Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6].S(Cl)([Cl:24])(=O)=O.O.C(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]([Cl:19])([Cl:20])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CCl
Temperature: 40 °C
Reaction time: 7 h
Yield: 100.7 %

Procedure:
A mixture of ethyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (20 g) and sulfuryl chloride (7.7 g) in acetic acid (20 ml) was stirred at 40° C. for 7 hours. After the reaction mixture was added to a mixture of water (100 ml) and methylene chloride (100 ml) with stirring, the separated organic layer was washed with 5% aqueous sodium bicarbonate and water, followed by drying over magnesium sulfate. Removal of the solvent gave ethyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-4-chloro-3-oxobutyrate (22 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1(CO)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.[C:41](=O)(O)[O-:42].[Na+]>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH:41]=[O:42])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1ccc(S(=O)(=O)N2CCCCCC2(CO)C(=O)OC(C)(C)C)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of Hydroxymethyl-1-(4-methoxy-benzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester (0.5 g, 1.25 mmoL) in 1.25 mL in THF was added sodium bromide (19 mg, 0.19 mmoL). This suspention was cooled to 0° C. and TEMPO (25 mg, 5%) was added in followed by 1.41 mL of a 0.129M solution of sodium bicarbonate in Clorox bleach. The magnetic stirring was increased to obtain a biphasic solution and kept at that rate for three hours while the reaction gradually warmed to ambient temperature. The reaction was then quenched with sodium sulfite (1.26 g). After 20 minutes water and ethyl acetate were added in, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent removed under reduced pressure, and the residue was purified by column chromatography (silica: 15% to 25% ethyl acetate in hexanes) to yield 3-Formyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =398, (M+NH4)+ =415.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:2]([NH:1][C:40]([C@@H:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39][N:30]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl (3S)-3-(N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2S)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (380 mg, 0.87 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (250 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (540 mg, 1.8 mmol), HOAT (140 mg, 1.0 mmol), and DMF (25 mL). Crude material was obtained in a quantitative yield and used without further purification. MS (ESI, pos. ion) m/z: 696 (M+H), (ESI, neg. ion) m/z: 694 (M−H). Calc'd for C35H42ClN5O6S: 695.25.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[NH:29]2.Br.BrCC1C=CC=CN=1.BrCC1(C(F)(F)F)CC=CO1>>[N:29]1[CH:25]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:26][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=3[O:21][CH2:20]2)[C:11]1=[O:19]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)C1(CBr)CC=CO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-2-(trifluoromethyl)furan, 1′-(pyridin-2-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (39%): mp 150-152° C.; 1H NMR (300 MHz, CD3OD) δ 8.89-8.78 (m, 1H), 8.62-8.47 (m, 1H), 8.07-7.00 (m, 2H), 7.42-6.70 (m, 7H), 5.52-5.31 (m, 2H), 5.05 (d, 1H), 4.89 (d, 1H); 13C NMR(75 MHz, CD3OD) δ 179.4, 163.5, 153.1, 152.7, 148.2, 143.8, 142.8, 133.1, 130.6, 129.3, 127.4, 126.8, 125.7, 125.6, 125.4, 114.9, 110.4, 104.9, 82.0, 58.9, 43.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[OH:7])=[O:5])[CH3:2].[OH-].[Na+].Cl[C:18](OCC)=[O:19]>>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:18](=[O:19])[O:7]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)N(O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-(4'-chlorophenyl)-3-hydroxyurea (8.0 g; 0.037 mole) prepared above was dissolved in cooled (10° C.) 2 N aqueous sodium hydroxide (21 ml.). Ethyl chloroformate (3.9 ml; 0.041 mole) was added dropwise at 10°-15° C. with stirring and the stirring was continued for about 1/2 hour after addition was completed. The desired compound precipitated as formed and was removed by filtration, washed with water, air dried, and recrystallized from methanol to yield solid 2-(4'-chlorophenyl)-4-ethyl-1,2,4-oxadiazolidine-3,5-dione as tan needle-like crystals melting 84°-86° C. and having the following elemental analysis as calculated for C10H9ClN2O3 :
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCOCC1>[CH3:24][C:23]([CH3:26])([O:27][C:28]([N:11]1[CH2:12][C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:10]1[C:13]([OH:15])=[O:14])=[O:29])[CH3:25]
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of (cis)-4-(phenylthio)-L-proline (5 g) and triethylamine (3.4 g) in water (13 ml), a solution of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (6.0 g) in dioxane (13 ml) is added. The mixture is stirred at ambient temperature. After one hour, water (50 ml) is added, the mixture is washed with ethyl acetate and acidified to a pH of 3-4 with 10% citric acid. The oil that separates is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The residue is dissolved in saturated sodium bicarbonate (50 ml) plus water (600 ml). The alkaline solution is washed with ether and acidified to a pH of 4 with 10% citric acid. The oil that separates from solution is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The solvent is removed in vacuo to give the product as an oil (5.9 g) that gradually solidifies, melting point 110°-118° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:25])=[O:26])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:9]1
Reactant: Cc1cc(OCC2CCCN(C(=O)OC(C)(C)C)C2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCC2CCCNC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 95.1 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[[N-(tert-butoxycarbonyl)piperidin-3-yl]methoxy]-5-methylphenyl ester (745 mg, 1.5 mmol), as prepared in the preceding step, was treated with 20 mL of 4N HCl in 1,4-dioxane at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with NH3) to give the title compound as a colorless syrup (565 mg, 94%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (t, 1H), 1.94 (m, 3H), 2.23 (s, 3H), 2.45 (bs, 1H), 2.77 (t, 2H), 3.50 (dd, 2H), 3.76 (m, 2H), 6.46 (d, 1H), 6.55 (d, 2H), 7.40 (dd, 1H), 7.62 (m, 2H), 7.96 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19 H22NO4SCl: 396.1 (M+H), 418.1 (M+Na), Found: 395.8, 418.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Yield: 80.5 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1-phenethyl-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (57 mg, 0.14 mmol) and N-bromosuccinimide (27 mg, 0.15 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes) to give 54 mg of the title compound as a light yellow solid. MS: (−) m/z 477.13, 479.08 (M-1, 79/81Br).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].O=C(CCC)OCC(OC(=O)CCC)COC(=O)CCC>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9]
Reactant: CC(O)c1ccccc1Br
Agent: CCCC(=O)OCC(COC(=O)CCC)OC(=O)CCC
Product: C[C@H](O)c1ccccc1Br
Temperature: 35 °C
Reaction time: 360 h
Yield: 36.9 %

