Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1.C(O)C.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C=C/c1c(F)cc(OC)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.5 %

Procedure:
Ethyl(2E)-3-(2,6-difluoro-4-methoxyphenyl)acrylate (1.1 g, 4.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (30 mL), 10% palladium-carbon (0.30 g) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the obtained filtrate was concentrated to give the title compound (1.17 g, yield 100%) as a colorless oil.
Reaction SMILES: FC1C2OC(CN)CNC=2C=CC=1.[CH3:14][C:15]1[C:24]2[O:23][CH:22]([C:25]([NH2:27])=O)[CH2:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>>[CH3:14][C:15]1[C:24]2[O:23][CH:22]([CH2:25][NH2:27])[CH2:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc2c1OC(C(N)=O)CN2
Agent: NCC1CNc2cccc(F)c2O1
Product: Cc1cccc2c1OC(CN)CN2

Procedure:
This compound is obtained using the same experimental conditions as those used for the synthesis of intermediate 2b but by replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-carboxamide (4b) with 3,4-dihydro-8-methyl-2H-1,4-benzoxazine-2-carboxamide (4c). The title compound of formula (2c) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=O)[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[SH:24]>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[S:24][C:13]([CH2:14][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][C:10]([OH:12])=[O:11])=[N:16][C:17]=2[CH:22]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2cc(Cl)ccc2s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
A mixture of 3-(4-chlorophenyl)glutaric anhydride (0.5 g) and commercial 2-amino-4-chlorothiophenol (0.37 g) is dissolved in boiling dichloromethane (3 ml). The solution is stirred overnight at rt. The precipitate is isolated by suction filtration, washed with dichloromethane, and dried in vacuo. The crude product is recrystallised from acetone to give 0.3 g of 4-(5-chloro-2-benzothiazolyl)-3-(4-chlorophenyl)butanoic acid as colourless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:2]1.S([O-])(=O)(=O)C.[C:22]([CH:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23].C(OCC)(=O)C.CCCCCC>C1COCC1.CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH:24]([C:22]#[N:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=2)=[O:12])=[CH:2]1
Reactant: CC(C)C(C(=O)O)c1csc2ccccc12
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: CS(=O)(=O)[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1csc2ccccc12
Reaction time: 0.25 h

Procedure:
A mixture of 2-(3-benzothienyl)-3-methylbutanoic acid (3.4 mmol) and KCHO3 (3.4 mmol) on 15 ml THF/DMF (1:1) is stirred for about 15 minutes. The mesylate of α-cyano-3-phenoxybenzyl alcohol (3.4 mmol) in 5 ml THF/DMF is added and the reaction mixture stirred for about 48 hours. The reaction is worked up as in Example 2, developing with 10% ethyl acetate/hexane to yield α-cyano-3-phenoxybenzyl 2-(3-benzothienyl)-3-methylbutanoate, colorless thick liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][N:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][NH:2][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:8]=1[CH:9]=[O:10]
Reactant: CNc1ncccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CNc1ncccc1C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
9.10 g (66.0 mmol) of (2-(methylamino)-3-pyridinyl)methanol was dissolved in chloroform (70 mL), and 17.4 g (200 mmol) of manganese dioxide was added thereto. The mixture was stirred overnight at 60° C. The reaction mixture was filtered, and the filtrate was concentrated. Thus, 8.66 g (yield: 96%) of the title compound was obtained as an orange-colored solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 76.1 %

Procedure:
A mixture of 0.50 g (0.0014 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281) and 0.27 g (0.0017 mole) of 4-amino-3-methoxy-benzoic acid in 3.2 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.53 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]2.[Cu][C:31]#[N:32].C(OCC)(=O)C.[OH-].[Li+]>CN(C)C=O.O1CCCC1.O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:31]#[N:32])=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: N#C[Cu]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(I)cc3C)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1Oc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of 0.34 g (0.63 mmol) of Ethyl 6-chloro-7-(2-methyl-4-iodophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 68 mg (0.76 mmol) of copper (I) cyanide in 4 mL of anhydrous dimethylformamide was stirred to 130° C. overnight. LC-MS indicated that the reaction was completed. After cooling to room temperature, the reaction was dumped into 100 mL of ethyl acetate. The organic solution was then washed with 30% aqueous ethylenediamine solution three times to remove cupper, then washed with with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane. The obtained compound (0.14 g, 0.32 mmol) was dissolved in 3 mL of tetrahydrofuran. To the resulting solution was added a solution of 67.2 mg (1.6 mmol) of lithium hydroxide (LiOH.2H2O) in 3 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to 50° C. for one hr, then at rt for one hr. The volatiles were removed. The residue was diluted with water, and acidified at 0° C. with dilute hydrochloric acid to pH=1, and the product was extracted with ethyl acetate. The combined organic extracts were washed with birne, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on reverse phase HPLC. The product was obtained as white solid, 70 mg, purity=100%, yield=27%. 1H NMR (CDCl3/CD3OD/300 MHz) 7.66(s, 1H), 7.56(d, 1H), 7.46(dd, J=1.5, 8.4 Hz, 1H), 7.34(s, 1H), 6.80(d, J=8.4 Hz, 1H), 6.51(s, 1H), 5.66(q, J=6.9 Hz, 1H), 2.31(s, 3H); MS (ES+) 410 (M+1, 100); HRMS (ES−) m/z calcd for (M−1; C19H10ClF3NO4) 408.0245, found 408.0227.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH3:16])[CH:10]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
60 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (44 mg, 0.206 mmol), 1-phenylpiperazine (0.031 mL, 0.206 mmol), DIPEA (0.054 mL, 0.310 mmol) and NaBH(OAc)3 (131 mg, 0.621 mmol).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:34])[O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](C(C)(C)C)(C)C)=[CH:14][C:13]=2[O:26][Si](C(C)(C)C)(C)C)[CH2:8][CH2:7]1)[CH3:2].[F-]>CO>[CH2:1]([NH:3][C:4](=[O:34])[O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:26])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Agent: [F-]
Solvent: CO
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl ethylcarbamate (18 mg), methanol (10 ml) and Amberlyst fluoride resin (0.3 g) were stirred at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) to give the title compound as a white solid (24 mg, 87%). δH (CD3OD) 1.10 (3H, t), 1.40-1:60 (4H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 2.72-2.80 (1H, m), 3.10 (2H, t), 4.50-4.60 (1H, m), 6.20-6.26 (2H, m), 6.88 (1H, d); m/z (ES+) 280 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])=[N:5][CH:4]=1)=[O:2].Cl.C(OCC)C>C(Cl)Cl>[NH2:16][C@@H:14]([CH3:15])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](N)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 137.6 %

