Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[N:10]=2)[N:7]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[S:28][N:27]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:30]=4)[CH2:32][CH2:33]3)=[O:19])[N:10]=2)[N:7]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cn2nc(Cl)ccc2n1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cn2nc(Cl)ccc2n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (6-chloroimidazo[1,2-b]pyridazin-2-yl)carbamate (700 mg, 2.04 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (456 mg, 1.85 mmol) and diisopropylethylamine (0.355 ml, 2.04 mmol) in dimethylsulfoxide (6.2 ml) was stirred at 70° C. for 1 day. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and a solid was separated by filtration, which was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 380 mg (42.3%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C[Al](C)C.[CH3:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[CH:27]=[CH:26][C:25]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42](OC)=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:42]([C:39]5[CH:38]=[CH:37][C:36]([C:25]6[CH:26]=[CH:27][C:28]([C:30]7[CH:35]=[N:34][CH:33]=[CH:32][N:31]=7)=[CH:29][C:24]=6[CH3:23])=[CH:41][CH:40]=5)=[O:43])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(-c2ccc(-c3cnccn3)cc2C)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (0.098 g, 0.403 mmol) (D8) was dissolved in toluene (5 ml) and was treated with trimethylaluminium (2.0 M in hexane) (0.810 ml, 1.612 mmol) with stirring under argon. After 0.25 h, a solution of methyl 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylate (D86, 0.136 g, 0.447 mmol) in toluene (5 ml) was added. The reaction mixture was then heated to 80° C. After 2 h, the reaction mixture was allowed to cool and was stirred at room temperature. The reaction mixture was then poured onto a slurry of silica gel (9385~20 ml) in dichloromethane (30 ml). After effervescence had ceased, the slurry was filtered and the filter pad was washed with 20% MeOH/CH2Cl2 (~200 ml). The filtrate was then evaporated under reduced pressure to give a brown oil, which was purified by silica-gel chromatography (9385, 10% MeOH/CH2Cl2 as eluant) to give the title compound as a cream solid (0.091 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:22])[C:12]=1[B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.O.O1CCOCC1>C(OCC)(=O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[C:11]([CH3:22])[C:12]([B:13]([OH:17])[OH:14])=[C:2]([CH3:1])[CH:3]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(C)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)c(B(O)O)c(C)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 27.6 %

Procedure:
A mixture of ethyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.233 g), acetic acid (0.2 mL), water (2 mL) and 1,4-dioxane (2 mL) was stirred at 75° C. for 2 days. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5-1/3) to afford 4-ethoxycarbonyl-2,6-dimethylphenylboronic acid (0.047 g).
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(C)(C)C.[CH:16]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[CH2:17].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[CH:16]=[CH:17][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:7][C:6]([OH:5])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid tert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg, 0.478 mmol), and tritolylphosphine (475 mg, 1.56 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. The reaction was cooled to room temperature and ice water (50 mL) was added. EtOAc (50 mL) was added and the organic solution was washed with 5.5% HCl followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1 to 4:1) provided the title compound (1.95 g). MS 381 (M+18).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N.Cl[P:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:13]([P:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:3][CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCP(Cl)c1ccccc1
Reactant: CCO
Agent: N
Product: CCCCCCP(OCC)c1ccccc1
Yield: 79.2 %

Procedure:
