Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15]CC)=[CH2:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.Br.OS([O-])=O.[Na+]>CC#N.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=[O:14])[CH2:15][Br:25])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of vinyl ether from Step 1 (1.02 g) in CH3CN:H2O 4:1 (25 mL) were successively added NBS (0.82 g) and concentrated HBr (20 μL). After being stirred at r.t. for 4 h. The reaction mixture was treated with 5% aqueous NaHSO3 (1 mL). Ethyl acetate was then added and the organic phase was washed with saturated aqueous NaHCO3, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (85:15)) afforded the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH2:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:20]([C:17]3([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]3)=[O:21])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: NC1CCc2cc(Br)cnc21
Product: O=C(NC1(C(=O)NC2CCc3cc(Br)cnc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], (rac)-3-bromo-6,7-dihydro-5H-[1]pyrindin-7-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to yield the title compound as grey solid. MS: 392.0 (MH+, 1Br).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH2:39][C:40]([N:26]1[CH2:27][CH2:28][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:24][CH2:25]1)=[O:41]
Reactant: O=C(Nc1ccccc1)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)c1ccccc1N1CCN(C(=O)CCl)CC1
Temperature: 4 °C
Reaction time: 2 h
Yield: 666.4 %

Procedure:
4-(2-phenylcarbamoyl-phenyl)-piperazine trifluroacetate (0.454 g, 1.150 mmol) is dissolved in 10 mL of CH2Cl2 containing diisopropylethyl amine (0.554 mL, 3.000 mmol). The mixture is cooled to 4° C. and chloroacetyl chloride (0.105 mL, 0.130 mmol) is added in a dropwise fashion. The reaction is stirred for 2 h in ice bath and then quenched with 20 mL of saturated NH4Cl. The reaction is diluted with 100 mL EtOAc and washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The crude product is purified via a SiO2 column and (0-75% EtOAc/hexanes) to give 310 mg of 2-[4-(2-chloro-acetyl)-piperazin-1-yl]-N-phenyl-benzamide in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[N:19]=1)([OH:17])[CH2:13]2.[C:32]([NH:39][CH2:40][CH2:41][NH2:42])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[N:19]=[C:20]([NH:42][CH2:41][CH2:40][NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:21]=[CH:22][CH:23]=1)([OH:17])[CH2:13]2
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: OC1(c2cccc(Br)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Temperature: 25 °C

Procedure:
Stir a solution of the product from Step 1 (64.5 mg, 0.128 mmol), N-Boc-ethylenediamine (123 mg, 0.77 mmol) and pyridine (12 mg, 0.154 mmol) at 110° C. in a sealed tube for 3.5 h. Cool to RT, add N-Boc-ethylenediamine (0.3 ml) and heat at 140° C. overnight. Cool to RT, quench the reaction with H2O, extract with EtOAc, dry and concentrate. Purify the residue by column chromatography to give the desired product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4][CH3:5].N[C@@H](CO)[C@H](C)[OH:36]>>[OH:1][CH2:2][C@@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[C@H:4]([OH:36])[CH3:5]
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Reactant: C[C@H](O)[C@@H](N)CO
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(N[C@H](CO)[C@@H](C)O)nc12
Yield: 42 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 12 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of D-threoninol. Yield=42%, Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.7 Hz, Harom), 7.97 (d, 2H, J=8.3 Hz, Harom), 7.78-7.69 (m, 2H, Harom) 7.63 (s, 1H, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.71 (bs, 1H, NH), 5.62 (d, 1H, J=6.6 Hz, NH), 4.77 (d, 2H, J=6.0 Hz, CH2), 4.22-4.15 (m, 1H, CH), 3.97-3.84 (m, 3H, CH 4-CH2), 3.01 (hept, 1H, J=7.0 Hz, CH), 1.29 (d, 3H, J=6.2 Hz, CH3), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (EST): m/z 448 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:15](OC)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:19][C:20]([F:22])([F:21])[F:23])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Methyl 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutanoate (1.15 g, 2.81 mmol), prepared in the previous step, was dissolved in 28 mL of anhydrous tetrahydrofuran and cooled to 0° C. Lithium aluminum hydride (1M solution in THF, 5.6 mL, 5.6 mmol) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched by careful addition of 0.22 mL of water, 0.22 mL of 15% aqueous KOH, followed by 0.66 mL of water and the mixture was stirred for 20 min. The mixture was diluted with ethyl acetate and filtered through the Celite™ reagent. The filtrate was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 5% acetone/hexane) afforded 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutan-1-ol (0.81 g, 76%) as a white solid. mp 120-121° C. HRMS: calcd for C13H12BrF3N2OS+H+, 380.98785; found (ESI, [M+H]+), 380.9886. Analytical HPLC: retention time 10.2 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[S:7](N)(N)(=[O:9])=[O:8]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][NH:6][S:7]1(=[O:9])=[O:8]
Reactant: NS(N)(=O)=O
Reactant: CNCCCN
Product: CN1CCCNS1(=O)=O

