Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:35]=[CH:34][C:17]3[NH:18][C:19]([C@@H:21]4[CH2:25][C@H:24]([CH3:26])[CH2:23][N:22]4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:20][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>[Cu]I.CN(C=O)C>[CH3:26][C@@H:24]1[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:21]([C:19]2[NH:18][C:17]3[CH:34]=[CH:35][C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:9][CH:10]=4)=[CH:15][C:16]=3[N:20]=2)[CH2:25]1
Reactant: C[C@H]1C[C@@H](c2nc3cc(-c4ccc(Br)cc4)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2nc3cc(-c4ccc(C#C[Si](C)(C)C)cc4)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Ethynyl-trimethyl-silane (34.44 mg, 49.55 μL, 0.3506 mmol), tert-butyl (2S,4S)-2-[5-(4-bromophenyl)-1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (80 mg, 0.1753 mmol), Pd(DPPF)(Cl)2.CH2Cl2(14.32 mg, 0.01753 mmol), TEA (35.48 mg, 48.87 μL, 0.3506 mmol) and CuI (3.339 mg, 0.01753 mmol) are dissolved to dry DMF (2 mL). The mixture is stirred at 70° C. under N2 overnight. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography on silica gel SP1 25M using methanol/CH2Cl2 (0-5%) in 20 cv to provide tert-butyl (2S,4S)-4-methyl-2-[5-[4-(2-trimethylsilylethynyl)phenyl]-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylate (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][N:52]=[CH:53][CH:54]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCCc1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccncc1)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-benzo[d]imidazole-2-carbonyl)piperidine-4-carboxylic acid (50 mg, 0.126 mmol), EDC (48.2 mg, 0.251 mmol), and 1-hydroxybenzotriazole (34.0 mg, 0.251 mmol) were dissolved in DCM (Volume: 2.0 mL). The reaction was allowed to stir for 10 minutes before the addition of Hunig's Base (0.044 mL, 0.251 mmol) and 2-(pyridin-4-yl)ethanamine (0.030 mL, 0.251 mmol). The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in diethyl ether/ethyl acetate to obtain white solid. 1H-NMR (500 MHz, DMSO-d6) 8.47-8.43, 7.93, 7.74, 7.61, 7.39, 7.35-7.24, 7.21, 5.55, 4.45, 3.98, 3.33-3.28, 3.04, 2.87, 2.73, 2.40-2.31, 1.74, 1.58-1.32
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 80 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.3 mmol) followed by dimethylamine (2.4 ml of a 2 M solution in tetrahydrofuran, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (160 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.31 mL, 0.43 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (190 mg, 80%) as a yellow solid: mp 210-213° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.22 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.84 (m, 5H), 7.48 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0 Hz, 2.0 Hz, 1H), 6.01 (br s, 1H), 4.58-4.49 (m, 2H), 4.40 (br s, 1H), 3.28-3.24 (m, 1H), 3.15-3.10 (m, 1H), 2.81 (d, J=4.5 Hz, 3H), 2.78 (d, J=4.5 Hz, 3H); ESI MS m/z 457 [M+H]+; HPLC (Method B) 96.5% (AUC), tR=14.4 min; [α]23D +10.4° (c 0.11, Methanol).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>C(OCC)(=O)C.CO.C1CCCCC1.CS(C)=O>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([CH:6]([C:4]#[N:5])[C:7]([O:9][CH3:10])=[O:8])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: C1CCCCC1
Product: COC(=O)C(C#N)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 54.9 %

Procedure:
In a similar device as in Example 1 were charged 3.40 g (62.9 mmol) of sodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere, then, while stirring at room temperature, 6.30 g (62.9 mmol) of methyl cyanoacetate with a purity of 99% was gradually added dropwise over 5 minutes. Moreover, 10 ml of cyclohexane was added to the mixture, and the temperature of the mixture was raised to 100 to 105° C., formed methanol was subjected to distillation (azeotropic distillation) with cyclohexane. This operation (distillation of methanol) was repeated twice, then, the mixture was cooled to room temperature, 5.10 g (41.9 mmol) of 2,4-difluoronitrobenzene with a purity of 98% was gradually added dropwise to the mixture over 10 minutes while maintaining the temperature to 30 to 40° C., and the resulting mixture was reacted by raising the temperature to 75° C. for one hour. After completion of the reaction, the mixture was cooled to room temperature, then, 100 ml of ethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent:hexane:ethyl acetate=9:1 (volume ratio)) to obtain 5.48 g of methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate (isolation yield: 71%) as a yellowish oily product with a purity of 97% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1.C(#N)C>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:25]2[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of 10 g (0.057 mol) of p-fluorophenyl methyl sulfone, 8.72 g (0.063 mol) of K2CO3, 24.66 g (0.172 mol) of 1,4-dioxa-8-azaspiro[4.5]-decane and 50 ml of acetonitrile is stirred overnight at 90°-100° C. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ethyl ether affords 13.11 g (77%) of title compound as a white solid: m.p. 192°-194° C.; IR (KBr) 1588, 1369, and 1290 cm-1 ; NMR (CDCl3) δ 7.74 (m, 2H), 6.96 (m, 2H), 4.02 (s, 4H), 3.54 (m, 4H), 3.03 (s, 3H), and 1.81 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc(N)ccc3s2)cc1
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 61.9 %