135 g (2.94 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 7.4 g (0,435 mol) of ammonia are then introduced at this temperature with constant stirring. 86 g (0.376 mol) of chloro-(n-hexyl)phenyl-phosphine are then added dropwise at this temperature in 40 minutes, then the mixture is allowed to come to room temperature with stirring, is filtered by suction and washed with ethanol. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is distilled. 71 g of ethyl n-hexyl(phenyl)phosphinite are obtained at 1.1 mbar and an overhead temperature of 110° C. This corresponds to a yield of 79% of theory.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[OH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:9][C:5]1[C:4]([OH:10])=[N:3][CH:8]=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccnc1O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of potassium hydroxide (2.52 g, 45.00 mmol) in methanol (30 mL), was added pyridine-2,3-diol (5.00 g, 45.0 mmol) in 3 portions and a clear red solution was obtained. To this clear red solution was added benzyl bromide (7.70 g, 5.35 mL, 45.00 mmol). The reaction mixture was kept stirring at ambient temperature for 30 minutes, then at 40° C. for 2 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL), and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from methanol (20 mL) to afford the title compound (4.60 g, 51%): 1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.44-7.33 (m, 5H), 6.96-6.88 (m, 2H), 6.07 (t, J=6.0 Hz, 1H), 5.00 (s, 2H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:45]2[CH:46]=[N:47][N:48]([CH3:50])[CH:49]=2)[C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[C:30]([N:32]3[C@H:41]([CH3:42])[CH2:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33]3)=[O:31])[N:20]([CH3:43])[C:19]=2[CH3:44])=[O:17])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH-].[K+]>CO.ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([C:30]([N:32]2[C@H:41]([CH3:42])[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])=[C:23]([C:21]2[N:20]([CH3:43])[C:19]([CH3:44])=[C:18]([C:16]([N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:45]3[CH:46]=[N:47][N:48]([CH3:50])[CH:49]=3)=[O:17])[CH:22]=2)[CH:28]=1
Reactant: Cc1c(C(=O)N(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2cnn(C)c2)cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2C)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)N(c2ccc(O)cc2)c2cnn(C)c2)cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2C)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.8 g of the compound obtained in Step C (1.03 mmol) in 2 mL of methanol, there are added 1.55 mL of a 1M solution of potassium hydroxide in methanol (1.55 mmol). The batch is stirred at ambient temperature for 30 minutes. The reaction mixture is then diluted with dichloromethane and successively washed with 1M aqueous HCl solution, saturated aqueous NaHCO3 solution and then brine until neutral. The organic phase is then dried over MgSO4, filtered and evaporated. The crude product thereby obtained is purified by chromatography over silica gel using dichloromethane and methanol as eluants. The solid thereby obtained is dissolved in a mixture of water/acetonitrile until dissolution is complete, filtered and then lyophilised.
Reaction SMILES: CO.Cl.[CH:4]1([C:7]([CH:9]([N:17]2[CH2:22][CH2:21][CH:20]([SH:23])/[C:19](=[CH:24]/[C:25]([OH:27])=[O:26])/[CH2:18]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:8])[CH2:6][CH2:5]1.CSSC.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(#N)C.O.C(#N)C>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH:4]1([C:7]([CH:9]([N:17]2[CH2:22][CH2:21][CH:20]([SH:23])/[C:19](=[CH:24]\[C:25]([OH:27])=[O:26])/[CH2:18]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:8])[CH2:6][CH2:5]1
Reactant: O=C(O)/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1/CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Reaction time: 1.5 h

Procedure:
