Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([C:23](=O)[CH3:24])[CH:22]=1>CO.C(O)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21](/[C:23](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:24])[CH:22]=1
Reactant: CNS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C(=O)N/N=C(\C)c2cc(Cl)ccc2O)c1
Temperature: 120 °C
Yield: 36.7 %

Procedure:
3-(hydrazinecarbonyl)-N-methylbenzenesulfonamide (120 mg, 0.523 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (89 mg, 0.523 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)-N-methylbenzenesulfonamide (75 mg, 0.192 mmol, 36.8% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.21 (m, 1H), 8.06 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.59 (t, 1H, J=8.0 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.18 (m, 1H), 6.90 (d, 1H, J=8.0 Hz), 2.56 (s, 3H), 2.36 (5, 3H). Mass [M+H]+: 382.1
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=O)[C@@H:17]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]2)=[C:21]([CH3:33])[CH:20]=1.C(O)(=O)C>>[C:3]([OH:5])(=[O:4])[CH3:2].[NH:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:16]1[C@@H:17]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[S:29](=[O:30])(=[O:31])[NH:28][C:27](=[O:32])[CH2:26]2)=[C:21]([CH3:33])[CH:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)Nc2ccccc2N)ccc1C1CC(=O)NS1(=O)=O
Solvent: CC(=O)O
Product: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)c2nc3ccccc3[nH]2)ccc1C1CC(=O)NS1(=O)=O

Procedure:
A solution of benzyl (1S)-2-[(2-aminophenyl)amino]-1-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylbenzyl]-2-oxoethylcarbamate trifluoroacetate (1.20 g, 1.84 mmol) and acetic acid (40.0 mL, 704 mmol) was stirred at 40° C. for 2 h. The solvent was removed in vacuo. The crude product was used in the next step without purification. MF=C27H26N4O5S; LCMS found for C27H27N4O5S (M+H)+: m/z=519.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:37]=[CH:38][CH3:39])([CH:34]=[CH:35][CH3:36])[C:23]1=[O:40].C(N(CC)CC)C>CN(C)C=O>[C:7]([O:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:34]=[CH:35][CH3:36])([CH:37]=[CH:38][CH3:39])[C:23]1=[O:40])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=CC1(C=CC)C(=O)N(O)C(=O)C1(C=CC)C=CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC=CC1(C=CC)C(=O)N(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)C1(C=CC)C=CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
0.14 mole of triphenylchloromethane and 0.14 mole of N-hydroxy tetrapropenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 90% of N-trityloxy tetrapropenylsuccinimide is recovered.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1(C)C=CC=CC=1>[CH2:1]([NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccccc1
Temperature: 80 °C
Yield: 83 %

Procedure:
27 g of stearylamine was dispersed in 100 ml of toluene. To this dispersion was added 13 g of benzoyl chloride at 70° C. An exothermic reaction occurred and the temperature of the mixture increased to 80° C. The reaction mixture was heated to 100° C. and that temperature was maintained for about 20 hours until generation of hydrogen chloride gas was terminated. The reaction mixture was cooled, from which white crude crystals were separated. The thus obtained white crystals were neutralized with sodium hydroxide and were then recrystallized from alcohol. This recrystallization gave white crystals melting at 85° C. to 87° C. The yield was 83%.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>S(=O)(=O)(O)O.CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: O=CCCCCC(=O)O
Yield: 56.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 0.5 g of sulfuric acid were refluxed for 3.5 hours, the methanol formed being distilled off constantly. Fractional distillation under reduced pressure gave 18.5 g (yield 57% of theory) of 5-formylvaleric acid of boiling point 106°-112° C./1 mbar. 13C NMR spectrum in D-chloroform: chemical shifts relative to tetramethyl silane as internal standard=21, 24, 34 and 44 ppm (4 methylene groups), 178 ppm (formyl group) and 203 ppm (carboxyl group).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:32]=[C:33]=[O:34])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:34])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 99.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-6-methoxyphenyl isocyanate (111 mg) was added, and the admixture was refluxed with heat for 29 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 84 mg of the title compound (yield: 100%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][O:18][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1(C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Reaction time: 8 h
Yield: 49.4 %

Procedure:
p-Toluenesulfonyl chloride (9.6 g, 50.35 mmol) was added at 0° C. to a mixture of (1-trifluoromethyl-cyclopropyl)-methanol (7 g, 49.96 mmol), triethylamine (7.7 mL, 55.24 mmol) and DMAP (0.61 g, 4.996 mmol) in 100 mL of DCM. The resulting mixture was stirred at 0° C. to RT overnight before being washed with aqueous 1M HCl. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (120 g SiO2, hexanes/[hexanes/Et2O 8/2] 100 to 0% hexanes) to give 7.26 g of toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (49% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11]CC3C=CC=CC=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([OH:11])[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O

