Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]1.CI>CN(C=O)C.O>[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:1])=[O:13])=[CH:8]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc[nH]c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
Potassium carbonate (0.65 g, 5.4 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (0.50 g, 4.5 mmol) in DMF (10 mL). Stirring for 2 h at room temperature, methyl iodide (0.34 mL, 0.77 g, 5.4 mmol) was added. The mixture was stirred overnight at room temperature, diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (7:3) on silica gel to give 0.17 g (30%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 3.82 (s, 3 H), 6.56-6.72 (m, 1 H), 6.73-6.83 (m, 1 H), 7.36-7.50 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10](Cl)=[O:11])[CH:8]=1.[CH3:14][NH:15][CH3:16]>CCOCC>[CH3:14][N:15]([CH3:16])[C:10](=[O:11])[CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[Br:13]
Reactant: CNC
Reactant: COc1ccc(Br)c(CC(=O)Cl)c1
Solvent: CCOCC
Product: COc1ccc(Br)c(CC(=O)N(C)C)c1
Temperature: 25 °C

Procedure:
5-Methoxy-2-bromophenylacetyl chloride (60 g, 0.23 mol) is dissolved in anhydrous Et2O (400 mL), stirred and cooled in an ice bath. A 2 M solution of dimethylamine (228 mL, 0.46 mol) is added dropwise and the mixture allowed to warm to room temperature and stirred for 2 hours. Additional Et2O (500 mL) is added. The organic solution is washed with 1 N HCl (2×500 mL), saturated NaHCO3 (500 mL) and brine (500 mL). The organic layer is dried (Na2SO4) and concentrated by rotary evaporator. The residue is purified using flash chromatography (hexanes/EtOAc, from 7:3 to 1:9). Trituration of the crude product with Et2O/hexanes gives N,N-dimethyl-5-methoxy-2-bromophenylacetamide as a white crystalline solid (m.p. 88–90° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:28][C:29](O)=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH2:28][C:29]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
The mixture of [[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid 100 mg, 0.211 mmol), Cyclohexylamine (25 mg, 0.253 mmol), EDC.HCl (48 mmg, 0.253 mmol), HOBt (34 mmg, 0.253 mmol) and DIPEA (82 mmg, 0.633 mmol) in acetonitrile (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 48 mg of rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide as a yellow solid. MS: [M+H]+=556.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH3:47][C:48]1[CH:61]=[CH:60][CH:59]=[CH:58][C:49]=1[CH2:50][S:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54]>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:52]([S:51][CH2:50][C:49]1[CH:58]=[CH:59][CH:60]=[CH:61][C:48]=1[CH3:47])[C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1ccccc1C
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccccc1C
Yield: 72 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (2-methylbenzylthio)acetate (7.9 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent, diethyl 2-dimethylamino-5-(2-methylbenzylthio)-2,4-hexadienedioate (9.5 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([S:26]([N:29]2[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([S:26]([N:29]3[CH2:32][C:31]([F:34])([F:33])[CH2:30]3)(=[O:28])=[O:27])[CH:25]=2)[CH:11]=1
Reactant: O=S(=O)(c1cncc(Br)c1)N1CC(F)(F)C1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)N2CC(F)(F)C2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 3-bromo-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]pyridine (Intermediate 34), the title compound was obtained as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12]C)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[OH:1][CH:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1
Reactant: COc1cccc2c1C(=O)OC2O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1OC(O)c2cccc(O)c21
Temperature: 27 °C
Reaction time: 5 h

Procedure:
3.0 g of 3-hydroxy-7-methoxy-phthalide ]see B. L. Chenard et al., J. Org. Chem. 49, 318 (1984)] are introduced in portions into a suspension of 8.2 g of aluminium trichloride in 50 ml of methylene chloride, the internal temperature being maintained at 27° C. The mixture is stirred at room temperature for a further 5 hours, is then poured into 200 ml of ice-cold 1N hydrochloric acid and extracted three times with 200 ml of ethyl acetate each time. The organic solution is washed with sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent and recrystallisation from ethyl acetate and n-hexane yield pure 3,7-dihydroxyphthalide, m.p. 124°-126° C.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(I)ccc12
Product: Clc1ncnc2cc(I)ccc12

