Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=O)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[NH:8][C:7]3[C:6]([O:9][CH3:10])=[CH:5][CH:4]=[C:3]([CH3:11])[C:2]=3[N:1]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COc1ccc(C)c(N)c1N
Solvent: ClC(Cl)Cl
Product: COc1ccc(C)c2nc(Cc3ccc(Cl)cc3)[nH]c12
Yield: 40.7 %

Procedure:
A mixture of 2,3-diamino-4-methoxytoluene [prepared by hydrogenation of 4-methoxy-2,3-dinitrotoluene (7.5 g) over 10% palladium-carbon (2.5 g) in ethanol] and 4-chlorophenylacetic acid (23 g) was heated at 130°-150° C. for 4.5 h under nitrogen. The mixture was cooled, dissolved in chloroform, washed with 10% sodium carbonate solution, then with water, dried (Na2SO4) and evaporated to dryness in vacuo. The product was recrystallized from chloroform-pentane to afford the title compound, (5.75 g), m.p. 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:14][O:15][C:16]=2[CH:17]([OH:26])C(O)C2C=CC=CC=2)=[N:6][CH:5]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[BH4-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:14][O:15][C:16]=2[CH2:17][OH:26])=[N:6][CH:5]=1
Reactant: CCCCc1noc(C(O)C(O)c2ccccc2)c1COc1ccc(C(=O)OC)cn1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.9 %

Procedure:
To a solution of 6-[3-butyl-5-(1,2-dihydroxy-2-phenylethyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (890 mg, 2.09 mmol) in benzene (10 mL) was added lead tetraacetate (1.39 g, 3.13 mmol) with benzene (5 mL) and the reaction was stirred at room temperature for 45 min. The suspension was filtered over celite and the filtrate was concentrated to a yellow oil. The oil was taken up in methanol (20 mL) and sodium borohydride (198 mg, 5.24 mmol) was added in portions over 3 min. Upon addition, the reaction became a clear light yellow solution containing a black precipitate. After stirring at room temperature for 15 min, the mixture was filtered over celite and the filter cake was washed with methanol. The filtrate was concentrated and the residue was portioned between 0.5M aqueous hydrochloric acid and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude material was purified by chromatography (silica, heptane:ethyl acetate 1:0 to 1:1) to afford the title compound (495 mg, 68%) as a colorless oil. MS: m/e=321.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the title compound was prepared as a solid (mp=116-119° C.). The reaction was monitored by tlc (Rf=0.4 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH2:22]=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([N:20]=[CH2:22])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: C=O
Solvent: CC#N
Product: C=NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1

Procedure:
A solution of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (5.0 g) and 37% formaldehyde solution (1.38 ml) in acetonitrile (150 ml) was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (50 g) eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol (200 ml) to give colorless crystals of 5-chloro-3-[(4-methyleneamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (5.1 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]=2[C:15]=1[C:14]([F:17])=[CH:13][CH:12]=3.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[F:17][C:14]1[C:15]2[C:16]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]=3[C:7]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:6][C:5]=2[N:4]1[CH2:3][CH2:2][NH:1][C:24]1=[O:25]
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: O=C1Nc2ccc(F)c3c(N4CCNC4=O)cc(-c4ccc[nH]4)c1c23

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (from Example 9 above) (31.1 mg, 0.1 mmol) in 1,2-dichloroethane (3 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 162 mg, 1.0 mmol) at room temperature. The reaction mixture was heated under reflux overnight. The reaction was then quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give 6-fluoro-5-(2-oxo-imidazolidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 19.5 mg, 58.0%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[CH2:8]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:27]=[S:28])=[CH:25][CH:26]=2)[CH2:18][CH2:19]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: S=C(Cl)Cl
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.36 ml of triethylamine in 15 ml of chloroform was treated dropwise at -10° C. with a solution of 2.18 g of p-[trans-4-(5-hexenyl)cyclohexyl]aniline in 20 ml of chloroform. After 5 minutes the mixture was treated with a solution of 690 μl of thiophosgene in 10 ml of chloroform, warmed to room temperature and stirred for 2 hours. Thereafter, the reaction mixture was partitioned between water and chloroform. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic separation on 140 g of silica gel using ethyl acetate/petroleum ether (vol. 5:95) and subsequent crystallization from 80 ml of methanol and low temperature filtration gave 1.24 g of p-[trans-4-(5-hexenyl)cyclohexyl]phenylisothiocyanate (purity 100%) as a milky liquid of m.p. (C-N) 15.2° C. and cl.p. (N-I) 46.1° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][NH:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C.[OH-].[Na+].Cl>CO>[C:17]([O:16][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])=[O:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCNC(=O)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCC(=O)NCCC(=O)O
Yield: 87 %

