Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[CH2:5][C:6]1[NH:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=1)C.[CH3:20][C:21](C)([O-:23])C.[K+].[C:26]([O:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:7]2[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:12])[CH3:13])[N:10]=[C:6]2[CH2:5][O:23][CH2:21][CH3:20])=[CH:41][CH:40]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [K+]
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 98.5 %

Procedure:
A procedure similar to that described in Example 82(a) was repeated, except that 315 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-ethoxymethylimidazole-5-carboxylate [prepared as described in Preparation 44(iii)], 145 mg of potassium t-butoxide and 510 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide were employed and the product was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to obtain 600 mg of the title compound as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1)[NH2:5].[C:16](N1C=CC=CC1=O)([N:18]1C=CC=CC1=O)=[S:17].N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([NH2:18])=[S:17])[CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1
Reactant: Cc1ncn(-c2c(F)cc(N)cc2F)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: N
Solvent: ClCCl
Product: Cc1ncn(-c2c(F)cc(NC(N)=S)cc2F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Step R (3): Dichloromethane (50 mL) was added to a flask charged with 3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.75 g, 8.33 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.90 g, 8.33 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. A solution of ammonia (2.0 M in methanol, 50 mL, 100 mmol) was added to the crude solid. The heterogeneous mixture was stirred at rt for 2 h, then evaporated to dryness under reduced pressure using a rotary evaporator. The solid residue was triturated with 40 mL of anhydrous ethanol and chilled to 0° C. for 1 h. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (1.76 g, 6.54 mmol, 79% yield) as a gray powdery solid. LC-MS (M+H)+ 270.0. 1H NMR (500 MHz, DMSO-d6) d ppm 10.16 (1 H, br. s.), 8.77 (1 H, s), 7.64 (2 H, d, J=10.4 Hz), 2.35 (3 H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[OH:9][S:10](O)(=[O:12])=[O:11].O=S(=O)=O>CO.CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:10]([OH:12])(=[O:11])=[O:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccnc(O)c1
Agent: O=S(=O)=O
Solvent: CC(C)=O
Solvent: CO
Product: O=S(=O)(O)c1cnc(O)cc1O
Temperature: -50 °C

Procedure:
5 g of 2,4-dihydroxypyridine are slowly added, at a temperature in the region of -10° C., to 12.5 cm3 of sulfuric oleum containing 20% SO3 and containing 250 mg of HgSO4. After having left to return to ordinary temperature, the mixture is progressively brought to 150° C. and then maintained at this temperature for 16 hours. The mixture is poured onto a MeOH/acetone (50/50) mixture cooled to around -50° C. A beige precipitate is formed which is recrystallized from the same MeOH/acetone mixture.
Reaction SMILES: C(OC([N:8]1[CH:15]2[CH:11]([N:12]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:13][CH:14]2[C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]2[NH:8][CH2:9][CH2:10][CH:11]12)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of 37 (410 mg, 0.88 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL). After 2 h, the solution was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 38 (305 mg) as a white foam that was used without further purification. Mass spectrum, m/z [366.4] (M+H)+.
Reaction SMILES: [C:1]1(=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[C:1]1(=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 66.2 %

Procedure:
A solution of 1,1-dimethylethyl (2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (7) (0.24 g, 0.61 mmol) in CH2Cl2 (6 mL) was cooled in an ice-water bath and stirred under a nitrogen atmosphere. To the cold solution was slowly added trifluoroacetic acid (6 mL). The reaction mixture was stirred in the ice-water bath under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated to give the crude product as a solid. The crude product was dissolved in CH2Cl2 and the solution was concentrated to give a solid. The crude product was transferred to a separatory funnel with the aid of CH2Cl2 and H2O. The organic phase was removed and the aqueous phase that contained suspended solids was extracted twice with CH2Cl2. The organic phase was removed and the aqueous suspension was filtered with the aid of H2O. The filtered white solid was dissolved in CH2Cl2 and MeOH and the solution was filtered. The filtrate was concentrated and the resulting solid was dried in a vacuum oven to give 135 mg (67%) of compound 8 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6H), 2.15 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 9.31 (s, 1H), 12.31 (br s, 1H). The sample was silated prior to EI analysis. HRMS (EI) Calcd for C28H38O3Si2: 478.2360 (M+). Found: 478.2376.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1>>[Br:23][C:21]1[CH:22]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Product: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 21 %