Procedure:
7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorous oxychloride (5 ml) at reflux under nitrogen for 2 hours. The mixture was cooled, evaporated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried and concentrated in vacuo to give the title compound (0.43 g); m/z (M+1+) 291.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3F)=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.ClC1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C([N+]([O-])=O)C=CC=1C)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Product: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 404, using compound 428 (19.2 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 followed by 2:3 as the eluent to afford the title compound as solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Br:29])=[O:38])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=C=Nc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)Nc3ccccc3Br)c3cnc4ccc(Br)cc4c32)cc1

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.050 g, 0.12 mmol) and potassium fluoride (0.010 g, 0.18 mmol) in dry benzene (6 ml) was added 1-bromo-2-isocyanatobenzene (0.036 g, 0.12 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was crystallized in ethyl acetate\pet ether to obtain the title compound. Yield: 0.017 g (22%); 1H NMR (DMSO-d6, 300 MHz): δ 11.82 (s, 1H), 8.78 (s, 1H), 7.90 (d, 1H, J=9 Hz), 7.81 (d, 2H, J=8.1 Hz), 7.61-7.65 (m, 3H), 7.28 (d, 1H, J=8.1 Hz), 6.95-7.05 (m, 2H), 6.74 (d, 1H, 7.8 Hz), 6.41 (t, 1H, 7.2 Hz), 1.79 (s, 6H); MS: m/z 606 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cn2)c1-c1ccccc1

Procedure:
5-Nitro-2-aminopyridine (5 mmol, 0.7 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting solid was triturated with chloroform, and the insoluble material filtered from the reaction mixture. The filtrate was purified over silica gel and yielded the named product (m.p. 146.6° C.-148.6° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH:7](OC)OC)[CH3:2].C(#N)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]2=[N:16][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(OC)OC
Reactant: Nc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2ccc(Br)cn12
Yield: 107.1 %

Procedure:
Reflux a solution of 4,4-dimethoxy-but-2-enoic acid ethyl ester (3.3 g, 19.12 mmol) and toluene-4-sulfonic acid (0.02 g, 0.12 mmol) in a solution of 2:1 acetonitrile:water (90 mL) for 30 min. Add 2-amino-5-bromo-pyridine (1.65 g, 9.56 mmol) and reflux for 15 h. Cool and concentrate to ˜20 mL. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Combine and concentrate organic extracts. Flash chromatography using ethyl acetate/dichloromethane/methanol mixtures gives the subtitled compound as a brown oil (2.9 g). TOF MS ES+ exact mass calculated for C11H11BrN2O2 (p+1): m/z=283.0075 Found: 283.0082. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.55 (d, J=10 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J=10 Hz, 1H), 4.15 (s, 2H), 4.09 (q, J=4 Hz, 2H), 1.18 (t, J=4 Hz, 3H). EA Calcd. For C11H11BrN2O2: C, 46.66; H, 3.92; N, 9.89; Found C, 46.56; H, 4.02; N, 9.60.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:22]1([CH2:31]O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1>CCO>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:31][N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=[N:23]3)[CH2:17]2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: OCn1nnc2ccccc21
Solvent: CCO
Product: CCCCCCCCOc1ccc(C2CN(Cn3nnc4ccccc43)CCO2)cc1
Temperature: 50 °C

Procedure:
To a solution of 2-(4-octyloxy-phenyl)-morpholine (0.75 g; 2.6 mmol) in EtOH (10 mL) was added 1H-benzotriazole-1-methanol (0.38 g; 2.6 mmol), and the reaction mixture was heated at 50° C. for 20 minutes. After cooling to RT, the solvent was removed in vacuo to afford 1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole; which was used as such.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.B(F)(F)F.[CH3:16]COCC>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:16])=[O:10])[CH:3]=1
Reactant: Cc1cc(CCC(=O)O)no1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CCc1cc(C)on1

Procedure:
A mixture of 75.4 g of 5-methyl-3-isoxazolepropanoic acid, 150 ml of boron trifluoride etherate and 400 ml of methanol was heated at reflux for eight hours. The reaction mixture was concentrated in vacuo, made basic with sodium bicarbonate solution and extracted with methylene dichloride. The extracts were concentrated in vacuo and the residue distilled at 90°-100° C. (0.05 mm) to give 73 g of methyl 5-methyl-3-isoxazolepropanoate which crystallized to a solid, m.p. 54°-55° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C@:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C@:11]([OH:12])([CH3:10])[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)CO2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 45 %

