). The reaction mixture is stirred for 10 minutes at 150° C. in a Emrys Optimizer EXP microwave reactor under microwave heating and cooled to room temperature. The reaction mixture is poured into water and acidified with concentrated HCl. Ethyl acetate is added and the organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=2)[CH2:9]1)C1C=CC=CC=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>C1(C)C=CC=CC=1>[CH3:23][S:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:9]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1cccc(NCC2CN(Cc3ccccc3)CCO2)c1
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSc1cccc(NCC2CN(C(=O)Oc3ccccc3)CCO2)c1

Procedure:
To a solution of 4-benzyl-2-(3-methylthioanilino)methylmorpholine (1.7 g.) in toluene (50 ml.) is added hexamethylphosphoramide (1 ml.) and then phenyl chloroformate (1.5 ml.). The mixture is heated under reflux for 18 hours, the toluene is then removed under reduced pressure, the oily residue is dissolved in ether and the ethereal solution is washed successively with sodium hydroxide solution, water, hydrochloric acid and water before drying over anhydrous magnesium sulphate. Evaporation of the dried filtered ethereal solution gives yellow oil (2.4 g.) or 2-(3-methylthioanilino)methyl-4-phenoxycarbonylmorpholine, which is dissolved in dimethylsulphoxide (20 ml.) and this solution is added to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (2.4 g.) and dimethylsulphoxide (50 ml.) ]. Water (1.8 ml.) is then added when the temperature of the mixture rises to about 60°C. The solution is stirred for 1 hour and then poured into water containing ice and the mixture extracted with ether (3 × 100 ml.). The ethereal solution is washed with water, dried (MgSO4) and filtered and the filtrate is treated with an ethereal solution of oxalic acid to precipitate 2-(3-methylthioanilino)methylmorpholine oxalate, m.p. 114°-115°C. after recrystallisation from acetone.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[C:32]1[S:33][CH:34]=[N:35][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:32]3[S:33][CH:34]=[N:35][N:36]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Brc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@@H]1CN(c2nncs2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 37.7 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (0.100 g, 0.296 mmol), diisopropylethylamine (0.0568 mL, 0.326 mmol), 2-bromo-1,3,4-thiadiazole (0.0587 g, 0.356 mmol) and cesium carbonate (0.106 g, 0.326 mmol) were suspended in N-methylpyrrolidone (2 mL). The suspension was heated using a microwave reactor at 180° C. for 30 minutes. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=1/1, then methanol/ethyl acetate=0/1, 1/9) to obtain 80 mg of the crude title compound. This was further purified by thin layer silica gel chromatography (developing solvent: methanol/dichloromethane=5/95) to obtain 43 mg of the title compound as a pale brown solid (36%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]1[C:20](=[O:43])[CH2:21][NH:22][C:23](=[O:42])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:9]1[C:20](=[O:43])[CH2:21][NH:22][C:23](=[O:42])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 48.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2.58 g of benzyl (4R)-3-{3-[2-(4-tert-butoxycarbonyl-2-benzyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenylacetate (isomer A) , 1.6 g of ammonium formate and 1.3 g of palladium on charcoal (10% Pd). 1.06 g of (4R) -3-{3-[2-(4-tert-butoxycarbonyl-2-benzyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenylacetic acid (isomer A), melting point 110° C., are thereby obtained; [α]D25 =-89.0°±1.6° (C %=0.51; methanol).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.N1CCCC1=O.C(Cl)[Cl:33]>>[CH2:10]([N:4]1[CH2:1][CH:2]([CH2:3][Cl:33])[CH:6]([Cl:7])[C:5]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)C(Cl)Cl
Reactant: ClCCl
Agent: O=C1CCCN1
Solvent: COCCOCCOC
Product: O=C1C(Cl)C(CCl)CN1Cc1ccccc1

Procedure:
Eleven and one-tenth grams of N-allyl-N-benzyl dichloroacetamide was dissolved in 12 ml. of diglyme and 1 g. of anhydrous ferrous chloride added. The mixture was heated at reflux under nitrogen until conversion to the pyrrolidinone was complete as indicated by GLPC. The mixture was diluted with methylene chloride, washed with 5 percent hydrochloric acid, separated, dried over anhydrous magnesium sulfate, treated with activated carbon and Florisil and stripped under vacuum. Yield was 6 g. of the title compound, nD30 1.5387.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:35][O:36][CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:39][CH2:38][CH2:37][O:36][CH3:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COCCN
Reactant: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2nc(C(=O)NCCOC)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 63 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (74c) (222 mg, 0.43 mmol), methoxyethylamine (0.1 mL, 1.15 mmol), WSC hydrochloride (260 mg, 1.36 mmol) and HOBT (55 mg, 0.41 mmol), to obtain 154.6 mg of the title compound as a white solid (63%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.Br[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[O:19]1[CH2:20][CH2:21][CH:16]([CH2:15][S:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:18]1
Reactant: Oc1cccc(S)c1
Reactant: BrCC1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(SCC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
3-Sulfanylphenol (250 mg) was dissolved in methanol (5 mL), and a 28% sodium methoxide-methanol solution (0.5 mL) was added thereto, followed by stirring at room temperature for 10 minutes. 4-(Bromomethyl)tetrahydro-2H-pyrane (410 mg) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain 3-[(tetrahydro-2H-pyran-4-ylmethyl)sulfanyl]phenol (265 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([NH2:24])[CH2:16]1>>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([NH:24][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=2)[CH2:16]1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1COc2ccccc21
Product: O=[N+]([O-])c1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
(2,3-Dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine was prepared according to step A in general example 2 from 2-chloro-6-nitro-quinoline and 2,3-dihydro-benzofuran-3-ylamine (CAS no.: 109926-23-4); MS: m/e=308.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[CH3:32])#[N:2].[BH4-].[Na+]>C(O)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[CH3:32]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(C)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(C)c2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a stirred solution of 2-(4-cyano-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (147 mg, 0.34 mmol) in ethanol was cooled to 0° C. and added NiCl2.6H2O (80 mg, 0.34 mmol) and stirred more than 15 mins. Sodium borohydride (81 mg, 2.35 mmol) was then added in small portions. The reaction was exothermic and effervescent. The resulting reaction mixture was allowed to warm to room temperature and left to stir for 2 h. The mixture was filtered using celite pad. The filtrate was concentrated was evaporated. The residue was dissolved in ethylacetate and washed with water and brine, but when it does not separate easily, small amount of 1N HCl and saturated NaHCO3 was used. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(Aminomethyl)-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (83 mg) was obtained as 56% yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[N:26]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[O:38][C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[O:38][C:39]2[N:44]=[CH:43][C:42]([C:45]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:25][C:7]=4[S:8][C:9]=3[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)=[O:46])=[CH:41][CH:40]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)nc1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)nc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and (±)-6-[[trans-2-(1-piperidyl)cyclohexyl]oxy]-3-pyridinecarboxylic acid (Part A) by essentially following the procedures detailed in Example 20, Parts D and E.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>COCCO>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: COCCO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.20 g), prepared in a similar manner to that described in Example 11, in 2-methoxyethanol (25 ml) was heated at 97° for 5.3 hours. The mixture was allowed to cool to ambient temperature and then evaporated in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 234°-235° (0.19 g).