Procedure:
Following Example 136e, 170a and 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 170b in 21% yield. LCMS: (M+H)+ 394. 1H NMR (500 MHz, MeOD) δ 8.84 (d, J=2.5, 1H), 8.42 (d, J=2, 1H), 7.72 (m, 1H), 7.42 (d, J=2, 1H), 7.11 (d, J=8.5, 1H), 3.72 (m, 8H), 3.63 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.N1C=CC=CC=1>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
32.2 ml (0.23 mol) of trifluoroacetic acid were added dropwise to a solution of 22.3 ml (0.15 mol) of 2-(4-methoxyphenyl)ethylamine and 24.7 ml (0.23 mol) of pyridine in 125 ml of absolute THF cooled to 5° C., and the resulting solution was stirred at RT for 3 h. The reaction solution was then poured onto 750 ml of ice, and the deposited precipitate was filtered off with suction and dried at 40° C. in a high vacuum. 36.3 g of the title compound were obtained as a beige solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].C([O-])(=[O:14])C.[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:26](=[O:27])[NH:1][C:11]3[C:6]([C:4]=2[C:2]([OH:14])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:23][CH:24]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)[O-]
Reactant: COc1ccc(CC(=O)O)cc1
Agent: [Na+]
Product: COc1ccc(-c2c(C(=O)O)c3ccccc3[nH]c2=O)cc1
Temperature: 175 °C

Procedure:
7.5 mmol of isatin (III), 1.875 mmol of sodium acetate, and 13.125 mmol p-methoxyphenylacetic acid were mixed, heated to 150-200° C. and refluxed for 1-5 h. The reaction was finished by TLC detection. The reaction solution was washed with petroleum ether and acetone successively. After separated by column chromatography, the title compound was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([OH:35])=[C:12]([C:17]3[N:18]=[N:19][C:20]([N:23]([CH3:34])[CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:35][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:38]#[N:39])=[CH:8]2)=[CH:13][C:12]=1[C:17]1[N:18]=[N:19][C:20]([N:23]([CH3:34])[CH:24]2[CH2:25][C:26]([CH3:33])([CH3:32])[NH:27][C:28]([CH3:30])([CH3:31])[CH2:29]2)=[CH:21][CH:22]=1
Reactant: CN(C)C=O
Reactant: CN(c1ccc(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(c1ccc(-c2cc3ccc(C#N)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Yield: 50 %

