Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][N:15]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]([OH:36])[CH2:20][C:18]2[C:17]([Cl:21])=[CH:16][N:15]=[C:14]([Cl:13])[N:19]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(Cl)ncc2Cl)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
N-butyllithium (1.6 M in hexanes, 4.99 mL) is added drop wise to diisopropylamine (1.13 mL) in tetrahydrofuran (20 mL) at −50 to −60° C. under an argon atmosphere. The mixture is stirred for 30 min at this temperature, cooled to −70° C., and 2,5-dichloro-4-methyl-pyrimidine (1.00 g) is added. After 1 h a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.37 g) in tetrahydrofuran (10 mL) is added and the resulting mixture is stirred for another hour. The reaction is quenched with acetic acid solution (1% in ethanol, 10 mL) and the mixture is diluted with ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→30:70) to give the title compound. LC (method 7): tR=1.40 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5](O)=[O:6].COC1C(Cl)=CC(Br)=C(Cl)C=1CO>>[CH3:1][O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[CH2:5][OH:6]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: COc1c(Cl)cc(Br)c(Cl)c1CO
Product: COc1c(Cl)ccc(Cl)c1CO

Procedure:
A process for the preparation of 2-methoxy-3,6-dichlorobenzoic acid comprising the steps of catalytically debrominating 2-methoxy-5-bromo-3,6-dichlorobenzyl alcohol to produce 2-methoxy-3,6-dichlorobenzyl alcohol, oxidizing said 2-methoxy-3,6-dichlorobenzyl alcohol to produce 2-methoxy-3, 6-dichloro benzonic acid, and recovering said 2-methoxy-3,6-dichlorobenzoic acid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)O1.Br[C:18]1[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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].O>[NH2:15][C:11]1[CH:10]=[C:9]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH:14]=[CH:13][N:12]=1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Reactant: CCOC(=O)c1coc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1coc(-c2ccnc(N)c2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (4.28 g), ethyl 2-bromo-1,3-oxazole-4-carboxylate (4.28 g), potassium carbonate (5.38 g) and DME (78 mL)/water (19.45 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.712 g), and the mixture was stirred at 80° C. for 3 hr under argon atmosphere, poured into water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.42 g).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Na].[N:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CO>[OH:18][C:15]1([CH2:4][N+:1]([O-:3])=[O:2])[CH2:14][CH2:13][N:12]([C:9]2[CH:8]=[CH:7][N:6]=[CH:11][CH:10]=2)[CH2:17][CH2:16]1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: C[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of nitromethane (2.31 ml) in methanol (5.4 ml) was added sodium (70 mg) at ice-cooled temperature. The resulting mixture was added dropwise to a solution of 1-(4-pyridyl)-4-piperidone (5.36 g) in methanol (10.7 ml) at ice-cooled temperature for 10 minutes, and stirred for 15 hours at room temperature. The precipitate was filtered, and washed with methanol to obtain the title compound (5.31 g).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>C(N(CC)CC)C>[CH:34]([O:33][C:31]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:32])([CH3:36])[CH3:35]
Reactant: CC(C)OC(=O)Cl
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Reaction of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with isopropyl chloroformate in the presence of triethylamine followed by hydrolysis of the methyl ester moiety according to example 1 gives N-isopropoxycarbonyl-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 452 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:20]=[C:17]([CH3:18])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Yield: 87.6 %

Procedure:
8.7 kg of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 11.7 kg of acetoamidine hydrochloride and 28.6 kg of potassium carbonate were stirred for 5 hours at about 50° C. in 34.5 kg of methanol. Insolubles were separated from the reaction mixture and washed with methanol, and the mother liquor and the washing were combined with water and neutralized with an 18% aqueous solution of hydrochloric acid. After neutralization, the crystal was ripened by stirring under reflux for 4 hours, and the precipitated crystal was isolated by centrifugation, washed with water, dried to obtain 7.4 kg of the target compound as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 86 %