Procedure:
An enzyme (Amano CES, tradename of a lipase made by Amano Seiyaku Company) (10 g), ±-1-(2-bromophenyl)ethanol (7.0 g, 35 mmol) and tributyrin (15.9 g, 52.5 mmol) were placed in a three-necked flask, followed by agitating these materials at 35° C. for 15 days, stopping the reaction, thereafter filtering off the enzyme, concentrating the filtrate and subjecting the concentrate to silica gel chromatography to isolate the respective objective products. As a result, (S)-1-(2-bromophenyl)ethanol ([α]D23.5° C. : -26.3° (C 3.72, CHCl3)) (2.6g) and R-1-(2-bromophenyl)-1'-butanoyloxyethane (25 g) were obtained, followed by hydrolyzing the latter compound to obtain R-1-(2-bromophenyl)ethanol ([α]D23.5° : 30 33.5° (C 3.52, CHCl3)) (1.7 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][OH:12])=[CH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCC1=CCC2(CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of spiro[4.5]dec-7-en-8-yl-methanol (0.7 g) obtained in Step 4 in a mixed solvent of tetrahydrofuran (7 mL)-methanol (7 mL) was added 5% palladium carbon (70 mg), followed by stirring the reaction mixture at room temperature under normal pressure in an atmosphere of hydrogen for 1.5 hours and then under increased pressure of 0.3 MPa in an atmosphere of hydrogen for 3 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in methanol (5 mL). To the solution was added sodium borohydride (0.14 g), followed by stirring the reaction mixture at room temperature for 30 minutes. After addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4) to give spiro[4.5]dec-8-yl-methanol (0.528 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](O)(=[O:14])[CH3:13]>>[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:14])[CH3:13]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Product: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
4-Nitrophenylhydrazine (15.0 g, 0.10 mole) and acetic acid (24.0 g, 0.40 mole) were mixed in a flask equipped with a stirrer and reflux condenser and heated at about 90° C for one hour. The solid mass was collected, washed with water, and then dissolved in hot ethanol. The resulting solution was chilled in ice to give tan needles. Yield 14.4 g (74%), mp 207°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1.CC1C=C(OC)C=CC=1.BrC1C=CC(C(Cl)=O)=CC=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69].[H-].[Na+].[Cl-].[NH4+]>ClC(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[CH2:18][O:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1
Reactant: CC(C)(C)OC(=O)NO
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: COc1cccc(C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(CONC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A solution of 3 g of (4-bromo-phenyl)-(2-methyl-4-methoxyphenyl)-methanone (prepared from 3-methylanisole and 4-bromobenzoyl chloride by Friedel-Crafts reaction analogously to Ex. 14a) in 100 ml of tetrachloromethane is treated with 2.1 g of N-bromosuccinimide and a spatula tip of dibenzoyl peroxide. The reaction mixture is stirred at room temperature for 6 hrs. under irradiation, subsequently diluted with 100 ml of methylene chloride and washed in succession with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase is dried, filtered and immediately reacted. The solution is added dropwise to a mixture, previously stirred at 0° C., of 2.13 g of tert-butyl N-hydroxy-carbamate and 0.38 g of sodium hydride in 30 ml of TMF. The reaction mixture is warmed to room temperature and stirred. For the working-up, the mixture is treated with 60 ml of saturated ammonium chloride solution and the separated organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. After chromatography of the residue (silica gel, ethyl acetate-hexane, 10:90 to 25:75) there are obtained 2.65 g of tert-butyl [2-(4-bromo-benzoyl)-5-methoxy-benzyloxy]-carbamate, MS: m/e 436 (M+H+, 1 Br).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127.9 %

