Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.CN(C)[CH:26]=[O:27]>C1COCC1>[Cl:13][C:14]1[C:23]([CH:26]=[O:27])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92%) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(O)C.[Cl-].[NH4+]>[Fe].O>[Br:1][C:2]1[C:3]([CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1c(N)cccc1Br
Temperature: 80 °C

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 114c (1.00 g, 2.89 mmol), ethanol (20 mL), iron powder (−325 mesh, 1.62 g, 28.9 mmol), ammonium chloride (3.09 g, 57.8 mmol) and water (4 mL), and the reaction mixture was heated at 80° C. for 1 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite 521. The filter cake was washed with ethanol (3×50 mL), and the combined filtrates were concentrated under reduced pressure. The resulting residue was triturated with water (10 mL) and then dried to a constant weight at 45° C. under vacuum to afford 114d in quantitative yield (949 mg) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 6.82 (m, 2H), 6.53 (m, 1H), 4.86 (s, 2H), 4.68 (br s, 2H), 0.79 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: C([C:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:40])([F:39])[CH:36]([F:38])[F:37])[CH:29]=1)([CH:12]([OH:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[C:9]([OH:11])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:26][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:40])([F:39])[CH:36]([F:38])[F:37])[CH:29]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(Cc1ccccc1)(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1

Procedure:
To a solution of benzyl 3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoic acid (5.07 g, 9.09 mmol, crude) in ethanol (500 ml) was added 10% palladium/carbon (containing water by 50%) (500 mg), and the mixture was stirred overnight under a 1 atm hydrogen stream. The reaction solution was filtered with celite, and the filtrate was concentrated to give the objective substance (4.22 g, 100%, crude). The present compound was used for the next reaction as a crude compound.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:16].[OH-].[NH4+]>O>[C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)(=[O:16])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: COc1cccc2c(C#N)cccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c(C(N)=O)cccc12

Procedure:
1-Cyano-5-Methoxy-naphthalene (36 g) is stirred with concentrated sulfuric acid (250 ml) and H2O (20 ml) on a steam bath for two hours and is allowed to cool. The reaction mixture is poured into a slurry of crushed ice and concentrated ammonium hydroxide (250 ml). The mixture is extracted with methylene chloride and the organic extract dried, filtered and evaporated, yielding the desired amide as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(NS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonylamino)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.57 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,4-difluorophenol were reacted as starting materials at 120° C. for 13 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (136 mg, 52.5%). Melting point: 141.7-142.5° C. (diethyl ether-hexane).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:37])[CH2:35][CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.25 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, propionyl chloride (0.2 g, 2.13 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (60 ml) and washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed and the resulting solid was slurried in hot C2H5OH (10 ml) to give after filtration N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.41 g, 64%) as a white solid: mp 219–221° C.; 1H NMR (DMSO-d6) δd 11.15 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 7.87–7.67 (m, 3H), 5.19–5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.98–2.84 (m, 1H), 2.65–2.48 (m, 2H), 2.26–2.17 (m, 2H), 2.09–2.04 (m, 1H), 1.05 (t, J=7.8 Hz, 3H); 13C NMR (DMSO-d6) δ d 173.52, 172.81, 169.79, 167.53, 167.01, 139.52, 134.79, 133.20, 131.55, 127.10, 121.86, 48.89, 37.69, 30.95, 28.43, 22.03, 9.90; Anal. Calcd. For C17H17N3O5+0.19 H2O: C, 58.88; H, 5.05; N, 12.12. Found: C, 58.77; H, 4.97; N, 12.12.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH3:13])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].C(Cl)(=O)OCC.C(NCC)C>ClCCl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](\[CH3:13])/[CH2:2][OH:1])[CH3:15]
Reactant: C/C(=C/C(=O)O)CC/C=C(\C)CO
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C(/C)CC/C=C(\C)CO