Procedure:
As described for example 146d, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (trituration with tert-butylmethylether, 194 mg, 86%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C@H:32]([CH3:33])[CH2:31][N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](O)CN1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 24.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (60 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl)-propan-2-ol (100 mg), HBTU (180 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 484.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (m, 1H), 8.08 (s, 1H), 7.93-7.92 (d, 1H), 7.75 (br. m, 1H), 7.47-7.45 (br. d, 1H), 7.40-7.37 (m, 1H), 4.52-4.42 (m, 2H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 2.92-2.78 (m, 2H), 2.63-2.60 (m, 2H), 2.46-2.43 (m, 2H), 2.19-2.14 (m, 1H), 1.86-1.78 (m, 1H) 1.07-1.06 (d, 3H) —NH and OH proton signal was not observed.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:30]([N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:15][CH2:16]2)[C:21]1=[O:29])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)n1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A mixture of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (60 mg, 0.154 mmol, this was prepared as Example 17), pyridine (1 ml), acetic anhydride (44 μl, 0.462 mmol), and dimethylaminopyridine (6 mg, 0.0462 mmol) was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by preparative TLC (acetone/hexane:1/2) to give 48.2 mg (72.5%) of colorless oil.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[K+].Cl[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]>CN(C)C=O>[CH2:1]([S:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])[CH3:2]
Reactant: CCS
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCSc1ccccc1S(N)(=O)=O
Reaction time: 0.25 h

Procedure:
62 g (1.0 mol) of ethanethiol were added to a mixture of 65.9 g (1.0 mol) of 85% strength potassium hydroxide powder and 500 ml of dimethylformamide at 25° C. while stirring, and stirring was continued for 15 minutes. Thereafter, a solution of 95.8 g (0.5 mol) of 2-chlorobenzenesulfonamide was added at 90° C. while stirring in the course of 30 minutes, and stirring was continued for 8 hours at 110° C. The mixture was cooled and was evaporated down under reduced pressure, after which the residue was partitioned between methylene chloride and water, and the organic phase was washed with dilute sodium chloride solution. Evaporating down under reduced pressure gave 88.4 g (81.5% of theory) of the title compound as a semicrystalline mass.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].Cl[C:41]1[N:46]=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=[CH:43][N:42]=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:41]2[N:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:44]=[CH:43][N:42]=2)[CH2:28]1)=[O:26]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: Clc1nccc(-c2ccccc2)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 19 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C28H24N4O, 432.53; m/z found, 433.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O.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>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
A solution of 26 g (121 mmol) of methyl 5-bromonicotinate in toluene (220 ml) was admixed under argon at RT with 2.8 g (2.4 mmol) of tetrakis(triphenylphosphine)palladium, and then a solution of 30 g (146 mmol) of 4-trifluoromethoxyphenylboronic acid in ethanol (58 ml) was added. After adding 14 g (243 mmol) of potassium fluoride in water (58 ml), the mixture was stirred under reflux overnight, a further 0.70 g (0.61 mmol) of tetrakis(triphenylphosphine)palladium was added, and the mixture was stirred under reflux for a further 24 h. After adding another 1.4 g (1.2 mmol) of tetrakis(triphenylphosphine)palladium, the mixture was stirred under reflux for 20 h, and the reaction solution was admixed with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, cyclohexane/dichloromethane 1:1→dichloromethane). Yield: 31 g (86% of theory)
Reaction SMILES: [F:1][C:2]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6](=[O:22])[O:7][C:8]2[CH:15]=[C:14]([O:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].[Br:30]N1C(=O)CCC1=O.Cl>C1COCC1>[Br:30][CH2:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17](=[O:21])[N:18]([CH3:19])[CH3:20])=[CH:15][C:8]=2[O:7][C:6](=[O:22])[C:5]=1[CH2:4][C:3]1[CH:23]=[CH:24][CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2F)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(CBr)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42.6 %