Procedure:
To a solution of N-methyl-1,3-diaminopropane (37.6 mL, 312 mmol) and sulfamide (10.0 g, 104 mmol) were heated at reflux for 16 hr. The solvent was evaporated in vacuo and the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH:30]([NH:32][NH2:33])=[O:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH:30]([NH:32][NH:33][C:27]([C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26]1)=[O:28])=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)O)CC3)s2)c1
Reactant: NNC=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)NNC=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
1-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylic acid (TFA salt, 110 mg, 0.206 mmol), formic acid hydrazide (37 mg, 0.617 mmol), HOBT (95 mg, 0.617 mmol), and EDC (118 mg, 0.617 mmol) were combined with DMF (5 mL) and DIEA (80 mg, 0.617 mmol). The reaction was stirred for 3 h at room temperature. It was subsequently diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether and filtered to provide N′-formyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarbohydrazide (88 mg, 92%) as a colorless solid. MS ESI: [M+H]+ m/z 463.0.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](O)=[O:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:20]([C:19]2[C:18]([F:17])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[OH:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1c(F)cccc1F)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,6-difluorobenzoic acid
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:18])[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([N:29]1[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:51]COC)([C:47]([F:50])([F:49])[F:48])[C:43]([F:46])([F:45])[F:44])=[CH:38][C:37]=2/[CH:55]=[CH:56]\[CH3:57])[CH2:31][C@H:30]1[CH3:58])=[O:28].O>CN(C)C=O>[F:45][C:43]([F:44])([F:46])[C:42]([C:39]1[CH:40]=[CH:41][C:36]([N:32]2[CH:33]([CH3:35])[CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:13]3[C:12](=[O:17])[C@@:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=4)([CH3:18])[NH:15][C:14]3=[O:16])[C@H:30]([CH3:58])[CH2:31]2)=[C:37](/[CH:55]=[CH:56]\[CH3:57])[CH:38]=1)([OH:51])[C:47]([F:50])([F:49])[F:48]
Reactant: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CBr)C[C@@H]1C
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CN2C(=O)N[C@@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
5-[4-(1-Methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (7.7 mg, 0.0311 mmol) was dissolved in N,N-dimethylformamide (500 μL), added potassium carbonate (8.6 mg, 0.0622 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, (2R,5S,Z)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-(prop-1-en-1-yl)phenyl}-2,5-dimethylpiperazin-1-yl)ethanone (17 mg, 0.0311 mmol) was added and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (1.0 mL), added a solution of 4N-hydrochloric acid-ethyl acetate (1.0 mg), and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (17.4 mg (yield 83%)) was obtained as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([SH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([CH2:15][S:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21](OS(C)(=O)=O)[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:14])[NH2:13]>CN(C)C=O>[C:3]([S:11][C@@H:21]1[CH2:20][N:19]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[C@H:18]([CH2:17][S:16][CH2:15][C:12](=[O:14])[NH2:13])[CH2:22]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(S)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CSC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (62.8% in oil) (0.22 g) in N,N-dimethylformamide (5 ml) was added dropwise thiobenzoic S-acid (0.66 ml) under ice-cooling. After stirring under the same condition for 30 minutes, this solution was added to a solution of (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g) in N,N-dimethylformamide (20 ml) at ambient temperature. The mixture was stirred at 70°-80° C. for 1 hour. The reaction mixture was poured into ice-water (50 ml) and extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.87 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
533 mg of Z-Val-Gly-Ala-Pro-OtBu are hydrogenated in 10 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 20 minutes. The catalyst is filtered off and the filtrate evaporated in a waterpump vacuum at 30° C. to give an oil. Rf = 0.52 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([CH3:29])=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18]([C:24](OCC)=[O:25])=[CH:17]2)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl.C(=O)([O-])O.[Na+]>C(O)C.C1COCC1.O>[OH:25][CH2:24][C:18]1[N:19]([CH3:23])[C:20]2[C:16]([CH:17]=1)=[C:15]([CH3:29])[C:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:7])([CH3:9])[CH3:8])=[CH:22][CH:21]=2
Reactant: CCOC(=O)c1cc2c(C)c(NC(=O)OC(C)(C)C)ccc2n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)OC(C)(C)C)ccc2c1cc(CO)n2C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of calcium chloride (81 g) in ethanol (147 mL) was added sodium borohydride (6.93 g) at 5° C., and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added dropwise at 5° C. a solution of ethyl 5-[(tert-butoxycarbonyl)amino]-1,4-dimethyl-1H-indole-2-carboxylate (195 g) obtained in Reference Example 44 in THF (1.2 L), and the mixture was stirred at the same temperature for 30 min and at room temperature for 15 hr. While maintaining the reaction mixture at 20° C. or below, 1N hydrochloric acid (1.4 L) was added dropwise to adjust to pH 3, and water (1 L) and saturated aqueous sodium hydrogen carbonate (190 mL) were added. The organic solvent was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was washed with ethyl acetate (200 mL) and petroleum ether (600 mL), and dried under reduced pressure to give the title compound (134 g, yield 79%) as colorless crystals.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:8][C:7]([CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=1.[C-:12]#[N:13].[Na+].[Cl-].[Na+]>CN(C)C=O.O.C(=O)(O)[O-].[Na+]>[C:12]([CH2:3][C:4]1[NH:8][C:7]([CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=1)#[N:13]
Reactant: [C-]#N
Reactant: CC(C)c1ncc(CCl)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ncc(CC#N)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 200 ml of cold thionyl chloride is added 0.1 mole of 3-isopropylimidazol-5-ylmethanol. After stirring for 1 hour at 25° C. the excess thionyl chloride is evaporated under reduced pressure to give crude 5-chloromethyl-2-isopropylimidazole hydrochloride. To an ice cold solution of 5 mmole of 5-chloromethyl-2-isopropylimidazole hydrochloride in 25 ml of dry dimethylformamide is added a cold solution of powdered sodium cyanide (18 mmole) in 30 ml of dimethylformamide. The mixture is stirred overnight at 25° C. then diluted with 200 ml of water and neutralized with sodium bicarbonate. The solution is saturated with sodium chloride and extracted with ethylacetate (5×50 ml). The organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a solid residue which is sublimed to give 5-cyanomethyl-2-isopropylimidazole. 5-cyanomethyl-2-isopropylimidazole (10 mmole) is heated with 10 ml of concentrated hydrochloric acid for 12 hours at reflux temperature then concentrated under reduced pressure to give 2-isopropylimidazol-5-ylacetic acid hydrochloride. To an ice cold solution of 0.08 mole of sodium carbonate in 40 ml of water is added 2-isopropylimidazol-5-ylacetic acid hydrochloride followed by 0.025 mole of tosyl chloride dissolved in 30 ml of ethyl acetate. After stirring for 5 hours at 25° C. the reaction mixture is neutralized with hydrochloric acid M and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to yield 2-isopropyl-1-tosylimidazol-5-ylacetic acid. To a suspension of the sodium salt of 2-isopropyl-1-tosylimidazol-5-ylacetic acid in 100 ml of benzene is added 1 equivalent of oxalyl chloride. The reaction mixture is stirred at 25° C. for 12 hours. The precipitate is filtered off and the filtrate concentrated under reduced pressure to give 2-isopropyl-1-tosylimidazol-5-ylacetyl chloride. To a solution of 29 mmole of diazomethane in 84 ml of ether cooled to 0° C. and magnetically stirred is added dropwise over 45 minutes a solution of 14.3 mmole of 2-isopropyl-1-tosylimidazol-5-ylacetyl chloride in 60 ml of ether. After stirring for 11/2 hours at 25° C. the reaction mixture is added to a solution of hydrogen fluoride/pyridine precooled to 0° C. The resulting heterogeneous solution is stirred at 25° C. for 11/2 hours then poured onto 150 g of ice. The organic phase is separated, washed with sodium bicarbonate (pH of 8) then with brine and dried over magnesium sulfate. Concentration of the mixture under reduced pressure yields 2-isopropyl-1-tosylimidazol-5-ylmethyl fluoromethyl ketone.
Reaction SMILES: C([O:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11]
Reactant: [H][H]
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(O)C=O)CC2)cc1
Yield: 75 %