Procedure:
Following the same manner as in Example 5, the reaction and after-treatment were conducted by using 1.0 g of (E,E) and (Z,E)-8-hydroxy-3,7-dimethyl-2,6-octadienoic acid, 0.9 ml of triethylamine, 0.62 ml of ethyl chlorocarbonate and 0.67 ml of diethylamine in 20 ml of dichloromethane to afford 850 mg of the end product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH3:21]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13]([N:20]([CH3:21])[CH3:19])(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:18]
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2cc(F)c(Cl)cc21
Reactant: CNC
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(Cl)c(F)cc2c1=O
Reaction time: 70 h

Procedure:
7-Chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (8.73 g) was added to a stirred solution of dimethylamine in ethanol (33%; 170 ml) at ambient temperature. The mixture was stirred for 70 hours and then evaporated to dryness. The residue was stirred with water (50 ml) for 30 minutes. The solid product was collected, dried and crystallised from industrial methylated spirit to give the novel compound 7-chloro-6-fluoro-1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 219°-221° (dec).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:10][C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1>[OH-].[Na+].C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:21])=[C:9]([CH3:20])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: Cc1nc(O)c(Cc2ccc(Cl)cc2)nc1C
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccc(Cl)cc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
Ethylene chlorohydrin (16.11 g, 0.20M) was added to a solution of 2-hydroxy-3-p-chlorobenzyl-5,6-dimethylpyrazine (11.06 g, 40 mM) in aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Dilute aqueous K2CO3 was added to the residue, the resulting mixture being extracted three times with chloroform, dried wit anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 641 (9.73 g, yield: 75.9%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C@@H:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A suspension of 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (1.0 g, 2.64 mmol) and N-bromosuccinimide (470 mg, 2.64 mmol) in carbon tetrachloride (5 mL) at 25° C. was treated with benzoyl peroxide (32 mg, 0.132 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred at this temperature overnight. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (60 mL). The organic phase was then washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (546 mg, 45%) as an amorphous solid: EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.1077, found 456.1077.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1.O.[NH2:19][NH2:20]>CO>[NH:4]1[C:5]([C:6]2[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH:19][NH2:20])=[O:13])=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: NN
Reactant: COC(=O)COc1ccc(-c2nn[nH]n2)cc1
Solvent: O
Solvent: CO
Product: NNC(=O)COc1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a suspension of methyl [4-(2H-tetrazol-5-yl)phenoxy]acetate (1.10 g, 4.06 mmol) in MeOH (30 mL) was added hydrazine hydrate (2.0 mL). After stirring for 90 min at rt, the reaction mixture was evaporated off. The residue was taken up with MeOH (10 mL) and a white solid precipitated out. Filtration, washing with MeOH (2×3 mL) and drying under vacuo at 70° C. for 16 hrs gave 741 mg of the title compound (78%) as a white solid in 99.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]4[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=4[N:10]=3)[CH2:3]2)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1ccc2nc(N3CC(N)C3)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc2c1
Yield: 42.1 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-1,3-benzothiazole-6-carboxylate obtained in Example (225c) (190 mg, 0.69 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (132 mg, 0.75 mmol), WSC hydrochloride (394 mg, 2.06 mmol), 1-hydroxybenzotriazole (102 mg, 0.75 mmol) and N-methylmorpholine (0.15 mL, 1.37 mmol), to obtain 126 mg of the title compound as a milk white solid (42%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[N:7]=[C:6]1CO.[O-][Mn](=O)(=O)=O.[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[N:7]=[CH:6]1
Reactant: Cc1cccc2c1nc(CO)n2Cc1c(F)cccc1F
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cccc2c1ncn2Cc1c(F)cccc1F
Reaction time: 1 h
Yield: 80 %

