Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C@:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]2)([OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH2:12][CH2:13]1
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2OCC2CC2)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N2. Then a solution of 1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH4Cl (10 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (560 mg, 91%). 1H NMR (400 MHz, CDCl3): 0.35 (m, 2H), 0.63 (m, 2H), 1.05 (m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H), 2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H), 4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Na+].S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.26 mmol) of ethyl 4-(2-(tert-butoxycarbonylamino)ethyl)benzoate in 40 mL of dry THF under a nitrogen atmosphere was added dropwise, 4.7 mL (4.7 mmol) of NaHMDS (1.0 M in THF) at 0° C. After stirring for 10 min, 0.50 mL (5.3 mmol) of dimethyl sulfate was added and the reaction was warmed to 22° C. and stirred for about 16 h. The reaction was quenched by adding 25 mL of saturated NaHCO3 and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were dried (Na2SO4) and evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 10% ethyl acetate/hexane to give ethyl 4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.O>CS(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]3[CH:20]=[CH:21][CH:22]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)CI
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)COc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A mixture of potassium carbonate (300 mg), 1-iodo-2,2-dimethylpropane (430 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (200 mg) in DMSO (5 mL) was stirred at 150° C. for 1 hr. Water was added to give a precipitate. The precipitate was collected by filtration and washed with Et2O-water. The precipitate was crystallized from CH3CN-IPE to give the title compound (182 mg) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:35])=[O:34])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3].Cl[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48]>O1CCCC1.O>[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:34])=[O:35])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[N:26][C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])=[CH:28][CH:29]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in tetrahydrofuran/water.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].F[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[N+:22]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:11]=1[N:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9])[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:24])=[O:23]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C1CSCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCSCC2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
Sodium hydride (60%, 171 mg, 4.27 mmol) was suspended in tetrahydrofuran (10 ml), and thiomorpholin-3-one (500 mg, 4.27 mmol) prepared in the Step 40-1-1 was added thereto. The mixture was stirred at a room temperature for 5 minutes, and a solution (10 ml) of ethyl 4-fluoro-3-nitrobenzoate (910 mg, 4.27 mmol) prepared in the Step 1-1-1 in tetrahydrofuran was slowly added to the mixture. The resulting mixture was stirred at a room temperature for 4 hours. The mixture was concentrated, and chloroform was added thereto. The resulting mixture was washed with a saturated sodium bicarbonate solution. The washed product was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) and washed with methanol to give the title compound (360 mg, 27%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:4]=2[S:5][CH:6]=1.[N+:14]([O-])([OH:16])=[O:15]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:4]=2[S:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc2c(Cl)csc2cc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)csc2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophene (0.39 g) was dissolved in ethyl acetate (26 ml). To the solution was gradually added a solution of nitric acid in dichloromethane (2M, 0.9 ml) at room temperature. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water and extracted with ethyl acetate and evaporated to dryness. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: [Mg].C(O[Ge:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.Br[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=1>C1COCC1>[CH2:13]([O:12][Ge:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=1)[CH3:14]
Reactant: CCO[Ge](OCC)(OCC)OCC
Reactant: Brc1ccc2c(c1)Sc1ccccc1S2
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Ge](OCC)(OCC)c1ccc2c(c1)Sc1ccccc1S2
Yield: 25.6 %

Procedure:
A 3-neck 500 mL flask was filled with magnesium turnings (8 g), THF (100 g) and tetraethoxygermane (35 g), and heated to reflux. Crude 2-bromothianthrene (30 g) from Example 1 was added to the flask in small portions. Grignard started after a few minutes and kept refluxing by its own heat for ten minutes. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with heptanes (300 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled three times at <1 mbar, giving colorless 2-(triethoxygermyl)-thianthrene (bp. 180 . . . 210° C., 11 g, 30.5% overall yield based on 2-bromothianthrene, purity 99.5% by GC/MS). FIG. 8 shows the mass spectrum of the compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>O1CCCC1>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CC(O)CN
Reactant: O=C(O)c1cccnc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)CNC(=O)c1cccnc1
Temperature: -4 °C
Reaction time: 2 h

Procedure:
To 4.29 g (0.039 mol) of nicotinic acid suspended in 120 mL of dry tetrahydrofuran, 4.04 g (0.039 mol) of freshly distilled triethylamine was added in one portion. The resultant clear solution was cooled to -4° C. in an ice bath under argon. Ethyl chloroformate (4.33 g, 0.039 mol) in 25 mL of tetrahydrofuran was added at such a rate that the temperature of the solution did not exceed 0° C. Then, 3 g (0.039 mol) of 1-amino-2-propanol were added directly to the cold reaction mixture. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The oily residue was washed several times with anhydrous ether and allowed to stand. The title compound was obtained as a white, hygroscopic, low-melting, waxy solid melting at 40° C. (6.11 g, 85%) and having the formula ##STR117##
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=2)=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C#Cc1ccc(CC)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccc(CC)cc1)n1cnc2ccccc21
Temperature: 100 °C