Procedure:
To a solution of 4-amino-2-(4-fluorobenzyl)-10-(benzyloxy)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.11 g, 0.25 mmol) in dichloromethane (10 mL) at 0° C., a solution of boron tribromide in dichloromethane (0.7 mL, 1M) was added. The resultant solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue subjected to purification on reverse phase HPLC. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1>[Pd].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:11]=2[CH:12]=1
Reactant: CN1CCC2(CC1)COc1ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CN1CCC2(CC1)COc1ccc(N)cc12
Yield: 59.6 %

Procedure:
2,3-Dihydro-1'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine](D4, 0.98 g, 4.0 mmol) was hydrogenated over 10% palladium on charcoal (0.18 g) in ethanol (50 ml) for 6 h. Catalyst was filtered off onto kieselguhr, and the filtrate was evaporated and chromatographed on silica gel, eluting with 0-25% methanol/chloroform (gradient), to give the title compound (0.52 g, 60%) as a cream solid.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[C:16]([CH3:29])[CH:15]=3)[C:10]2=[O:30])=[CH:6][CH:5]=1)(=[O:3])N.[OH-].[K+].C(O)(=[O:37])C>C(O)C.O>[CH3:29][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:7]3[CH:31]=[CH:32][C:4]([C:1]([OH:3])=[O:37])=[CH:5][CH:6]=3)[C:10]2=[O:30])[S:18][C:17]=1[C:19](=[O:20])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 5-(3-(4-carbamoylbenzyl)-2-oxoimidazolidin-1-yl)-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (0.16 g, 0.36 mmol) and 5 N aqueous potassium hydroxide solution (5.0 mL, 25.0 mmol) in ethanol (5 mL) was stirred at reflux for 2 h, cooled to 0° C. and acidified with glacial acetic acid to pH˜6. The mixture was diluted with water (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ether in hexanes to afford the title compound as a colorless solid in 50% yield (0.08 g): mp 120° C. (dec.): 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.46 (s, 1H), 8.30 (t, J=5.8 Hz, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.44-7.32 (m, 2H), 6.24 (s, 1H), 4.47 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.88-3.79 (m, 2H), 3.51-3.43 (m, 2H), 2.37 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 167.0, 162.9, 155.5, 148.8, 147.8, 142.5, 141.7, 139.0, 135.0, 130.0, 129.6, 127.7, 123.4, 119.9, 113.8, 112.1, 46.8, 42.5, 41.5, 15.7: MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:4][N:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][O:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:4][N:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1cc(-c2cccs2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccs2)on1
Yield: 81.8 %

Procedure:
3-Hydroxy-5-(2-thienyl)isoxazole (0.42 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.63 g, 82%) as colorless crystals.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[OH:20])[N:10]=[CH:9][N:8]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[O:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
To 3.2 ml of tetrahydrofuran were added 0.37 g of 4-chloro-6-(cis-2-hydroxycyclohexyloxy)pyrimidine and 0.45 ml of triethylamine, to which 0.25 ml of chlorotrimethylsilane was slowly added dropwise with stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.5 g of 4-chloro-6-(cis-2-trimethylsilanyloxycyclohexyloxy)pyrimidine.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:29])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)[CH3:19])[CH2:12][CH2:11]1.[CH3:36][NH:37][C:38]1[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][CH:39]=1>>[C:45]([O:44][C:42](=[O:43])[C:41]1[CH:49]=[CH:50][C:38]([N:37]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:8](=[O:29])[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:11][CH2:12]2)[CH3:19])=[O:28])[CH3:36])=[CH:39][CH:40]=1)([CH3:47])([CH3:46])[CH3:48]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCO
Reactant: CNc1ccc(C(=O)OC(C)(C)C)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCN(C)c1ccc(C(=O)OC(C)(C)C)cc1
Yield: 25.9 %

Procedure:
The compound (163 mg, 0.338 mmol) obtained in Example 39b was used according to the method described in Example 4g to give a crude aldehyde compound (160 mg). The resulting crude aldehyde compound and the compound (69 mg, 0.334 mmol) obtained in Example 35a were used a to give the title compound (58 mg; yield, 26%) as a white solid according to the method described in Example 18b.
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17](=N)[NH2:18].[OH-].[Na+].O.ClC1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27]N=1>C(O)C>[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17]1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][N:18]=1
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Reactant: CC1(C)CC(Cl)=NO1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 1.93 g (5.00 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 10 ml of ethanol were added 0.48 g (12.00 mmol) of sodium hydroxide and 10 ml of -water, followed by 30 minutes of stirring at room temperature. Thereto was added 0.67 g (5.00 mmol) of 3-chloro-5,5-dimethyl-2-isoxazoline at room temperature, followed by further 12 hours of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.02 g (yield: 56.7%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[F:20][C:21]([F:39])([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)[CH:22]([F:28])[O:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O.CCOCC>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([S:19][CH2:37][CH:34]2[CH2:35][CH2:36][CH:31]([CH2:30][O:29][C:21]([F:20])([F:39])[CH:22]([F:28])[O:23][C:24]([F:26])([F:27])[F:25])[CH2:32][CH2:33]2)[CH:13]=[N:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(OC(F)(F)F)C(F)(F)OCC1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCC2CCC(COC(F)(F)C(F)OC(F)(F)F)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a suspension of 0.47 g of potassium carbonate in 10 ml of dimethylformamide, 0.75 g of 2-tert.butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.3 g of 4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)methyl-cyclohexylmethyl-bromide. Were added it was stirred for 2 hours at room temperature, it was diluted with ether, then it was washed with diluted HCl and brine; it was anhydrified, the solvent was evaporated and the obtained rough product was eluted by silica gel chromatography with hexane/ethyl acetate 98/2. 0.65 g of a mixture of CIS/trans (15/85) product was obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:15]([O:17][CH3:18])=[O:16]>O>[CH3:18][O:17][C:15]([N:5]1[CH2:4][CH2:3][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1)=[O:16]
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 958.5 %