Procedure:
To a solution of methyl (1R,2S)-2-{[(benzyloxy)carbonyl]amino}cyclopentanecarboxylate (6.5 g, 23.5 mmol) in ethyl acetate (200 mL), 5% Palladium on carbon (1.3 g, 20% w/w) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 1.5 h, passed through a plug of Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-aminocyclopentanecarboxylate (4.30 g, 30.05 mmol, quantitative), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.57 (2H, m), 1.90 (3H, m), 2.05 (1H, m), 2.81 (1H, m), 3.61 (1H, m), 3.72 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4]C=1C.[Mn]([O-])(=O)(=O)=O.[K+].[C:16]([O:19]CC)(=[O:18])[CH3:17]>O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:17]=1[C:16]([OH:19])=[O:18]
Reactant: Cc1ccc(I)cc1F
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Product: O=C(O)c1ccc(I)cc1F

Procedure:
2-Fluoro-4-iodo-1-methylbenzene (1.0 g) was added to a solution of potassium permanganate (2.0 g) in water (25 ml). The mixture was gently refluxed for 2 h. Tetrabutylammonium bisulphate (100 mg) was added and the mixture was refluxed for 18h. The cooled solution was treated with ethyl acetate (100 ml) and water (50 ml) and the brown suspension was filtered. The dried organic phase was evaporated and the resulting solid was partitioned between aqueous sodium bicarbonate (2N; 50 ml) and diethyl ether (2×30 ml). The basic solution was acidified with hydrochloric acid (2N) and extracted with dichloromethane (3×50 ml). The dried extract was evaporated to give the title compound as a white solid (120 mg), m.p. 158°-159°.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1>C(Cl)(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([N:5]=[C:1]=[S:2])=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(Cl)nc1
Yield: 56.9 %

Procedure:
A solution of thiophosgene (3.21 mL, 42.1 mmol) in chloroform (10 mL) was heated at reflux and treated with a solution of 5amino-2-chloropyridine (3.61 g, 28.1 mmol) in chloroform (25 mL) for 40 minutes. The solution was heated an additional 2 hours, the reaction mixture was cooled, and the solids formed were removed by filtration. Concentration of the filtrate provided 2.73 g of the desired product as a white solid.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[N:19]([CH3:20])[N:18]=[C:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[OH:46]>O>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:46][C:37]3[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:36]=3[F:35])=[C:7]([Cl:6])[CH:8]=2)[N:19]([CH3:20])[N:18]=1
Reactant: Oc1ccc(C(F)(F)F)cc1F
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To 100 ml of N,N-dimethylformamide are added 5-(3-chloro-4-chloromethylphenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) and potassium carbonate (0.60 g) and 2-fluoro-4-trifluoromethyl phenol (0.80 g) is added thereto at room temperature with stirring, which is stirred at 70° C. for 3 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.62 g of desired compound (refractive index: 1.6010).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: CCC(NC(=O)Cc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above) the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.BrC[CH:44]1[CH2:46][CH2:45]1>ClCCl.O1CCOCC1>[CH2:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:44]2[CH2:46][CH2:45]2)[CH2:16][CH2:17]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: BrCC1CC1
Reactant: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CO[C@H](CN1CCN(CC2CC2)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, 4.60 mmol) was dissolved in 30 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The resulting solution was concentrated under reduced pressure. The residue was added with 40 mL of acetonitrile. In an ice-water bath, the resulting solution was added with triethylamine (2.09 g, 20.70 mmol), stirred for 0.5 hours followed by the addition of bromomethyl-cyclopropane (0.88 g, 6.47 mmol). The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure, added with 20 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2S)—N,N-dibenzyl-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35c (1.52 g, yield: 81.3%) as a brown oil.