Procedure:
THF (0.9 mL) was added to dimethylcarbamic acid 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-4) (47.6 mg), and the resultant suspension was stirred at −78° C. for 20 minutes to yield a dark brown solution. This solution was added at 0° C. to a solution of N-bromosuccinimide (28 mg) in THF (0.8 mL) (which had been prepared in advance in a separate container), and the mixture was stirred at 0° C. for 40 minutes. This reaction solution was poured into 1N hydrochloric acid (0.119 mL) diluted with ice water (20 mL), and then extracted with ethyl acetate. The organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to yield the title compound (24.3 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[CH:6]/[C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[C:9](Br)[CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(Br)cc2c1OCC2(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc2c1OCC2(C)C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A solution of (E)-3-(5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-acrylic acid ethyl ester (Intermediate 74, 0.97 g, 2.98 mmol) in 13 mL of ethyl acetate was treated with a slurry of 10% palladium on carbon (0.25 g) in 7 mL of ethanol and the resulting reaction mixture was stirred overnight under an atmosphere of hydrogen. The solids were then filtered over a bed of celite and the filtrate was evaporated to an oil. The oil was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as a pale yellow oil (0.71 g, 96%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21](Br)[CH2:20]1)[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([S:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)[CH2:20]1)[CH3:15]
Reactant: CC(C)Cc1ccc(S)cc1
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccc(CC(C)C)cc2)C1
Temperature: 25 °C

Procedure:
31.4 G. of 4-i-butylthiophenol and a solution of 10.6 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 49.5 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A yield of 42.5 g. of 3-(4-i-butylphenylthio)-4-ketocyclohexane acetic acid ethyl ester was obtained, b.p. 205-220/2.0 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][C:40](=O)[CH3:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[BH3-]C#[N:45].[Na+]>CO>[NH2:45][CH:40]([CH3:41])[CH2:39][O:38][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])=[O:16])[CH2:10]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: [Na+]
Solvent: CO
Product: CC(N)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 494.6 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-oxopropoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.0487 g, 0.078 mmol, 1.0 equiv), NaBH3CN (0.0296 g, 0.471 mmol, 6.0 equiv), NH4OAc (0.2550 g, 3.31 mmol, 42 equiv), and 4 A molecular sieves (0.0555 g) in MeOH (1 mL) was stirred at rt for 22 h. The reaction mixture was diluted with MeOH and filtered through filter agent, Celite® 545. The filtrate was evaporated under reduced pressure to afford 0.2405 g of crude 2-(trimethylsilyl)ethyl (2S)-2-((3R)-3-((1R)-(2-aminopropoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate, which was used in the next step without further purification. MS ESI +ve m/z 625 (M+H).
Reaction SMILES: [C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:49][CH:48]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:45][O:46][C:47]1[CH:48]=[CH:49][C:50]([N:53]2[CH2:58][CH2:57][N:56]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:55][CH2:54]2)=[CH:51][CH:52]=1
Reactant: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCC(COC(=O)N2CCN(c3ccc(OC)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
(1-(2-methoxyethyl)piperidin-4-yl)methanol (Intermediate 3, step 2; 1.34 g, 7.74 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (0.94 mL, 8.51 mmol) and 4-nitrophenyl chloroformate (1.56 g, 7.74 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes and then added to a solution of 4-(4-methoxyphenyl)piperazine (1.64 g, 8.51 mmol) and DIPEA (6.10 mL, 35.0 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq NaOH solution (5×125 mL), brine (100 mL), and then dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (0.637 g, 21.6%) as a pale yellow oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23].CC(C)=O.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]=2[CH:15]=1
Reactant: CN=C=O
Reactant: Oc1ccc2onc(NCCN3CCOCC3)c2c1
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CNC(=O)Oc1ccc2onc(NCCN3CCOCC3)c2c1
Yield: 32.9 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]-amino]-1,2-benzisoxazol-5-ol (1 g) and a catalytic amount of copper(I)chloride (0.05 g) in EtOAc (100 ml) was added methyl isocyanate (0.26 g). After 24 hours TLC (silica gel, 1:1:20 acetone/MeOL/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (1 l) and the filtrate was concentrated in vacuo. The residue was further purified by flash chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM to yield 0.4 g of the product, m.p. 135°-136° C.