Procedure:
In 150 ml of water was dissolved 4.13 g (0.10 mol). of sodium hydroxide. To the solution was added 15.27 g (10.4 mmol.) of 2,3,4,5-tetrahydro-1H-3-benzazepine. The reaction mixture was cooled with ice, and there was added dropwise 7.9 ml (0.10 mol.) of methyl chloroformate. The mixture was stirred for 2.5 hours at room temperature, then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off to leave 20.46 g (96%) of 3-methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine as colorless crystals. Recrystallization from diethyl ether--n-hexane gave colorless needles, m.p. 53°-54° C. Elemental Analysis for C12H15NO2 :
Reaction SMILES: Cl[C:2]1[N:6]([C@H:7]2[O:15][CH2:14][C@@H:12]([OH:13])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH:22]1([NH:29][C:2]2[N:6]([C@H:7]3[O:15][CH2:14][C@@H:12]([OH:13])[C@H:10]([OH:11])[C@@H:8]3[OH:9])[C:5]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=3[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O[C@@H]1[C@H](O)[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)OC[C@H]1O
Reactant: NC1CCCCCC1
Solvent: CCO
Product: O[C@@H]1[C@H](O)[C@@H](n2c(NC3CCCCCC3)nc3cc(Cl)c(Cl)cc32)OC[C@H]1O
Reaction time: 48 h

Procedure:
Compound 4 (200 mg, 0.57 mmol) was dissolved in ethanol (4 mL). Cycloheptylamine (3.9 mL, 28 mmol) was added, the flask was sealed and the reaction mixture stirred at 60 ûC. for 2 days. The mixture was decanted and evaporated to dryness at 65 ûC. under high vacuum. The residue was dissolved in ethyl acetate (20 mL), and crystals of cycloheptylammonium chloride were removed by filtration. The organic extract was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel chromatography [2×15 cm, eluent:gradient of methanol (0-6%) in dichloromethane]. Fractions that contained the major spot [Rf (system 3): 0.30] were evaporated and the resulting solid was suspended in boiling dichloromethane. Methanol was added until complete dissolution of the solid. Compound 7 crystallized from this solution (150 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: Cc1cc(=O)cc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccccc3C#N)cc2)cc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
369 mg of 2,6-dimethyl-4(1H)-pyridone was dissolved in 5 ml of N,N-dimethylformamide. To this solution was added 144 mg of 60% sodium hydride, followed by stirring at room temperature for 15 minutes. Subsequently, 900 mg of 4-bromomethyl-2'-cyanobiphenyl was added to the mixture, and the mixture was stirred at room temperature for two hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, to which was added ethyl acetate. The precipitated crystals were collected by filtration and then dried, and, on the other hand, the filtrate was purified by a silica gel column chromatography (80 g, chloroform:ethyl acetate=3:1 to 2:3), whereby 296 mg and 329 mg of 2,6-dimethyl-4-(2'-cyanobiphenyl-4-yl)methoxypyridine were obtained, respectively (total amount: 625 mg, yield: 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]2[CH2:32][CH2:31][CH2:30][C:29]=2B(O)O)=[CH:17][CH:16]=1>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([C:29]2[CH2:30][CH2:31][CH2:32][C:28]=2[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:37][CH:36]=2)[CH:3]=[CH:4][C:5]=1[F:13])[CH3:11]
Reactant: CCOC(=O)c1cc(Br)ccc1F
Reactant: OB(O)C1=C(c2cc(Cl)ccc2OCc2ccc(F)cc2)CCC1
Product: CCOC(=O)c1cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)ccc1F
Yield: 23 %

Procedure:
Prepared according to general procedure C(iii) using ethyl 5-bromo-2-fluorobenzoate and 2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopentene-1-boronic acid to give the product as a colourless solid 43 mg 23%.