Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH2:7].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:7][N:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(N)c1cccs1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(NC(=O)c1ccc(Cl)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77087.8 %

Procedure:
To a solution of tert-butyl 1-(thiophen-2-yl)hydrazinecarboxylate (100 mg, 0.467 mmol) in THF (5 mL) was added triethylamine (64 μL, 0.476 mmol, 1 eq.) and 4-chlorobenzoyl chloride (60 μL, 82 mg, 0.467 mmol, 1 eq.), and the resulting mixture was stirred for 1 hour at room temperature. A sample of the reaction mixture (quenched in water, and extracted with EtOAc) showed the presence of the intermediate crude product tert-butyl 2-(4-chlorobenzoyl)-1-(thiophen-2-yl)-hydrazinecarboxylate, as determined by NMR. The reaction mixture was then poured in water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product (278 mg) was purified by automated column chromatography (EtOAc/heptane) to yield tert-butyl 2-(4-chlorobenzoyl)-1-(thiophen-2-yl)-hydrazinecarboxylate (127 mg, 360 mmol, yield 77%) as a light brown solid with an HPLC purity of greater than 99%. LC-MS (M−1) 351 (C16H17ClN2O3S-1, expected 352.06).
Reaction SMILES: C([O:4][C@H:5]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(=O)C.C[O-].[Na+].CO>CO>[C:31]1(=[O:40])[N:30]([C@@H:6]2[C@@H:5]([OH:4])[C@H:20]([OH:21])[C@@H:19]([CH2:25][OH:26])[O:18][C@H:7]2[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 6 h
Yield: 99 %

Procedure:
Compound 61a (26.0 g, 46.18 mmol) was treated with NaOMe/MeOH (25 wt. %, 2.7 mL) in MeOH (200 mL) at room temperature. After 6 h, the mixture was neutralized (IRC-50 resin, weak acid) and concentrated to give product 61b (20.0 g, 99%) as semisolids: 1H-NMR (500 MHz, CDCl3), δ 7.78-7.82 (m, 2H), 7.68-7.72 (m, 2H), 5.16 (d, J=8.5 Hz, 1H), 4.63 (d, J=4.5 Hz, 1H), 4.25-4.31 (m, 2H), 4.06 (dt, J=2.0, 8.5 Hz, 1H), 3.88-3.89 (m, 2H), 3.76 (dt, J=10.0, 6.5 Hz, 1H), 3.65-3.71 (m, 1H), 3.59 (s, 3H), 3.48 (t, J=6.5 Hz, 1H), 3.43 (dt, J=9.5, 3.5 Hz, 1H), 3.38 (dt, J=10.0, 6.5 Hz, 1H), 1.90-2.02 (m, 2H), 1.31-1.43 (m, 4H), 1.00-1.09 (m, 2H); 13CNMR (125 MHz, CDCl3), δ 174.0, 168.4, 134.0, 131.6, 123.4, 98.31, 75.53, 71.53, 71.20, 69.43, 61.63, 56.66, 51.38, 33.65, 28.84, 25.18, 24.34; HRMS (M+Na) calcd for C21H27O9NNa 460.1584, found 460.1598.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH:10]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[C:13]3[N:12]([C:22](=[O:23])[NH:20][C:18](=[O:19])[C:17]=3[C:16]([CH3:21])=[N:15]2)[CH2:11][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nn2c(c1C(N)=O)NCC=C2c1cc(Cl)ccc1Cl
Solvent: C1COCCO1
Product: Cc1nn2c3c1c(=O)[nH]c(=O)n3CC=C2c1cc(Cl)ccc1Cl

Procedure:
To a 3.0 g amount of 7-(2,5-dichlorophenyl)-4,5-dihydro-2-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 9) suspended and stirred in 100 ml of dry p-dioxane, under nitrogen is added 8.0 g of 1,1'-carbonyldiimidazole. The mixture is evaporated to dryness in vacuo and the residue is treated with water to decompose the excess 1,1'-carbonyldiimidazole. The remaining solid is collected by filtration, then stirred with 50 ml of tetrahydrofuran. The solid is collected and dried to give 1.6 g of the desired product as a white solid. The product is recrystallized from ethanol-acetonitrile and gives mp 205-209° C.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C3C=CC=CC=3)=[CH:23][CH:22]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C[C@H]1COCCN1C1C=C(C(S(C(C)C)(=O)=O)(C)C)N=C([C:59]2[CH:64]=[CH:63][C:62]([NH:65]C(=O)OC3C=CC=CC=3)=CC=2)N=1>>[CH:62]1([NH:65][C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[CH:13]=[C:8]([CH2:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])[N:9]=3)=[CH:22][CH:23]=2)[CH2:63][CH2:64][CH2:59]1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CCC3)cc2)n1

Procedure:
The following compounds were made in an analogous fashion from either phenyl (4-{4-[(isopropylsulfonyl)methyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)carbamate or phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22]#N)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1(C[Mg]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:22][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)CC2CCCCC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CC2CCCCC2)CC2CCCCC2)CC1
Yield: 46 %