Procedure:
A solution of N-(benzyloxy)-N-((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)formamide (100 mg, 0.22 mmol) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (10%, 23 mg, 0.02 mmol, 0.1 eq.) for 2 h at room temperature. The mixture was filtered on a bed of cellite, evaporated to give the title product as an orange foam (60 mg, 75%). HPLC, Rt: 1.95 min (purity: 100%). M+ (LC-MS (ESI)): 364.4.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([O:13]CC=C)[C:6]=2[CH3:17].O.C(N(CC)[C:23]1[CH:28]=CC=C[CH:24]=1)C>>[F:1][C:2]1[C:3](=[O:18])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([CH2:28][CH:23]=[CH2:24])=[C:7]([OH:13])[C:6]=2[CH3:17]
Reactant: C=CCOc1ccc2c(C)c(F)c(=O)oc2c1C
Reactant: CCN(CC)c1ccccc1
Solvent: O
Product: C=CCc1cc2c(C)c(F)c(=O)oc2c(C)c1O
Yield: 55 %

Procedure:
A solution of 3-fluoro-4,8-dimethyl-7-allyloxycoumarin (1.56 g, 6.28 mmoles) in 20 mL of N,N-diethylaniline was deoxygenated with argon for 30 minutes and then was heated at reflux for 4 hours, while being purged by bubbling argon through the solution. The reaction mixture was chilled in ice, the resulting precipitate was collected by suction filtration and dried in vacuo. Recrystallisation from a mixture of methanol:water gave 0.859 g (55% yield) of 3-fluoro-4,8-dimethyl-6-allyl-7-hydroxycoumarin (3, R═F, R′=H) as a white solid: mp 163-164° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:12]([O:14][CH3:1])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h

Procedure:
Trimethylsilyldiazomethane (2M/ether, 3.5 mL) was added slowly to a solution of 3,5-dichlorobenzoic acid (2-C) (955 mg, 5.0 mmol) in methylene chloride (5.0 mL) and methanol (2.0 mL) until the yellow color persisted. After stirring for 10 min, the mixture was evaporated in vacuo to give methyl 3,5-dichlorobenzoate (2-D).