Procedure:
3.94 g of this ester were dissolved in 20 ml of methanol and, while stirring at 0°, 1 mol equivalent and after 30 minutes a further 0.2 mol equivalents of 1N sodium hydroxide solution were added. The mixture was then stirred at room temperature for one hour, 1.2 mol equivalents of 1N hydrochloric acid (PH 4) were added portionwise, the solvent was evaporated under reduced pressure and the aqueous phase was extracted several times with methylene chloride. Drying and evaporation of the extracts yielded an oily residue which crystallized upon the addition of hexane. Recrystallization from hexane yielded N-[5-(1-t-butoxyformamido)valeryl]-β-alanine in 87% yield, melting point 70°.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:17][CH2:16][NH:15]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid n-decyl amide (285) (160 mg; 0.470 mmol) is dissolved in methylene chloride (4 mL) at ambient temperature. Trifluoroacetic acid (2 mL) is added and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (20 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 5 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (289) as a solid. ISMS: MH+ 241.2
Reaction SMILES: Cl[C:2]1([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH:27]1([OH:33])[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:3]2[C:2]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([O:32][CH:29]3[CH2:30][CH2:31][CH:27]([OH:33])[CH2:28]3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1
Reactant: OC1CCC(O)C1
Reactant: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Product: O=C1c2ccccc2C(OC2CCC(O)C2)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1

Procedure:
3-Chloro-2-(4-chlorobenzyl)-3-(4-chlorophenyl) isoindolin-1-one (157 mg, 0.390 mmol) was reacted with 1,3-cyclopentanediol (0.18 mL, 1.95 mmol.) as for general procedure C and the solvent evaporated under vacuum to leave a clear oil of crude 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxycyclopentyloxy)isoindolin-1-one. This was purified by HPLC to give the pure product which was a clear glass (83 mg, 0.177 mmol., 45%). Rf 0.08 (40:60 EtOAc:petrol). λmax (CH3OH)/nm=220.5 (Abs=1.333). IR: 3426, 2935, 1696, 1695, 1597, 1489, 1467 cm−1. 1H NMR (300 Hz, DMSO); δ1.03-1.86 (m, 6H, cyclopentanediol C—H), 2.02 (m, 1H, N—CH2), 3.48-3.75 (M, 1H, N—CH2), 4.00-4.50 (m, 2H, cyclopentanediol O—C—H), 6.66-7.15 (m, 9H, Ar—H), 7.32-7.53 (m, 2H, Ar—H), 7.83 (m, 1H, Ar—H). 13C NMR (75 Hz, DMSO); δ 31.4 (N—CH2), 32.1, 33.8, 34.0, 42.9, 44.1 (cyclopentanediol), 95.0 (Ar2C(O)—N), 72.1, 73.0 (cyclopentanediol C—OH), 124.0, 124.3, 128.5, 128.6, 130.2, 130.8, 130.8, 132.7 (Ar). LC/MS-ES+ m/z 470.3, 468.3, 245.1, 243.1. Anal. Calcd. for C26H23Cl2NO3.0.4H2O: C, 65.66; H, 5.04; N, 2.95%. Found C, 65.49; H, 4.94; N, 3.02%. HRMS (EI) m/z: 467.1055. Found 467.1055.
Reaction SMILES: C(O[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:20]3[N:24]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH:26]=4)[C:23](=[O:35])[N:22]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=4[O:45][CH3:46])[C:21]=3[C:47]#[N:48])=[CH:12]2)[CH:7]=[CH:6]1)(=O)C.[C:49]1(=O)[NH:53][C:52](=O)[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.[K].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[C:47]([C:21]1[N:22]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:23](=[O:35])[N:24]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)[C:20]=1[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:53]3[CH2:49][C:50]4[C:51](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:52]3)[CH:6]=[CH:7]2)[CH:12]=1)#[N:48]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(Cn2c(C#N)c(-c3cn([C@@H]4C=C[C@H](OC(C)=O)CC4)c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C#N)c(-c3cn([C@@H]4C=C[C@H](N5Cc6ccccc6C5)CC4)c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
In a flask was added 0.064 g (0.10 mmole) of the product obtained in step b), 0.046 g (0.25 mmole) of potassium phthalimide, 0.0096 g (0.01 mmole) of Pd2(dba)3, 0.013 g (0.05 mmole) of triphenylphosphine, 1 mg of lithium chloride and finally 7 ml of dry DMF. The flask was sealed and stirred under nitrogen at 70° C. under nitrogen for 90 minutes. The mixture was partitioned between EtOAc and water, and the organic phase was collected and concentrated. The residue was purified on silica (Heptane:EtOAc 1:3), giving 0.040 g (55%) of the sub-title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(Cl)c2Cl)CC1
Temperature: 140 °C