Procedure:
A solution of 4-(1-cyano-2-cyclohexyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.81, 5.65 mmol) in THF (20 mL) and cyclohexylmethylmagnesium bromide (1.51 g, 22.60 mmol, 0.4 M in Et2O) was stirred at 23° C. for 24 h. The reaction was quenched with EtOAc and washed with brine, dried (Na2SO4), and evaporated. Final purification by flash chromatography (hexane-EtOAc 15:1) afforded 1020 mg of the title compound. MS m/z 393.3 (M++1).
Reaction SMILES: S1(CCCC1)(=O)=O.[F-:8].[Cs+].Br[C:11]1[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=[C:13]([C:28]#[N:29])[C:12]=1[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31]>CCOCC>[C:28]([C:13]1[C:12]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[C:11]([F:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=1)#[N:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: [F-]
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(F)c1S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of dry sulpholane (15 ml) and 4Å molecular sieve (3.0 g) was stirred under nitrogen with caesium fluoride (2.4 g) at 60° C. for 1,2 hour. To this was added 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (2.0 g) and the mixture stirred at 60° C. for 2 hours, and left overnight at room temperature. This was diluted with ether (50 ml), filtered, and washed with water (100ml). The aqueous layer was reextracted with ether (3×50 ml) and the combined organic solution re-washed with water (4×50ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo to give an oil. Purification by chromatography, eluting with ether/hexane (1:4) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoro-4-trifluoromethanesulphonylpyrazole (0.17 g), m.p. 95°-98° C., in the form of a white solid, after recrystallisation from hexane.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C(O)C.[Pd]>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc(CN)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CNC(=O)C2CCNCC2)c(OC)c1

Procedure:
1-Benzyloxycarbonyl-4-[N-2,4-dimethoxybenzylcarbamoyl]piperidine was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2,4-dimethoxybenzylamine. The product was identified by n.m.r. spectroscopy. This product (7.6 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal at 50°/50 p.s.i. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give 4-[N-(2,4-dimethoxybenzyl)carbamoyl]piperidine (5.0 g) as a solid. A sample in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and recrystallised from isopropanol, m.p. 222°-224°.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[H][H]>[Ni]>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[CH2:12][OH:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Ni]
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
A commercially available aqueous solution of high purity maltose having the same sugar composition used in the first step of Example 5 was adjusted to have a concentration of 35%, and then reduced by Raney nickel catalyst, imposed a hydrogen pressure of 100 kg/cm2, under a condition at a temperature of 120° C. for a reaction time of 90 minutes, to obtain aqueous solution of maltitol. The sugar composition in the solid component of the resulting aqueous solution of maltitol was that maltitol was 85.0%, sorbitol was 0.5%, oligosaccharide alcohol which was equal or more than DP3 was 14.5%.
Reaction SMILES: I[C:2]1[C:7]2[C:8]3[C:9]([NH:15][C:6]=2[C:5](=[O:16])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=3.[CH2:26]([S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH3:27].O1CCOCC1>C(Cl)Cl>[CH2:26]([S:28]([C:31]1[CH:36]=[C:35]([C:2]2[C:7]3[C:8]4[C:9]([NH:15][C:6]=3[C:5](=[O:16])[N:4]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:3]=2)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=4)[CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:30])[CH3:27]
Reactant: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2cn(Cc3ccc(OC)cc3)c(=O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 150 °C

Procedure:
In an appropriate microwave reaction vessel was placed, 5-iodo-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (8.0 g, 17.967 mmol), 3-(ethylsulfonyl)phenyl boronic acid (4.62 g, 21.6 mmol), and Tetrakis(triphenylphosphine)Pd(0) (6.23 g, 5.4 mmol). The solids were then suspended in a dioxane/saturated K2CO3 solution (40.0 mL, 4/1) and the mixture was heated in a large scale CEM microwave for 20 minutes at 150° C. The reaction mixture was diluted with DCM (400 mL), then filtered off undissolved solids. The organic layer was washed with brine (300 mL), dried with MgSO4, filtered and concentrated in vacuo affording an orange solid. The crude solid was washed with a hot ethyl acetate/hexanes solution (400 mL, 1/1) followed by a hot ethanol/DCM solution (400 mL, 4/1). The product was isolated by filtration, washed with ether and dried under vacuum affording an off-white solid. (6.83 g, 78%) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.45 Hz, 3H) 2.44 (s, 3H) 3.20 (q, J=7.33 Hz, 2H) 3.80 (s, 3H) 5.37 (s, 2H) 6.90 (d, J=8.59 Hz, 2H) 7.16 (s, 1H) 7.37 (d, J=8.59 Hz, 3H) 7.75 (t, J=7.71 Hz, 1H) 7.78-7.87 (m, 2H) 8.03 (d, J=7.58 Hz, 1H) 8.12 (s, 1H) 8.43 (s, 1H). ESI-MS: m/z 488.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[Br:12][CH2:13][CH:14](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]2[CH2:9][O:10][CH:14]([CH2:13][Br:12])[O:8][C:6]=2[CH:7]=1
Reactant: COC(CBr)OC
Reactant: OCc1c(O)cc(Br)cc1F
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc2c1COC(CBr)O2

