Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 75.3 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 75.3%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCCC1
Reactant: N#CCc1ccsc1
Product: N#CC(=C1CCCCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cycloheptanone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.CN(C)C([N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1)=O.[I-].[Na+].N>C(#N)C>[CH3:20][C:18]1[NH:17][C:16]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:15][CH:19]=1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: N
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(Cc2ccc(C#N)cc2)[nH]1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (11.0 g), 1-(dimethylcarbamoyl)-4-methylimidazole (8.6 g) and sodium iodide (8.4 g) in acetonitrile (75 mL) is heated and stirred at reflux for 15 hours. The mixture is cooled to 0° (ice-bath) and ammonia gas is bubbled through the solution for 15 minutes. The volatiles are then evaporated and the residue is partitioned between water (150 mL) and ethyl acetate (150 mL). The organic solution is washed with water (2×50 mL) and is then extracted with 3 N hydrochloric acid. The combined acidic extracts are made basic (pH 9) with 6 N sodium hydroxide and the product is extracted into ethyl acetate (3×60 mL). After drying (MgSO4), solvent evaporation affords crude 4-[1-(5-methylimidazolyl)methyl]-benzonitrile which forms a hydrochloride salt, m.p 203°-205°, when its solution in acetone is treated with ethereal HCl.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH:7]([C:10]1[NH:14][N:13]=[C:12]([C:15]([OH:17])=O)[C:11]=1[N+:18]([O-:20])=[O:19])([CH3:9])[CH3:8].C[N:22](C)C=O>ClCCl>[CH:7]1([C:10]2[NH:14][N:13]=[C:12]([C:15]([NH2:22])=[O:17])[C:11]=2[N+:18]([O-:20])=[O:19])[CH2:8][CH2:2][CH2:1][CH2:9]1
Reactant: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1n[nH]c(C2CCCC2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (7.65 ml, 87.7 mmol) was added dropwise to a suspension of 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid (6.58 g, 29.2 mmol) in dichloromethane (100 ml) containing dimethylformamide (0.5 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 1 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was azeotroped with dichloromethane (2×50 ml) and dissolved in toluene (100 ml). Ammonia gas was bubbled into the solution for 2 hours and the reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5 changing to 90:10, by volume) to give 5-cyclopentyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (5.48 g) as a yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=13.67-13.79 (1H, brs), 7.88-8.03 (1H, brs), 7.59-7.77 (1H, brs), 3.46-3.60 (1H, quin), 1.97-2.11 (2H, m), 1.58-1.81 (6H, 2×m) ppm. LRMS (electrospray): m/z [M−H]+ 223, [2M−H]+ 447. Anal. Found C, 56.12; H, 7.39; N, 27.55. C9H12N4O3. 0.2 mol acetone requires C, 56.01; H, 7.44; N, 27.22%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH:13]([CH3:17])[N:12]1[C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([N:12]1[CH:11]([CH3:10])[CH2:16][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH:13]1[CH3:17])(=[O:20])[CH3:19]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N1C(C)CNCC1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Temperature: 130 °C
Yield: 46.7 %

Procedure:
To a solution of 4-fluoro-benzaldehyde (3.0 g, 0.024 mol) and 1-(2,6-dimethyl-piperazin-1-yl)-ethanone (3.0 g, 0.019 mol) in anhydrous DMF (15 mL) was added potassium carbonate (6.6 g, 0.048 mol). The reaction mixture was heated to 130° C. for 32 hours. The DMF was removed and the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde as light yellow solid (2.31 g, 46.2%).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]12[O:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][NH:15][CH2:14]2.[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:41])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>>[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH:41][C:1]([N:15]4[CH2:14][C@H:13]5[O:20][C@H:17]([CH2:18][CH2:19]5)[CH2:16]4)=[O:12])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CC2CNCC1O2
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1C[C@H]2CC[C@@H](C1)O2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 8-oxa-3-aza-bicyclo[3.2.1]octane and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=415.6 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Temperature: 115 °C
Yield: 34.6 %

Procedure:
Methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 70) (2.70 g, 12.3 mmol) was suspended in toluene (27 mL), and cyclohexylamine (1.40 g, 14.1 mmol) was added. The reaction was heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether (50 mL) was added, and the resultant precipitate was collected by filtration to give N-cyclohexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (1.22 g, 35%) as an off white solid. M.p.: 221° C. 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 3.86 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 10.35 (d, J=7.6 Hz, 1H), 11.83 (bs, 1H). MS 287 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])([CH3:38])[CH3:37]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:4]([C:1]2[O:3][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:14]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl (4-acetyl-phenoxy)acetate (2.14g, 9.67 mmol), trimethylsilyl triflate (4.48 mL, 23.20 mmol), triethylamine (12.93 mL, 38.6 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (2.00g, 6.45 mmol) m.p. 194°-196° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.57 (m, 9H), 3.41 (m, 1H), 4.81 (q, 2H), 4.89 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.05 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: C(OC(C(OC(C(C(F)(F)F)(F)F)(F)F)(C(F)(F)F)[F:8])=O)(C)C.[CH:24]([O:33][C:34]([C:36]([O:42][C:43]([C:46]([C:49]([F:52])([F:51])[F:50])([F:48])[F:47])([F:45])[F:44])([C:38]([F:41])([F:40])[F:39])[F:37])=[O:35])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]>C1C=CC=CC=1>[C:24]([O:33][C:34]([C:36]([O:42][C:43]([C:46]([C:49]([F:50])([F:51])[F:52])([F:48])[F:47])([F:44])[F:45])([C:38]([F:40])([F:39])[F:41])[F:37])=[O:35])([C:29]([F:32])([F:31])[F:30])([C:25]([F:28])([F:27])[F:26])[F:8]
Reactant: O=C(OC(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: CC(C)OC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: c1ccccc1
Product: O=C(OC(F)(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h