In 60 ml of a (1:1) mixed solvent of methanol and acetonitrile, 0.50 g (1.3 mmol) of (E)-1-(α-cylopropylcarbonyl-2-fluorobenzyl)-3-carboxymethylidene-4-mercaptopiperidine hydrochloride and 0.05 ml of dimethyl disulfide were dissolved, followed by exposure to light for 90 minutes under cooling by using a low-pressure mercury lamp of 32 W. After the completion of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was subjected to high-performance liquid chromatography (column: TSK-GEL ODS-80TS, mobile phase; acetonitrile/water=3/7 (containing 0.016% of trifluoroacetic acid), temperature: room temperature), whereby two diastereomers of the title compound, that is, 14.0 mg (Isomer A) and 13.5 mg (Isomer B) were obtained, each as white powder (amorphous). The retention times of Isomer A and Isomer B in high-performance liquid chromatography (column: Inertsil ODS-2, mobile phase: acetonitrile/water=20/80 (containing 0.02% of trifluoroacetic acid), temperature: 27° C., flow rate: 1.5 ml/min) were 16.5 minutes and 18.5 minutes, respectively.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:35][C:32]5[CH:33]=[CH:34][C:29]6[N:28]=[CH:27][N:26]([CH3:25])[C:30]=6[CH:31]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)CC6CC6)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (50.0 mg, 0.340 mmol) at 105° C. for 90 h to afford the title compound. Yield of TFA salt: 25 mg (22%) of brown powder; LC/MS: 459 (M+H); HPLC: 97% pure, RT=2.49 min; 1H NMR: (DMSO, δ) 10.01 (s, 1H), 9.24 (s, 1H), 9.12 (s, 1H), 8.55 (m, 2H), 8.27 (s, 1H), 7.92 (d, J=7.8, 1H), 7.85 (t, J=7.8, 1H), 7.79 (d, J=9.0, 1H), 7.74 (d, J=9.0, 1H), 7.32 (d, J=4.7, 1H), 7.06 (d, J=4.7, 1H), 3.79 (s, 3H), 3.29 (d, J=7.0, 2H), 0.83 (m, 1H), 0.41 (m, 2H), 0.07 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=1.CN(C)C=O.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.[I-].[K+]>C(N(CC)CC)C>[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:3][CH2:4][NH:5][C:6]4[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=4)[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=c1cc(NCCCl)cn[nH]1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1cc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)cn[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
2.72 g (12.9 millimoles) of 5-(2-chloroethylamino)-2H-pyridazine-3-one-hydrochloride, 11 ml of anhydrous dimethyl formamide, 5.0 g (22.7 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 6.3 ml of triethyl amine and 0.21 g of potassium iodide are admixed. The reaction mixture is heated to boiling under stirring for 8 hours, cooled to room temperature and filtered. To the mother lye a solution of 2.6 g of sodium hydrogen carbonate and 40 ml of water is added dropwise. The precipitate is filtered, suspended in 100 ml of dichloro methane, stirred for 30 minutes and filtered. The crude product is recrystallized from a 4:1 mixture of water and acetonitrile. The crystals are filtered off. Thus 2.98 g of the desired compound are obtained. Yield 64.6%. M.p.: 97–99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1O)=[O:25]>CO.ClCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)=[O:25]
Reactant: COC(=O)c1sccc1O
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sccc1OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 44 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-thiophene-2-carboxylic acid methyl ester (20 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 32 mg (44%) of the titled compound. ESI-MS m/z 432 (MH+), 430 (M−H−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:41])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:28][CH2:27][C:26]=2[CH:40]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:41][C:23]2[C:22]([O:21][CH3:20])=[CH:40][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CCN1CCOCC1)CC2
Yield: 13 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a white foam (15 mg, 13%). MS (ESI+): 568 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.91 (s, 1H), 7.40 (s, 1H), 6.66 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.32 (s, 2H), 5.56 (br s, 1H), 5.29 (br s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 3H), 3.74 (t, J=4.5 Hz, 4H), 3.09 (s, 1H), 2.89 (br s, 5H), 2.71 (br s, 6H), 2.57-2.52 (m, 7H), 2.27 (d, J=9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:21][C:12]=2[CH3:13])[N:4]=1
Reactant: NNc1ccccc1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(OC)nc(-c2c(C)[nH]c3ccccc23)n1
Yield: 62 %

Procedure:
In 10 ml of toluene were dissolved 1.61 g (8.2 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 1.08 g (10 m moles) of phenylhydrazine. Thereto was added 1.36 g (10 m moles) of zinc chloride, followed by refluxing for 1 hour. The reaction mixture was allowed to cool, and ethyl acetate and water were added to dissolve the whole reaction mixture. The oily layer was washed with water, separated and dried over Glauber's salt. The resulting oily layer was concentrated under reduced pressure to obtain an orange solid. The solid was recrystallized from methanol to obtain 1.37 g (5.1 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole. Yield: 62% Melting point: 182 to 184° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.3 %