Procedure:
To a solution of 4-(2,3-dichlorophenyl)piperidine (10 mg) in acetonitrile (2 ml), was added potassium carbonate (10 mg) and 1-iodoethane (5 mg) and the mixture was heated to 140° C. in a sealed tube under microwave radiation for 400 s. MS m/z (rel. intensity, 70 eV) 258 (M+, 11), 257 (18), 256 (14), 244 (66), 242 (bp).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10]([CH3:21])([C:16]([O:18][CH2:19]C)=[O:17])[CH2:11]2.CO.O>ClCCl>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10]([CH3:21])([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2
Reactant: CCOC(=O)C1(C)Cc2cccc(OC)c2C1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(C)Cc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 15.2 ml (15.24 mmol) of a 1 M solution of boron tribromide in dichloromethane were added to a solution of 1.19 g (5.08 mmol) of ethyl 4-methoxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 20 ml of dichloromethane. Stirring at 0° C. was continued for one hour. 16 ml of methanol were then added, and the reaction mixture was stirred overnight. 10 ml of water and 10 ml of dichloromethane were then added. After phase separation, the aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over magnesium sulfate. After filtration, the solvent was evaporated to dryness under reduced pressure. This gave 897 mg (4.35 mmol, 86% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH2:45][OH:46])([CH3:44])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:65][S:66](Cl)(=[O:68])=[O:67].O>O1CCCC1>[CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([CH2:45][O:46][S:66]([CH3:65])(=[O:68])=[O:67])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(CO)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COS(C)(=O)=O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (700 mg) and triethylamine (0.25 ml) in tetrahydrofuran (8 ml) was added dropwise methanesulfonyl chloride (0.11 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (793 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:10](=[O:11])[N:9]=[CH:8][NH:7][C:6]=2[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32]>C1COCC1>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:7]1[C:6]2[N:12]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[C:10](=[O:11])[N:9]=[CH:8]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CSc1nc2[nH]cnc(=O)c2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc2c(s1)c(=O)ncn2Cc1cccc(Cl)c1Cl
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
To a suspension of 2-(methylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one (2.978 g, 14.94 mmol) in THF (200 mL) at 0° C. was added dropwise of LiHMDS (18.3 mL, 16.44 mmol). The resulting mixture was stirred at 0-5° C. for 3 hours and 1-(bromomethyl)-2,3-dichlorobenzene (3.946 g, 16.44 mmol) in THF (30 mL) was added dropwise to the reaction mixture over a period of 2 hours. The reaction mixture was allowed to warm to ambient temperature slowly and stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (2×20 cm, DCM:MeOH=30:1 elution) to give the desired product as a white solid (0.671 g, 13%). 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.50 (m, 1H), 7.26˜7.16 (m, 2H), 5.56 (s, 2H), 2.74 (s, 3H); LC-MS: 358 (MH+); IR (thin film): 3073, 2986, 1651, 1619, 1598, 1426, 1384, 1221, 1055 cm−1.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 1 g (5.48 mmol) 4-chloro-3-nitrobenzonitrile, Compound 126, and 1.14 g (11.51 mmol) of cyclohexylamine were heated overnight in 5 mL anhydrous DMF. After cooling to room temperature, the solution was added dropwise into 100 mL H2O stirring vigorously. The solids were collected by filtration and dried under vacuum yielding 1.34 g (100%) bright yellow solids which were used as such without analysis in the next step.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)CC)C>C(Cl)Cl.O>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.300 g, 1.04 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.707 g, 1.60 mmol), and 2-aminobenzimidazole (0.213 g, 1.6 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.45 mL, 3.2 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (20 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (0.396 g, 95%) as a white solid: mp 193.4-196.8° C.; EI-HRMS m/e calcd for C21H2,Cl2N3O (M+) 401.1062, found 401.1058.