Procedure:
5-Nitro-2-p-tolylbenzo[d]thiazole (400 mg, 1.48 mmol) was suspended in ethanol/water (8 mL/4 mL) and heated at 80° C. Ammonium chloride (160 mg, 2.96 mmol) and iron powder (414 mg, 7.40 mmol) were added to the suspension, and the mixture was left stirring at 80° C. for 75 min. After cooling, the solution was filtrated through a pad of Celite® and the pad washed with ethanol. Water was added to the filtrate, ethanol was evaporated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 220 mg (62%) of the title compound (LCMS RT=6.51 min, MH+ 241.0)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.C([O-])(=O)C.[K+].Br[C:21]1[N:22]=[C:23]2[C:29]([C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Pd].[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2].C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:2]3[CH:3]=[CH:4][C:5]4[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[NH:7][C:6]=4[CH:14]=3)[N:22]=2)[NH:27][CH:28]=1)=[O:35]
Reactant: CC1(C)Oc2ccc(Br)cc2NC1=O
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc4c(c3)NC(=O)C(C)(C)O4)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
6-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.24 mmol, Bioorg. Med. Chem., 15 (2007), 5912) and bispinacolato diboron (73 mg, 0.29 mmol) were dissolved in 2.5 ml 1,4-dioxane. The solution and flask were purged with argon. Potassium acetate (59 mg, 0.6 mmol) and palladium bis(diphenylphosphino)ferrocene dichloride (10 mg, 0.012 mmol) were added and the sealed reaction was stirred at 100 C. for 3 hr. The reaction was cooled to room temperature and 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.1 g, 0.35 mmol) was added. The reaction was diluted with 1 ml 1,4-dioxane and 0.6 ml water. Palladium bis(diphenylphosphino)ferrocene dichloride (15 mg, 0.019 mmol) and potassium carbonate (98 mg, 0.71 mmol) were added. The sealed vial was placed in a microwave reactor and run at 15° C. for 30 min. More palladium catalyst (7 mg, 0.0095 mmol) was added and the reaction repeated at 14° C. for 30 min. The reaction mixture was poured into ethyl acetate and sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 31 mg (35%) of the product. MP=>300 C., (M+H)+=379.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:39])=[C:10]([O:40][CH3:41])[CH:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:39])=[C:10]([O:40][CH3:41])[CH:9]=1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 82.4 %

Procedure:
A solution of 3-aminoisoxazole (0.664 ml, 8.98 mmol) and racemic perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (4.705 g, 8.16 mmol) in 100 mL THF, was cooled to 0° C. LHMDS 1N in THF (17.15 ml, 17.15 mmol) was added dropwise. After stirring for an hour, HCl 1N aqueous (32.7 ml, 32.7 mmol) was added, and the reaction mixture was extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was triturated with ether, and the resulting solid was collected and dried yielding 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.20 g, 6.72 mmol, 82% yield). A portion of this material was resolved. Chiral separation was performed by SFC: (S,S) Whelk-O, 50% isopropanol yielding (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.150 g, 0.315 mmol, 3.86% yield) and (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.154 g, 0.323 mmol, 3.96% yield). Analytical data for both isomers is identical. m/z (ESI) 476.1 (M+H)+. 1H NMR (ACETONITRILE-d3) δ: 8.37 (d, J=1.9 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.78 (dd, J=8.9, 2.2 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.3, 2.1 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.71-6.79 (m, 2H), 6.45 (d, J=1.8 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48]OS(C)(=O)=O)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 91.8 %

