Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O>[C:16]1([S:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(Sc2ccccc2)cc1
Temperature: 80 °C
Yield: 31.6 %

Procedure:
Using 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1 g) in a similar manner to that of Example 18-(1), a diazonium salt-containing aqueous solution was produced. With stirring at 80° C., this solution was added dropwise to a solution composed of thiophenol (1.04 g), sodium hydroxide (0.45 g) and water (5 ml) and the mixture was refluxed for further 15 minutes. After cooling, the precipitate was recovered by filtration and dissolved in a mixture of chloroform and methanol. The solution was washed with aqueous sodium hydroxide and water in that order and concentrated to dryness under reduced pressure. The residue was purified by silica gel (30 g) column chromatography (eluent: ethyl acetate) to give 6-(4-phenylthiophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.46 g).
Reaction SMILES: [BH4-].[Na+].CN(C)C=O.Cl[C:9](=[O:28])[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1>O>[OH:28][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CCCO)CC1
Yield: 61.6 %

Procedure:
To a stirred and cooled (ice bath, 10° C.) mixture of 3.4 parts of sodium tetrahydroborate and 188 parts of N,N-dimethylformamide were added dropwise 28 parts of (phenylmethyl) 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate (exothermic reaction, the temperature rose to 38° C.). Upon completion addition, the reaction mixture was stirred over weekend at room temperature. The reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 15.4 parts (61.6%) of (phenylmethyl) 4-(3-hydroxypropyl)-1-piperidinecarboxylate as a residue (int. 35).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH2:19]=O.[BH4-].[Na+]>CO.CCOCC.Cl>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH3:19])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(C)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.3 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (20 mg, 0.07 mmol) in 2 mL of methanol was added formaldehyde (0.017 mL of 37% aqueous solution, 0.21 mmol) followed by sodium borohydride (14 mg, 0.35 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added two drops 12 N HCl. The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 15 mg (71%) of the title compound of Example 62 as an off-white solid. 1H NMR (CD3OD): 7.35 (s, 1H), 7.00 and 6.97 (s, 1H), 4.07-4.02 (m, 1H), 3.91-3.85 (m, 1H), 3.74-3.69 (m, 1H), 3.61-3.55 (m, 1H), 3.45-3.28 (m, 2H), 3.14 and 3.08 (s, 3H), 2.69 (q, 2H), 1.25 (t, 3H). LRMS (ESI): 265.2/267.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1[CH:36]=[C:35]([CH2:37][NH2:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([NH:38][CH2:37][C:35]5[CH:36]=[N:31][CH:32]=[N:33][CH:34]=5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: NCc1cncnc1
Product: O=C1N=C(NCc2cncnc2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and C-Pyrimidin-5-yl-methylamine following General Procedure B.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][NH:36][CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]([OH:54])=O)[CH2:47][CH2:46]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][N:36]([CH3:37])[C:52](=[O:54])[CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Reactant: O=C(O)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
Into a 50-mL vial, was placed N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-morpholinoacetic acid (28.9 mg, 0.20 mmol, 1.20 equiv), EDC HCl (47.4 mg, 0.25 mmol, 1.50 equiv), and 4-dimethylaminopyridine (30.4 mg, 0.25 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×50 mL of aqueous NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 116 mg (59%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 9.12 (m, 1H), 8.86 (d, J=9.2 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.17 (m, 1H), 8.12 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.60 (m, 3H), 4.96 (m, 2H), 4.72 (s, 2H), 4.50 (m, 2H), 3.98 (m, 4H), 3.70 (m, 4H), 3.1 (s, 3H), 2.10 (m, 4H), 1.98 (s, 2H). MS (ES, m/z): 730 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2.[N+:24]([O-])([O-:26])=[O:25].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[C:10]([N+:24]([O-:26])=[O:25])[CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)N1C2=C([N+](=O)[O-])C=C(Br)CC2CCC1CC(=O)OC
Reaction time: 1.5 h
Yield: 106.7 %