Procedure:
Preparation according to Preparation 9. 5-bromo-3-fluoro-2-(hydroxymethyl)phenol (0.79 g, 3.6 mmol), 2-bromo-1,1-dimethoxyethane (4.2 ml, 36 mmol), dry THF (10 ml) and concentrated H2SO4 (1.5 ml).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][C@@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
In 30 ml of ethanol is dissolved 2.1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, and 0.4 g of acetic acid, 2.5 g of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 20 minutes, and a solution of 0.4 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours. The reaction solution is allowed to stand at room temperature overnight, and concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and ccncentrated under reduced pressure. Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and admixed with 300 ml of petroleum ether, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate are added to the precipitate portion, followed by adding excess sodium hydrogencarbonate to conduct neutralization. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material. This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][CH2:9][C@@H:10]([C:27]([OH:29])=[O:28])[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:34]I.O>CN(C)C=O>[CH3:34][O:28][C:27](=[O:29])[C@H:10]([CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:15])[CH3:14]
Reactant: COc1ccc(CSC[C@H](NC(=O)C(C)(C)SCc2ccc(OC)cc2)C(=O)O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CSCc1ccc(OC)cc1)NC(=O)C(C)(C)SCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of S-p-methoxybenzyl-N-(2-p-methoxybenzylthio-2-methylpropionyl)-L-cysteine (3.0 g) in dimethylformamide(20 ml), sodium hydride(0.3 g) was added under nitrogen atomosphere at room temperature and the mixture was stirred for 1 hour. Methyl iodide(0.5 ml) was added to the mixture. The reaction mixture was stirred for 4 hours at room temperature. Water(300 ml) was added to the reaction mixture and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.8 g(90%) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](Cl)=[O:31])=[CH:27][CH:26]=1>C(Cl)Cl>[C:11]([O:10][C:8]([NH:7][C@@H:3]([CH2:2][NH:1][C:30]([C:28]1[S:29][C:25]([Cl:24])=[CH:26][CH:27]=1)=[O:31])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Commercially available (S)-3-Amino-2-tert-butoxycarbonylamino-propionic acid (BOO-Dap-OH) (408 mg, 2 mmol) was suspended in 4 ml DCM and DIPEA (1.75 ml, 10 mmol). 5-Chloro-thiophene-2-carbonyl chloride (362 mg, 2 mmol) (described in WO 2005068456) in 4 ml DCM was added slowly and the mixture was stirred at RT for 2 h. The reaction was filtered and the solvent evaporated. The resulting solid (895 mg) was used without further purification in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:20][C:17]([O:16][C:14](=[O:15])[NH:13][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:3][OH:2])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution (R)-β-[[(1,1-Dimethylethoxy)carbonyl]amino]-benzenebutanoic acid methyl ester (1.5 g, 5.1 mmol, J. Med. Chem. 1985, 28, 434) in THF (10 mL), was added lithium borohydride (218 mg, 10 mmol), followed by ethanol (10 mL), dropwise. After stirring at rt for 18 hours, an additional lithium borohydride (218 mg 10 mmol) was added and stirring continued for 6 hours. The reaction mixture was ice cooled and adjusted to pH 4 by the addition of a 10% citric acid solution. Organic solvents were removed and the resulting cloudy aqueous solution was extracted with dichloromethane. The extracts were combined, dried (MgSO4) and concentrated in vacuo to afford a clear colorless oil residue which was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes to yield (1.2 g, 89%) of the title compound as a clear colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 141b (132 mg, 0.19 mmol) in DCM (2.0 mL) was added DIPEA (135 μL, 0.78 mmol) followed by methanesulfonyl chloride (30 μL, 0.39 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the subsequent step without further purification. LCMS (Method 4): Rt 3.30 min, m/z 759 [MH+].
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].[C:14]([Cu])#[N:15]>CN1C(=O)CCC1>[Cl:13][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[NH:6][C:5]=2[CH:11]=[CH:12][C:2]=1[C:14]#[N:15]
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Temperature: 220 °C
Yield: 35.5 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.050 g, 0.192 mmol) and CuCN (0.030 g, 0.576 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water. The organic portion was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.014 g): MS (ESI) m/z 206 (M+1).
Reaction SMILES: C([NH:8][C:9]([C:11]1[N:12]([CH3:32])[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=1)=[O:10])C1C=CC=CC=1.N[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:32][N:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=[C:11]1[C:9]([NH:8][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1
Product: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 310 and aniline to provide 312. LC-MS (M+H=410, obsd.=410).