Procedure:
In this Example, 1-(2,6-difluorobenzyl)-4-methylbenzimidazole (49) was prepared according to Method D. To 1-(2,6-difluorobenzyl)-2-hydroxymethyl-4-methylbenzimidazole (Example 40) (1.82 g, 4.52 mmol) dissolved in 1.5 M H2SO4 (40 mL) was added KMnO4 (1.50 g, 9.49 mmol, 160 M %). After 1 h at room temperature, the reaction mixture was filtered and washed with water. The brown solid was collected, suspended in acetone/methanol and filtered. The filtrate was collected and purified by flash chromatography eluting with 10% MeOH/CH2Cl2 increasing to 50% MeOH/CH2Cl2 to produce 1.42 g (4.70 mmol, 80% yield) of white powder. 1H-NMR (200 MHz, CD2Cl2): δ 7.99 (br s, 1H, H2), 7.37 (br d, J=7.9 Hz, 1H, H7), 7.32 (m, 1H, H4″), 7.17 (dd, J=7.3, 7.9 Hz, 1H, H6), 7.03 (d, J=7.3 Hz, 1H, H5), 6.96 (m, 2H, H3″,5″), 5.40 (s, 2H, CH2PhF2), 2.59 (s, 3H, CH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a solution of 9-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Preparation 90) (80 mg, 0.189 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.066 ml, 0.378 mmol) followed by ethyl 3-bromopropanoate (0.048 ml, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. The residue was purified by column chromatography on silica. Elution with 40-60% ethyl acetate in cyclohexane to give the title compound as an olive green coloured oil (28 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)CCCCBr
Agent: [Na+]
Solvent: CO
Product: COCCCCC(=O)OC
Yield: 97.7 %

Procedure:
A solution of methyl 5-bromovalerate (10.0 g, 51.3 mmol), NaOMe (12.3 ml of 25% solution, 53.8 mmol) in 100 ml of MeOH was refluxed for 5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water (100 ml). After drying (Na2SO4) and evaporation of solvent, methyl 5-methoxyvalerate (7.33 g, 97.8%) was obtained as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[S:21][C:22]2[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=2[N:24]=1>O.COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:20]3[S:21][C:22]4[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
0.697 g (4.2 mmol; 1.1 equivalent) of 1,3-benzodioxol-5-yl boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.1 g (3.82 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 133 mg (0.115 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 90° C. for 4 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a solution of water saturated with sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 0.960 g (yield of 76%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[F:12][C:13]([F:19])([F:18])[C:14](OC)=[O:15].Cl>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([C:14](=[O:15])[C:13]([F:19])([F:18])[F:12])[CH:3]=[C:4]([F:11])[C:5]=1[O:9][CH3:10]
Reactant: COC(=O)C(F)(F)F
Reactant: COc1c(F)cc(Br)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(F)cc(C(=O)C(F)(F)F)cc1F
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl triflouroacetate (3.67 g, 28.69 mmol) was added dropwise and then the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The organic combinded layers were washed with brine dried (Na2SO4), filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken on to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H), 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:37][CH2:38][CH:39]([OH:51])[CH2:40][N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1>CN(C=O)C>[CH2:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:49][CH2:50][N:41]1[CH2:40][CH:39]([OH:51])[CH2:38][NH:37][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[CH:10]=1
Reactant: Cn1cnc2cc(OCC(=O)O)ccc21
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1cnc2cc(OCC(=O)NCC(O)CN3CCc4ccccc4C3)ccc21
Temperature: 29 °C
Reaction time: 16 h
Yield: 4.3 %

Procedure:
To a solution of 2-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)acetic acid (160 mg, 0.776 mmol) in DMF (4 ml) was added TEA (336 mg, 3.33 mmol), HOBt (157 mg, 1.164 mmol), EDCI (223 mg, 1.164 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (192 mg, 0.931 mmol) at 29° C. The reaction mixture was stirred for 16 h at 29° C. until TLC showed the reaction to be complete. After evaporation of the solvent, the mixture was purified by preparative HPLC to give the title compound (13.1 mg, 4.2%) as colorless oil. 1H NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.09-6.97 (m, 5H), 4.59 (s, 2H), 4.03-3.97 (m, 1H), 3.84 (s, 3H), 3.65 (dd, J1=14.8 Hz, J2=30.4 Hz, 2H), 3.47-3.42 (m, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.72 (t, J=5.6 Hz, 2H), 2.53-2.51 (m, 2H). LCMS (m/z): 395.2 (M+1).