Procedure:
Following the procedure of Example 1 (10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 91.8%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([NH:34][NH2:35])(OCC1C=CC=CC=1)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1.CCO.[Pd].CCOC(C)=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:34][NH2:35])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [Pd]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The benzimidazole carboxylic acid of example 2 (0.500 g, 1.61 mmol) was stirred in DMF (10 mL) with N-Cbz-hydrazine (0.268 g, 1.61 mmol), TBTU (0.620 g, 1.93 mmol) and DIEA (0.727 g, 563 mmol) for 3 days. EtOAc was added and the reaction mixture was washed twice with 10% aqueous citric acid, twice with saturated aqueous NaHCO3 and once with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give a brown foam that was hydrogenolyzed in THF-EtOH (1:1) with 10% Pd/C (70 mg) under an atmosphere of hydrogen for 8 h. The suspension was filtered and concentrated to dryness to give 1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid hydrazide as a brown foam.
Reaction SMILES: CS([O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[CH2:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)(=O)=O.[F:21][C:22]1[C:27]([F:28])=[C:26]([O:29][CH2:30][CH3:31])[CH:25]=[CH:24][C:23]=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([O:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH:19]=[CH2:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[C:22]([F:21])[C:27]=1[F:28])[CH3:31]
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Reactant: CCOc1ccc(O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
9.8 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate and 5.96 g of 2,3-difluoro-4-ethoxyphenol were dissolved in 90 mL of DMF. 10.4 g of tripotassium phosphate was added, followed by stirring at 90 to 100° C. for 3 hours. The reaction mixture was poured into water, extracted with toluene, washed in turn with water, 10% hydrochloric acid, water, and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified in turn by subjecting to column chromatography (silica gel/toluene), recrystallization (methanol/acetone), column chromatography (alumina/acetone), washing with ion-exchange water, silica treatment, and recrystallization (methanol/acetone) to obtain 8.5 g of 4-ethoxy-2,3-difluoro-1-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene (IIIa) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H-].[Na+].[CH2:23](I)[CH3:24]>CN(C=O)C.[NH4+].[Cl-].O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc2[nH]c3ccc(OC)cc3c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c1cc(OC)ccc1n2CC
Reaction time: 0.5 h

Procedure:
A solution of 6-methoxycarbazole-3-carboxylic acid ethyl ester (1.28 g, 4.77 mmol) in DMF (8 mL) was added to a suspension of sodium hydride (60% in mineral oil, 0.286 mg, 7.15 mmol) in DMF at 0° C. The reaction was stirred for 30 minutes then ethyl iodide was added (0.89 g, 5.72 mmol). The reaction was allowed to reach room temperature and was stirred for further 15 hours then was diluted with NH4Cl sat. and water. The reaction was extracted with tert-butylmethyl ether and the organic phase was washed with water then brine. The organic layer was dried over sodium sulfate and the solvent concentrated in vacuo to give a crude which was purified by column (10% ethyl acetate/hexane) to afford 0.79 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2Cl.CN1C(=O)CCC1.[N-:27]=[N+:28]=[N-:29].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:27]=[N+:28]=[N-:29]
Reactant: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 60 °C

Procedure:
Into a 250 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer, silicone oil heating bath, nitrogen inlet and gas outlet was placed 3.2 g (9.50 mmoles) of 6-bromo-4-chloro-2-(3-fluorophenyl)-quinoline. To this was added 75 mL of N-methyl pyrrolidinone then 6.0 g (95 mmoles, 10 equiv.) of sodium azide. The stirring mixture was then warmed to 60° C. for 18 hr. At the end of this time the reaction was cooled, then poured into a 1 L separatory funnel containing 500 mL water and 250 mL of ethyl acetate. The pH was adjusted to 9.0 the layers were separated. The aqueous layer was then extracted twice with 100 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give a product, which was carried to the next step without further purification.
Reaction SMILES: Cl[C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]1[O:14][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[N:12]=1)[CH3:17]
Reactant: CCOC(=O)N[C@@H]1CCc2ccccc2[C@H]1Cl
Solvent: CCO
Product: CCOC1=N[C@@H]2CCc3ccccc3[C@@H]2O1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A solution of (±) trans-1-chloro-2-ethoxycarbonylamino-1,2,3,4-tetrahydronaphthalene (L. M. Gaster and B. S. Orlek, EP 88575)(1.0 g, 4.0 mmol) in ethanol (100 ml) was treated dropwise with a solution of KHCO3 (0.44 g, 4.4 mmol in 30 ml water) over a period of 3 h. After stirring for a further 30 min the reaction was concentrated under high vacuum to approximately one quarter the original volume, then diluted with water and extracted into diethyl ether (3×100 ml). The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacua. Flash chromatography on silica gel using petroleum ether 60/80-ethyl acetate as eluant, followed by distillation in a kugelrohr (b.p. 180° C. at 0.4 mmHg) afforded the title compound as a colourless oil (0.69 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-difluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.58 (s, 1H), 7.17 (dd, J=8.7, 2.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.51 (s, 1H), 6.49 (m, 2H), 3.28 (s, 3H), 1.99 (m, 4H), 0.81 (t, J=7.4 Hz, 6H). MS (ESI) m/z 347 ([M+H]+); MS (ESI) m/z 345 ([M−H]−); Anal. calcd for C19H20F2N2O2: C, 65.88; H, 5.82; N, 8.09. Found: C, 64.99; H, 5.63; N, 7.89.