Procedure:
Following the procedure as described in Example 68, except using material from Example 69 (265 mg, 0.743 mmol), CH2Cl2 (50 mL), HCl, 11.0M in diethyl ether (5 mL, 5.00 mmol) and stirring at room temp for 2.5 days, 262 mg (quantitative yield) of the title compound is obtained as a pale yellow solid, as a bis HCl salt by weight. LC/MS (Condition A): ret. T=0.93 min, (M+H)+ 257.14.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8](OC(C)=O)=[O:9].C([O-])(O)=O.[Na+].Cl>O>[OH:4][CH2:3][C:2]([NH:1][C:8](=[O:9])[CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-2-methyl-propan-1-ol (2.0 mL, 20.4 mmol), acetanhydride (1.9 mL, 20.4 mmol) and NaHCO3 (2.6 g, 30.6 mmol) in H2O (20 mL) is stirred at RT for 16 h. For workup 1N HCl is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined extracts, filtration and evaporation of the solvent yields the title compound as a colorless solid. MS (LC-MS): [M+H]+=132.2. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.38 min.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C@@H:23]([OH:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.OO.[OH-].[Li+].S([O-])([O-])=[O:38].[Na+].[Na+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([C@@H:23]([OH:32])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([OH:9])=[O:38])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S([O-])[O-]
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H](CC1CCCC1)[C@@H](O)CCc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)[C@@H](O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 166.4 %

Procedure:
Acyloxazolidinone 3 (226 mg, 0.500 mmol) was dissolved in 3 mL of THF and 1 mL of distilled water. The resulting solution was cooled to 0° C. To this solution was added 30% aqueous hydrogen peroxide (0.40 mL, 4.0 mmol), followed by a solution of lithium hydroxide (19 mg, 0.80 mmol) in 0.5 mL of distilled water. After the solution was stirred for 16 h, sodium sulfite (567 mg, 4.50 mmol) in 3 mL of distilled water was added. The bulk of tetrahydrofuran was removed under reduced pressure, and the resulting mixture (pH 12˜13) was extracted with three 20 mL portion of methylene chloride to remove the oxazolidinone auxiliary. The aqueous layer was cooled in an ice bath and acidified to pH 1 with 6 M aqueous hydrochloric acid. The resulting cloudy solution was extracted with five portion of 30 mL ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 230 mg (81%) of the desired acid 4 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.18-7.35 (5H, m), 3.87 (1H, m), 2.81-2.87 (1H, m), 2.60-2.76 (1H, m); 2.54-2.60 (1H, m), 1.00-1.95 (m, 13H). 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:13])=[N:6][C:7]([N+:10]([O-])=O)=[CH:8][CH:9]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[C:5]([CH3:13])=[N:6][C:7]([NH2:10])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])nc1C
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(N)nc1C
Yield: 90.8 %