Procedure:
Further, the same operation was repeated once. The total amount of benzene injected was 0.219 g, and the total amount of R-113 injected was 21 ml. Further, nitrogen was supplied for 1.5 hours. The product was quantified by 19F-NMR, whereby the yield of the above identified compound to (CH3)2CHOCOCF(CF3)OCF2CF2CF3, was 48.1%, and the yield of (CF3)2CHOCOCF(CF3)OCF2CF2CF3 to (CH3)2CHOCOCF(CF3)OCF2CF2CF3, was 19.1%.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 185 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 295 mg (83%) of the title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH3:21][N:22]([CH3:37])[C@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH2:24]1.C(O)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][N:22]([CH3:37])[C@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][CH:12]=4)[CH:5]=[CH:4][C:3]=3[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:33])=[CH:30][CH:29]=2)[CH2:24]1
Reactant: CN(C)[C@H]1CCN(c2ccc(C(=O)O)cc2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)[C@H]1CCN(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Yield: 68 %

Procedure:
Following the same procedure as described in Example 1a, step 6 (scheme 1) and using compound 4 but substituting compound 7 for compound 99, the title compound 100 was obtained (0.407 g, 68% yield) [after flash chromatography (eluent: 10% isopropanol in DCM with 0.1% triethylamine)].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH2:20][C:21]1[O:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:20]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([CH2:4][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=3)[CH:5]=1)[C:21]1[O:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1)=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: Clc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Product: OCc1ccc(C(c2cn(Cc3ccccc3)c3cccc(Cl)c23)c2cn(Cc3ccccc3)c3cccc(Cl)c23)o1

Procedure:
The compound Bis(4-chloro-1-benzylindol-3-yl)-(5-hydroxymethyl-2-furyl)methane was prepared following procedure B, starting from 4-chloro indole and benzylbromide, and the resulting compound was reacted with 5-hydroxy methyl furfural following general procedure A. LC: Tr 2.89 min, MS: 591 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13](O)[CH3:14].O.C(=O)(O)[O-]>Cl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH2:13][CH3:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CCO
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CCOC(=O)c1cc(F)c(N)cc1F
Yield: 92 %

Procedure:
A solution of 4-amino-2,5-difluorobenzoic acid (intermediate 137; 2.7 g; 0.015 mol) in hydrogen chloride 1.25 mL in ethanol (91 mL, 0.113 mol) was stirred for 24 hours at 60° C. The solvent was removed under reduced pressure and the crude obtained was treated with water and solid bicarbonate to obtain a basic pH, after few minutes stirring an extraction with ethyl acetate was done. The organic layer was washed with brine, dried and the solvent was removed under reduced pressure to give the title compound as a white solid (92%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.CC1O[N:29]=[C:28](C2C=CC=CC=2)[C:27]=1[CH2:37][O:38][C:39]1N=CC(C(O)=O)=N[CH:44]=1.NC1CCOCC1.C(OCC)(=O)C>CO.C(Cl)Cl>[O:38]1[CH2:37][CH2:27][CH:28]([NH:29][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:44][CH2:39]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1cnc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Agent: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cnc(C(=O)NC2CCOCC2)cn1