Procedure:
To the solution of 2-Chloro-4-nitro-1H-imidazole (89.4 g, 606 mmol) and tert-butyl (S)-4-(2-methyloxiran-2-ylmethyl)piperazine-1-carboxylate (119 g, 466 mmol) in ethanol (475 ml), sodium hydrogen-carbonate (58.7 g, 699 mmol) was added followed by stirring under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was dispersed into ethyl acetate, and filtered off to afford a solid. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford a solid. The solids were combined and dried under reduced pressure to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate (84.7 g, yield 45%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(Cl)Cl.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)CCCc1cccs1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCc1cccs1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 13.6 %

Procedure:
Preparation of example 47 from the title compound of Example 7 (30 mg, 0.11 mmol), 4-thien-2-ylbutanoic acid (24 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) in N,N-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2 increasing to 6% methanol in CH2Cl2), also in an analogous manner, followed by methanol trituration afforded the title compound (6.5 mg, 0.015 mmol) as a yellow powder in 14% yield.
Reaction SMILES: [CH2:1]([N:5](C(=O)[C@@H](C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3]>ClCCl.N1CCCCC1>[CH2:1]([NH:5][NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.67 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethoxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in a mixture of 20 ml of dichloromethane and 5 ml of piperidine was stirred at room temperature for 2 hours. The solution was evaporated and the residue was triturated with hexane/diethyl ether (2:1). The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (5:95) for the elution to give 0.75 g of (E)-2′-(D-alanyl)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (R)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=1.46 min, m/z=558.9 [M+H]+, m/z=581.0 [M+Na]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7](O)[CH3:8].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>C1(C)C=CC=CC=1.O>[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][CH:7]([CH3:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Cl
Reactant: CC(O)Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cc1cccs1)NCc1ccccc1Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(2-thienyl)-2-propanol (14.4 g) and triethylamine (10.5 g) in 60 ml of toluene, a solution of p-toluensulfonylchloride (19.0 g) into 40 ml of toluene is added dropwise. The mixture is stirred for 24 hours. The precipitate of triethylamine HCl is removed by filtration and the filtrate is added dropwise to a solution of 2-chlorobenzylamine (28.3 g, 0.2 moles) into 100 ml of toluene at the reflux temperature over the course of 12-14 hours. The heating is continued for an additional 6 hours. Thereafter the mixture is cooled to 80° C., 200 ml of water is added, and the mixture is further cooled to room temperature. The organic phase is separated and acidified with 3 M hydrochloric acid. The resulting hydrochloride is collected by filtration and washed with acetone to yield, after drying, 16.4 g (61.7%) of N-2-chlorobenzyl-1-methyl-2-(2-thienyl)ethylamine HCl having a m.p. 164-165° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(N)(=O)C.C(O[CH:21]1[O:38][CH2:37][C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:2]1[N:3]([C@@H:37]2[O:38][CH2:21][C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:32]2[O:33][C:34](=[O:36])[CH3:35])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)OC1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(N)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 1.5 h
Yield: 25.5 %

Procedure:
2-Bromo-5,6-dichlorobenzimidazole (0.25 g, 0.94 mmol), N,O-bis(trimethylsiyl) acetamide (Aldrich, 1.4 ml, 5.6 mmol), and acetonitrile (Aldrich Sure Seal, 20 ml) were combined and magnetically stirred under a nitrogen atmosphere for 1.5 h. To the silylated base was added 0.30 g (0.94 mmol) 1,2,3,4-tetra-O-acetyl-xylopyranose (Aldrich, Milwaukee) followed by stannic chloride (1.4 mmol, 0.12 ml, Aldrich, Milwaukee). The solution stirred under nitrogen overnight, and additional stannic chloride (0.35 ml, 4.1 mmol) was added the following day. One hour after the second addition of stannic chloride, the reaction was poured into saturated aqueous sodium sulfate, and filtered through a celite pad which was washed with chloroform and water. The filtrate layers were separated. The chloroform layer was washed with 2×150 ml saturated aq. sodium bicarbonate then with 1×150 ml of water. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with hexanes and a step gradient from 0 to 25% ethyl acetate to give the product, 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole (0.13 g, 0.24 mmol, 26%); 1H NMR (DMSO-d6) δ8.47-8.42 (bs,1H), 7.91 (s, 1H), 6.07-6.02 (bs, 1H), 5.66-5.54 (bs, 3H), 4.18-4.13 (m, 1H), 3.95-3.89 (m, 2H), 2.02 (s, 3H), 1.99 (s, 3H), 1.77 (bs, 3H).