Procedure:
18.2 g of the nitro compound obtained above was suspended in 300 ml of ethanol, which was reduced over 2 g of 5% palladium black under atmospheric pressure. After reaction, the catalyst was filtered off and the solvent was evaporated in vacuo. The residue was crystallized from benzene to obtain 13.8 g of 3-ethoxy-2-methyl-6-aminopyridine (Compound IV where R2 =C2H5), m.p. 98°-99° C.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl.CC#N>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(c2ccccc2)N2CCNCC2)c1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
To a solution of phenyl(3-(trifluoromethyl)phenyl)methanol (10.0 g, 39.6 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (5.78 mL, 79.3 mmol) dropwise at rt. After the addition, the reaction was warmed to 40° C. for 18 h. The solvent was evaporated in vacuo and the residue was dried under vacuum pump for 1 h. The residue was dissolved in CH3CN and added to a solution of piperazine (13.7 g, 159 mmol) in CH3CN and heated to 100° C. for 12 h. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3 or Na2SO4, filtered, and concentrated. The crude product 1-(phenyl(3-(trifluoromethyl)phenyl)-methyl)piperazine (10.8 g, 85.0% yield) an oil was used without further purification or can be purified by ISCO flash chromatography using 0-15% 2N NH3 methanol solution in CH2Cl2. MS (ESI, pos. ion) m/z: 321.1 (M+1).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.C(NC(C(N1CCC[C@H]1C(O)=O)=O)CSC(=O)C)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: COc1ccc(COC(=O)NCCCC(CS)C(=O)N2CCC[C@H]2C(=O)O)cc1

Procedure:
By substituting 1-[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline for the N,S-diacetyl-DL-cysteinyl-L-proline in the procedure of Example 5, 1-[2-mercaptomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]2[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][C:9]=1[CH3:21])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)(Cl)Cl>[OH:25][C:24]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]3[NH:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][C:9]=2[CH3:21])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2c(C)cc(-c3n[nH]c(=O)[nH]3)cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2n[nH]c(=O)[nH]2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of the title compound of Step B (4.7 mg, 0.013 mmol) in chloroform (0.5 ml) was added boron tribromide (1M in dichloromethane, 0.26 ml, 0.26 mmol) and the mixture was stirred at room temperature for about one hour. The reaction was quenched with water (5 ml), acidified with 1N HCl (1 ml), and extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried, filtered, and concentrated to afford the title compound (4.2 mg). MS (APCl−) Calc: 339.2, Found: 338.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22].ClCCl.[C:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:28])[CH3:27]>C(N(CC)CC)C>[C:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][S:18]([C:16]1[S:17][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13](=[O:14])[C:12]=2[CH:15]=1)(=[O:20])=[O:19])(=[O:28])[CH3:27]
Reactant: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Reactant: CC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCNS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(C)nc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To 8.0 g of 3,4-dihydro-3-(2-chlorophenyl)-6-chlorosulfonyl-2-methyl-4-oxothieno[2,3-d]pyrimidine were added 150 ml of dichloromethane, 3.3 g of 4-acetylaminobutylamine and 5.9 ml of triethylamine, and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was washed with water, the concentrated residue was purified by means of silica gel chromatography to obtain 5.71 g of oily substance, which was crystallized from ethyl acetate-hexane to afford 4.44 g of the title compound, m.p. 203°-206° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[C:14](#[N:16])C.[C-]#N>C1(C)C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([C:14]#[N:16])=[O:7]
Reactant: CC#N
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Cu]
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C#N)cc1OC
Reaction time: 0.5 h

Procedure:
A well stirred mixture [paddle stirrer] of 3,4-dimethoxybenzoyl chloride [AcrosOrganics] (14.05 g; 0.070 mol), dry toluene (32 cm3), dry acetonitrile (8.0 cm3), copper I cyanide (8.5; 0.095 mol) and Celite (5 g) was heated under reflux until no acid chloride remained (−1.5 hrs). The dark reaction mixture was cooled to ˜70° and diluted with toluene (150 cm3). After stirring for an additional ˜30 minutes, the resulting slurry was filtered through a bed of chromatographic silica gel (˜2.5 cm) and the pale yellow filtrate evaporated in vacuo to constant weight to give the title compound as a lemon yellow solid. Yield=11.41 g (85.3%), Mpt=143-145° C. The product was used directly in next stage.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][O:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:8][C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH:11]([O:10][CH3:9])[CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: COC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC1CCN(c2cccc(Br)c2)C1
Reaction time: 8 h

Procedure:
Into a 250 mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (11.9 g, 50.42 mmol) in toluene (100 mL). To this was added 3-methoxypyrrolidine (6.1 g, 60.40 mmol). Addition of Pd(OAc)2 (113 mg, 0.50 mmol) was next. This was followed by the addition of BINAP (940 mg, 1.51 mmol). To the mixture was added Cs2CO3 (40.9 g, 125.54 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:30 ethyl acetate/petroleum ether solvent system. This resulted in 8.3 g (64.3%) of 1-(3-bromophenyl)-3-methoxypyrrolidine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[CH3:20][S:21][CH2:22][S:23]([CH3:25])=[O:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:22]([S:21][CH3:20])[S:23]([CH3:25])=[O:24])[CH:15]=[N:14]1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CSCS(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CSC(=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)S(C)=O

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde [15 g) and methyl methylthiomethyl sulphoxide (6 ml) were heated under reflux in tetrahydrofuran (100 ml) containing Triton B solution (6 ml; 40% in methanol) for 12 hours. The mixture was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-methylthio-2-methylsulphinylvinyl)- 2H-1,2,3-triazole, m.p. 122°-123°.