Procedure:
As described for example 2b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (44 mg, 13.3 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid, was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (SiO2, ethyl acetate then DCM:MeOH=90:10, 31 mg, 56%) which was obtained as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C=O)C.O>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=2)=[CH:12][CH:11]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-chlorosuccinimid (134 mg) is added to a solution of crude 4-bromo-naphthalene-1-carbaldehyde oxime (250 mg) in DMF (3 ml). After 1 hour at 40° C., the reaction is cooled down to 0° C. and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (240 mg) and triethylamine (0.15 ml) are added. The reaction is further reacted at room temperature for 16 hours. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-(4-bromo-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole as colorless crystals: m.p. 127-130° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])OC(C)(C)C)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23].[Br:24][C:25]1[CH:26]=[C:27](C(OC2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:28][C:29]=1[CH3:30]>C[O-].[Na+]>[Br:24][C:25]1[CH:26]=[C:27]([C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:23][CH3:22])[N:7]=3)[CH2:13][CH2:12]2)=[O:21])[NH:28][C:29]=1[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)n2)CC1
Reactant: CO
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
tert-Butyl [1-(6-chloropyridin-2-yl)piperidin-4-yl]carbamate (Intermediate 66) (300 mg, 0.99 mmol) was dissolved in 0.5 M solution of sodium methoxide in MeOH (9 ml, 4.45 mmol) at room temperature and the mixture was refluxed for 72 h. The solvent was removed in vacuo, extracted with EtOAc then washed with water. The organic phase was concentrated in vacuo and treated with 4 N hydrochloric acid in dioxane (10 ml) for 2 h. The solvent was removed in vacuo and dried to remove excess hydrochloric acid. The solid was dissolved in NMP (3 ml) and pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17) (80 mg, 0.216 mmol) and TEA (137 μl, 0.9 mmol) were added. The mixture was stirred at room temperature for 2 h and the mixture was purified by semi-preparative HPLC using a gradient of 15-95% CH3CN/H2O (0.1% TFA) to give the title compound (23 mg).
Reaction SMILES: CC(NC1C=C(N)C=CC=1)=O.NC1C=CC=CC=1.[Br:19][C:20]1[CH:53]=[CH:52][C:23]([CH2:24][C:25]2[N:26]([C:38]3[CH:39]=[C:40]([N:44]4[S:48](=[O:50])(=[O:49])[NH:47][C:46](=[O:51])[CH2:45]4)[CH:41]=[CH:42][CH:43]=3)[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:29]=2)=[CH:22][CH:21]=1.BrN1NC(=O)CS1.[CH:61]1([CH2:66][CH:67]([C:69]2[CH:74]=[CH:73][C:72](B3OC(C)(C)C(C)(C)O3)=[CH:71][CH:70]=2)[OH:68])[CH2:65][CH2:64][CH2:63][CH2:62]1>>[Br:19][C:20]1[CH:53]=[CH:52][C:23]([CH2:24][C:25]2[N:26]([C:38]3[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=3)[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:29]=2)=[CH:22][CH:21]=1.[CH:61]1([CH2:66][CH:67]([C:69]2[CH:70]=[CH:71][C:72]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][C:25]4[N:26]([C:38]5[CH:39]=[C:40]([N:44]6[S:48](=[O:50])(=[O:49])[NH:47][C:46](=[O:51])[CH2:45]6)[CH:41]=[CH:42][CH:43]=5)[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=5[Cl:37])[N:29]=4)=[CH:52][CH:53]=3)=[CH:73][CH:74]=2)[OH:68])[CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: CC1(C)OB(c2ccc(C(O)CC3CCCC3)cc2)OC1(C)C
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Agent: CC(=O)Nc1cccc(N)c1
Agent: O=C1CSN(Br)N1
Solvent: Nc1ccccc1
Product: Nc1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C(O)CC5CCCC5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamine was prepared from 3-aminoacetanilide according to general procedure M, then the aniline was converted to 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidin-3-one-1,1-dioxide as described in general procedures E and F. The bromo-thiadiazolidinone (100 mg, 0.17 mmol) was coupled with 2-cyclopentyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanol according to general procedure G to provide 5-{3-[2-[4′-(2-cyclopentyl-1-hydroxy-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidin-3-one-1,1-dioxide.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH2:27])[C:17]1=[O:28])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:29]([CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CO>[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH:27][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:17]1=[O:28])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium cyanoborohydride (0.152 g, 0.0014 mol) was added to a solution of 1-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.45 g, 0.0014 mol) and benzylpyruvic acid (0.48 g, 0.0028 mol) in methanol (35 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. Additional benzylpyruvic acid (0.48 g, 0.0028 mol) was added, and the reaction mixture stirred for an additional 18 hours. Concentrated hydrochloric acid (0.5 ml) was added and the resulting solution stirred for 1 hour. The solvents were removed under reduced pressure and the residue treated with dichloromethane (100 ml) to precipitate sodium chloride. After filtration, the solvent was removed under reduced pressure and the residue chromatographed on silica gel (30 g). Elution with ethyl acetate/methanol/acetic acid (90:10:0.2) gave 1-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as an oil; NMR(CDCl3) 7.35 (m, 14H), 5.10 (s, 2H), 4.60(m, 2H), 3.00(m, 12H).
Reaction SMILES: C=O.[ClH:3].[CH:4]1([SH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:11](=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:3][CH2:11][S:10][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: SC1CCCCC1
Reactant: Cl
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCSC1CCCCC1
Temperature: 40 °C

Procedure:
Into a 1 L four necked flask equipped with a nitrogen supply tube, a stirrer and a thermometer, 12.1 g of paraformaldehyde and 60 g of toluene were mixed and stirred, and then 120 mL of concentrated hydrochloric acid was added thereto. Thereafter, the reaction solution was heated to 40° C., and 60 g of a toluene solution containing 35.4 g of cyclohexanethiol was added over a period of 20 minutes. After completion of the dropwise addition, the reaction solution was stirred while maintaining it at 50° C. After confirming the completion of the reaction by TLC, the water phase was discharged, and the organic phase was made alkaline with a saturated sodium carbonate aqueous solution to obtain a toluene solution of chloromethylcyclohexylsulfide.