Procedure:
A degassed mixture of 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl trifluoromethanesulfonate (21 mg, 0.033 mmol), zinc cyanide (5.00 mg, 0.043 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.8 mg, 1.6 μmol) in DMF (0.8 mL) was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was filtered through celite, washed with EtOAc and concentrated. The residue was loaded on a 1 g SCX column, washed with MeOH, and eluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. The crude product was purified via HPLC to give the title compound as a light yellow solid (6.9 mg, 50% yield). LCMS Rt=0.55 min [Method Q], MS (M+1)=416.3. 1H NMR (METHANOL-d4) δ 8.26 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 1.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J=9.6 Hz, 1H), 5.05 (t, J=11.9 Hz, 1H), 2.94 (s, 3H), 1.61 (dd, J=13.1, 3.5 Hz, 2H), 1.49 (t, J=12.4 Hz, 2H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[C:16]([NH2:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([NH2:21])=[C:16]([NH2:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-Amino-5-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15 g, 44.6 mmol) in methanol (2200 mL) was added 20% Pd(OH)2/C (1.6 g) and the suspension flushed well with nitrogen, followed by hydrogen. The resulting suspension was stirred overnight at room temperature under an atmosphere of hydrogen (ca. 1 atm). The resulting suspension was filtered under nitrogen through a pad of Celite and washed with methanol (400-500 mL). The resulting material was used immediately. LCMS (M+H)+ m/z 307.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[F:16][C:17]([F:28])([F:27])[CH2:18][CH2:19][Si:20](OC)([O:23][CH3:24])[O:21][CH3:22]>C1COCC1>[F:28][C:17]([F:16])([F:27])[CH2:18][CH2:19][Si:20]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1)([O:21][CH3:22])[O:23][CH3:24]
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[Si](CCC(F)(F)F)(OC)C1NCCc2ccccc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
3,3,3-Tritluoropropyl(1,2,3,4-tetrahydroisoquinolinyl)dimethoxysilane--A 500 mL round bottomed flask was charged with tetrahydrofuran (300 mL) and isopropyl-magnesium chloride (30 mL of a 2.0 M solution in THF, 60 mmol). The contents were cooled to 15° C. 1,2,3,4-Tetrahydroisoquinoline (60 mmol) was added over fifteen minutes via pressure equalizing addition funnel. The cold bath was removed and the contents stirred for two hours. 3,3,3-Trifluoropropyltrimethoxysilane (54.5 mmol) was added via pressure equalizing addition funnel. The contents were brought to reflux (65-70° C.) for two hours and reaction progress was monitored by GC. Isolation was accomplished by removing the THF via rotary evaporation, taking the residue up in ether (250 mL), filtration and ether removal via rotary evaporation. Purification was accomplished by distillation to provide 3,3,3-trifluoropropyl(1,2,3,4-tetrahydroisoquinolinyl)dimethoxysilane (54 mmol; 99% yield). C14H20NO2SiF3 (mw=319.39) bp=98° C. at 0.3 mmHg; 1H NMR: (CDCl3) δ 7.2-6.9 (m, 4H), 4.2-4.0 (d, 2H), 3.6-3.4 (s, 6H), 3.3-3.1 (dt, 2H), 2.8-2.6 (m, 2H), 2.2-1.9 (m, 2H), 0.9-0.8 (m, 2H); 13C NMR: (CDCl3) δ 135.9, 135.1, 129.4, 128 (quartet J=275 Hz), 126.0, 125.9, 125.8, 50.4, 46.5, 42.1, 29.9, 28 (quartet, J=30 Hz), 2.8; MS: m/z (relative abundance) 319 (38.3), 318 (100), 222 (7.9), 132 (21.0), 104 (21.4), 79 (9.8), 59 (13.4).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].[NH3:25]>C(O)C>[CH3:11][Si:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][O:7][C:1]([C:2]1[CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[C:2]([C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:12])([CH3:11])[CH3:13])=[O:6])=[C:3]([CH3:5])[NH:25][C:3]=1[CH3:5])=[O:6]
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: CC1=C(C(=O)OCC[Si](C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC[Si](C)(C)C)=C(C)N1

Procedure:
After boiling 5.0 g of 2-trimethylsilylethyl acetoacetate, 1.9 g of 3-nitrobenzaldehyde and 1.5 ml of concentrated ammonia in 10 ml of 96 percent strength ethanol for 20 hours, then cooling and filtering off the product, 3.5 g of pale yellow crystals of melting point 120° C. (ethanol) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2ncc(Br)cn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ncc(Br)cn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(5-bromo-pyrimidin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1.[CH3:15][N:16]([CH:18]=O)C>>[CH2:13]([N:16]1[CH2:18][CH2:13][C:10](=[CH2:9])[CH2:11][C@H:15]1[CH2:1][OH:4])[C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Product: C=C1CCN(Cc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A solution of intermediate 6.vi (2.93 g) in DMF (35 ml) was treated with K2CO3 (3.70 g) and BnBr (2.15 ml). The reaction mixture was stirred at rt for 5 h and concentrated in vacuo. The residue obtained after work up (EA) was purified by chromatography (Hex/EA 1:1) to give 3.56 g (92% yield) of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Yield: 88.4 %