Procedure:
58 ml (203 mmol) of sodium dihydrido-bis-(2-methoxyethoxy)aluminate (70% in toluene) were added dropwise under argon at room temperature while stirring to a solution of 17.4 g (58.5 mmol) of (RS)-[1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridin-3-yl]-methanol in 580 ml of absolute toluene. Subsequently, the mixture was stirred at 80° C. for 4 hours. 100 ml of water were added dropwise to the reaction mixture at room temperature, with working-up thereafter being carried out by extraction with water and ethyl acetate. The crude product was chromatographed on silica gel with hexane and ethyl acetate as the eluent. There were obtained 3.90 g (44% of theory) of (3RS,4SR)-[1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-yl]-methanol; MS: 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](O)=[O:20])[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCOCC1.O>[CH:27]1([NH:30][C:19]([C:4]2[C:3]([S:22][C:23]([F:24])([F:26])[F:25])=[C:2]([NH2:1])[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=3[Cl:18])[N:5]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: Nc1c(SC(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NC1CC1
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(SC(F)(F)F)c(C(=O)NC2CC2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio-1H-pyrazole-3-carboxylic acid (0.85 g, 1.83 mmol) and 1,1-dicarbonylimidazole (0.36 g, 2.20 mmol) in dioxane was heated to. 55° C. for 2 hours. Cyclopropylamine (0.20 ml, 2.83 mmol) was then added and stirring continued at 55° C. for 6 hours. The cooled mixture was diluted with water, extracted with ethyl acetate, washed with aqueous potassium hydrogensulfate (5%), dried over magnesium sulfate and evaporated to give the title compound (0.762 g, yield 87%) as off-white crystals, mp 193° C., 1H NMR (CDCl3): 0.64 (m, 2H, cyclopropyl), 0.83 (m, 2H, cyclopropyl), 2,87 (m,1H, cyclopropyl), 4.31 (bs, 2H, NH2), 6.82 (bs,1 H, C(O)NH), and 7.80 (s, 2H, Ar—H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Temperature: 0 °C
Yield: 92.2 %

Procedure:
1.6 g of p-toluene sulonic acid monohydrate were added to a solution of 16.4 g of the product of Step B in 160 ml of toluene and the mixture was refluxed until gas evolution ceased (about 30 minutes) and was cooled to 0° C. and filtered The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 70-30-1 n-hexane-ethyl acetate-acetic acid mixture yielded 13.3 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate melting at 99° C. and having a specific rotation of [α]D20 =+52.5° ±2.5° (c=0.5% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([S:25]([F:30])([F:29])([F:28])([F:27])[F:26])[CH:16]=2)=[CH:6][C:5]=1[CH3:31].[O-]S([O-])=O.[Na+:37].[Na+].[OH-].[Na+].Cl>O>[CH3:13][S:10]([C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:32])[C:5]([CH3:31])=[CH:6][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[C:17]([S:25]([F:26])([F:27])([F:28])([F:30])[F:29])[CH:16]=1)(=[O:11])=[O:12].[Na+:37]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(=O)(=O)Cl)c(S(F)(F)(F)(F)F)c2)cc1C
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
3.5 g of methyl 4-(4-chlorosulfonyl-3-pentafluorosulfanylphenoxy)-5-methanesulfonyl-2-methylbenzoate (example 3) were added in portions to a solution, at 70° C., of 8.10 g of Na2SO3 in 75 ml of water and kept at about pH=10 with 10 molar aqueous NaOH solution. Subsequently, the mixture was stirred at 70° C. for 45 minutes, then allowed to cool and adjusted to pH=2 with aqueous HCl solution. The mixture was extracted 3 times with 200 ml each time of EA. The mixture was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was suspended in 100 ml of water and adjusted to pH=10 with a 2 molar aqueous NaOH solution, and the volatile constituents were removed under reduced pressure. The mixture was subsequently extracted twice with 100 ml each time of toluene and then coevaporated with 100 ml of anhydrous DMF, and the residue (3.0 g) was reacted further without purification.