Procedure:
To a solution of benzimidazole (118 mg, 1.00 mmol) in DMF (3 mL) was added ethyl 3-(4-ethylphenyl)-2-propynoate (202 mg, 1.00 mmol) and potassium carbonate (152 mg, 1.10 mmol). This suspension was heated to 100° C. for 48 hours, then cooled to room temperature, and evaporated in vacuo. The residue was partitioned between water and dichloromethane, and the separated aqueous layer extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4) to afford (in order of elution), ethyl (2Z)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate, mixed fractions, and ethyl (2E)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:15])[CH:13]=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 28 (640 mg, 3.1 mmol) and 1-bromopentadecane (5.0 g, 17.2 mmol), alcohol 90 was obtained as a colorless oil (690 mg, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
To a solution of 5,6-dichloropyridin-3-amine (commercially available) in THF (0.2 M) stirred at 0° C. was added (BOC)2O (1.2 eq). The reaction mixture was heated at 40° C. until full conversion as monitored by TLC. The reaction mixture was then concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded tert-butyl 5,6-dichloropyridin-3-ylcarbamate.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.30 min; [M+H]+=491.0.
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=O)[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[Li+].[BH4-]>C1COCC1>[C:1]12([C@@H:7]3[CH2:8][CH2:9][C@H:4]1[C@@H:5]1[C@H:6]3[C:10](=[O:11])[O:12][CH2:13]1)[CH2:3][CH2:2]2
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1[C@H]1CC[C@@H]2C12CC2
Reaction time: 1 h

Procedure:
To a solution of Compound 2 (450 mg, 2.3 mmol) in THF (10 mL) was added LiBH4 in THF (2M soln. 1.4 mL, 2.8 mmol) at ambient temperature. The mixture was stirred for 1 h, and the reaction was quenched with 5% H2SO4 in water (10 mL). The solution was diluted with 25 mL of EtOAc, the layers separated, and the product was extracted from the aqueous layer with EtOAc (2×25 mL). The combined organic layers were washed with brine, and dried (MgSO4), and the solvents were concentrated under vacuum. The residue was purified by flash chromatrography on silica gel using 25% EtOAc in hexane as the eluent. The title compound, Intermediate B, was isolated as a white solid after removal of the solvent under vacuum.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([CH2:14][C@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:24])([F:23])[F:22])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@@H:58]([CH2:67][CH3:68])[CH:59]([OH:66])[C:60]([NH:62][CH:63]1[CH2:65][CH2:64]1)=[O:61].CCN(C(C)C)C(C)C>ClCCl>[CH:63]1([NH:62][C:60](=[O:61])[CH:59]([OH:66])[C@@H:58]([NH:57][C:16](=[O:17])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:21]([F:23])([F:24])[F:22])[CH2:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)(=[O:13])=[O:12])[CH2:67][CH3:68])[CH2:64][CH2:65]1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)C[C@H](N[C@@H](c2ccc(F)cc2)C(F)(F)F)C(=O)O)c1
Reactant: CC[C@H](N)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)c1cccc(S(C)(=O)=O)c1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
A solution of (R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-amino)propanoic acid (7.3 g; 15 mmol) and HATU (6.84 g; 18.0 mmol; 120 mole %) in anhydrous dichloromethane (200 mL) was stirred at ambient temperature for 5 minutes, then (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (35.0 mmol; 233 mole %) was added and the mixture stirred for 5 minutes. The reaction mixture was then cooled to 0-5° C. and treated with the dropwise addition of DIPEA (7.8 mL; 5.8 g; 45 mmol; 300 mol %). After the addition was complete, the cooling bath was removed and the reaction was stirred for 2.5 h at ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed in sequence with a solution of 10% aqueous potassium hydrogensulfate, water, 10% aqueous sodium bicarbonate, water, and finally saturated aqueous sodium chloride. The organic phase was dried (MgSO4), and concentrated almost to dryness. The residue was triturated with diethyl ether then some hexane was added. The resulting solid was filtered and washed with hexane to give 8.6 g (96%) of (3S)—N-cyclopropyl-2-hydroxy-3-((R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)pentanamide as an off-white solid. LC-MS, positive ion mode: m/z=638 [M+H]+ (100%); negative ion mode: m/z=636 [M−H]− (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. No. 7,488,848.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]2[CH:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=[O:3])[CH3:2].O.O.P([O-])(O)(O)=O.[Na+].C([O-])(O)=O.[Na+].ClCCl>O>[C:1]([O:4][C@@H:5]1[C@H:12]2[C@H:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 42.5 °C
Yield: 42.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-yl acetate (124 g) to the RB flask along with buffer solution (118 g Sodium dihydrogen phosphate dihydrate dissolved in 600 ml water & pH adjusted to 6.5 with saturated NaHCO3 aqueous solution). CAL-B enzyme (19.5 g) was added to the reaction mass and stirred at 40-45° C. Reaction was monitored by Chiral-GC. Reaction was cooled to room temp., dichloromethane (1300 ml) was charged to reaction mass and filtered through hyflow bed. Dichloromethane layer was separated and washed with Sodium chloride solution (10%, 650 ml) and water (3×650 ml). Dichloromethane layer was concentrated under vacuum to get residue of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate (Yield 53 g). Further, the product was purified by fractional distillation under vacuum at 98-118° C. to get main fraction 39.5 g having purity 97.98%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (291 mg, 0.87 mmol) [Prepared according to the procedure of preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (250 mg, 50%): LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: C[O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][SH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CO.C(#N)C.C(OCC)(=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:10][CH2:9][C:5]1[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: SCc1cccs1
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: ClCCCSCc1cccs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.5 ml of a 30% sodium methylate solution in methanol is added in drops to 1.0 g of thiophen-2-yl-methanethiol in 8 ml of anhydrous acetonitrile at 0° C. After 5 minutes, the drop-by-drop addition of 1.1 ml of 1-bromo-3-chloropropane is carried out. Then, the reaction solution is allowed to stir for 5 hours at room temperature. For working-up, the batch is diluted with ethyl acetate, washed with water and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 1.3 g of 2-(3-chloropropylthiomethyl)-thiophene as an oil.