Procedure:
125 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene and 120 g of zinc powder or granules are suspended in 1300 ml of ethanol. 220 ml of acetic acid are added dropwise at boiling heat. The precipitate is filtered off with suction and washed with ethanol, and the filtrate is concentrated under reduced pressure. The residue is taken up in hydrochloric acid and extracted with toluene. The aqueous phase is rendered alkaline using 50% strength sodium hydroxide solution, the precipitate is filtered off with suction and the filtrate is extracted with toluene. The organic phase is dried using sodium sulfate and concentrated. 98 g of the title compound are obtained as a crystallizing oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:13][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=C1CCCN1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCN1c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
8.06 g of N-phenylpyrrolidinone were dissolved in 33 ml glacial acetic acid; the mixture was cooled to 0°-5° C. and then a solution of 2.65 ml bromine in 12 ml of glacial acetic acid was added dropwise. Stirring was continued for 30 minutes at room temperature. Work-up was accomplished by pouring the mixture into 1 l of water and neutralizing the mixture with KOH. The solid was filtered and dissolved in ethylacetate and washed with a sodium thiosulphate solution until the brown colour disappeared; washing with brine and drying with MgSO4 provided 8.5 g of a white crystalline mass that could be recrystallized from ether; m.p. 102° C.
Reaction SMILES: [BrH:1].[OH:2][C@H:3]([CH2:14]O)[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7].C(OC(=O)C)(=O)C.CO>C(O)(=O)C>[Br:1][CH2:14][C@@H:3]([OH:2])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7]
Reactant: O=C(NC[C@H](O)CO)c1ccc(Cl)s1
Reactant: Br
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C(NC[C@H](O)CBr)c1ccc(Cl)s1
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
301.7 ml of a 33% solution of hydrobromic acid in acetic acid are added to a suspension of 100 g of N-((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) in 250 ml of glacial acetic acid at from 21 to 26° C. over a period of 30 minutes. Subsequently, 40 ml of acetic anhydride are added and the reaction mixture is stirred at from 60 to 65° C. for three hours. At 20 to 25° C., 960 ml of methanol are then added over a period of 30 minutes. The reaction mixture is stirred under reflux for 2.5 hours and then overnight at from 20 to 25° C. For workup, the solvents are distilled off under reduced pressure at approx. 95 mbar. The remaining suspension is admixed with 50 ml of 1-butanol and 350 ml of water. The precipitated product is filtered off with suction, washed with water and dried.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.F[S:24]([C:27]1[N:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]>C1COCC1>[CH3:34][O:33][C:30]1[N:29]=[N:28][C:27]([S:24]([C:14]2[O:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[OH:22])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: O=C1COc2ccccc21
Reactant: COc1ccc(S(=O)(=O)F)nn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
n-Butyl lithium (12 mmol, 4.7 mL) was added dropwise to a solution of diisopropyl amine (12 mmol, 1.7 mL) in THF (5 mL) at −78° C. After 10 minutes, a solution of 3-coumaranone (10 mmol, 1.92 g) in THF (10 mL) was added. The temperature was maintained at −78° C. and stirred for 10 minutes. To this was added a solution of 3-fluorosulfonyl-6-methoxy-pyridazine. The reaction mixture was brought to room temperature over one hour and quenched with ammonium chloride (1 g) and extracted with EtOAc (2×25 mL). The EtOAc extract was washed with H20, the organic layer was collected, dried, filtered and the filtrate was evaporated to a residue. This residue was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to yield 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (17%, 622 mg).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])=[CH:27][CH:28]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(Cl)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]12[CH2:15][C:10]3([OH:16])[CH2:11][CH:12]([CH2:14][C:8]([OH:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3].[CH:18](=[O:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1CC[CH2:34][CH2:33]1>>[C:1]([O:5][C:6]12[CH2:15][C:10]3([O:16][CH:18]([OH:20])[CH3:19])[CH2:11][CH:12]([CH2:14][C:8]([O:17][CH:33]([OH:32])[CH3:34])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC=O
Reactant: C=CC(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OC12CC3CC(OC(C)O)(C1)CC(OC(C)O)(C3)C2
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To 30 ml of tetrahydrofuran were added 5 mmol of 1-acryloyloxy-3,5-dihydroxyadamantane and 15 mmol of acetoaldehyde and 1 mmol of p-toluenesulfonic acid, and the mixture was stirred at 30° C. for 6 hours. Then, the reaction mixture was condensed under acidic conditions and crystallized by adding dropwise to diethyl ether to give the object compound 1-acryloyloxy-3,5-di(1-hydroxyethoxy)adamantane (acetal compound).