Procedure:
To a refluxed solution of 6-bromo-2-methoxycarbonylmethyl-N-ethoxalyltetrahydroquinoline (40 g) and ammonium nitrate (8 g, 0.1 mol) in chloroform (100 mL) was added dropwise trifluoroacetic anhydride (56.5 mL, 0.4 mol) over 40 min. The reflux was continued for 90 min and crashed ice was added. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to give 46 g of the title compound (quant): 1H NMR (270 MHz, CDCl3) δ8.11 and 7.99 (d and d, 1H, J=2 Hz), 7.66 and 7.61 (d and d, 1H, J=2 Hz), 5.03~5.16 and 4.74~4.85 (m and m, 1H), 4.37~4.49 and 4.13 (m and q, 2H, J=7.2 Hz), 3.72 and 3.62 (s and s, 3H), 2.44~3.02 (m, 5H), 1.65~1.80 and 1.50~1.60 (m and m, 1H), 1.42 and 1.23 (t and t, 3H, J=7.2 and 7.2 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: COc1ccccc1I
Product: COc1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert 2-iodoanisole and thiophenol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (412 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.41–7.25 (m, 6H; Hc, He, He′, Hf, Hf′, Hg), 7.12 (dd, J=6.03, 1H; Ha), 6.96–6.89 (m, 2H; Hb, Hd), 3.90 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 157.21 (C6), 134.39 (C8), 131.50 (C2), 131.35 (C9, C13), 129.07 (C10, C12), 128.27 (C4), 126.99 (C11), 123.96 (C1), 121.16 (C3), 110.76 (C5), 55.78 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.23; H, 5.70; S, 14.67.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH:35]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:35][NH:40][CH:37]2[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C=O)C(C)C)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CNC3CC3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 10.9 mmol) in dichloroethane (100 mL), cyclopropylamine (0.85 mL, 12 mmol) and NaBH(OAc)3 (4.32 g, 15.3 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. TLC, Rf (AcOEt)=0.1. MS (LC-MS): 541.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.52 min.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nccc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cn2nccc2Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
Methyl 4-((5-bromo-1H-pyrazol-1-yl)methyl)benzoate (264 mg, 0.95 mmol), NaOH (200 mg, 5 mmol) were placed in a 100-mL flask with covered with MeOH and H2O (1:1) and stirred for 4 h at room temperature. The solution was then evaporated, taken up in water and acidified with 2M HCl with the resulting the solid filtered off yielding the desired product as a white solid (200 mg, 90%). LCMS (m/z): 281.1 [M+H]+
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[S:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[C:18]([N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[S:35][CH:36]=2)=[N:8]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2nn(C(C)(C)C)c3ccnc(OC)c23)cs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
To a solution of 1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (1.60 g) obtained in Step C of Example 86 in DME (100 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.46 g) and 2M aqueous sodium carbonate solution (11.3 mL), and then tetrakis(triphenylphosphine)palladium(0) (523 mg) was added thereto under nitrogen atmosphere. The reaction mixture was stirred overnight under nitrogen atmosphere at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.88 g).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:25])=[CH:20][CH:19]=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][CH3:16].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O>[C:36]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:1][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][CH3:16])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
A mixture of 0.70 g of product from Example 88, 2.96 g of acetic anhydride, 0.027 g of 4-N,N-dimethylaminopyridine and 15 ml of pyridine is heated at 110° C. for 35 hours and at reflux temperature for 57 hours. The reaction is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 0.366 g of product as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH2:13][CH:14]=C)[C:3]=1[OH:16].C[OH:18]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH2:13][CH2:14][OH:18])[C:3]=1[OH:16]
Reactant: CO
Reactant: C=CCc1cc(OC(F)(F)F)cc(Br)c1O
Solvent: ClCCl
Product: OCCc1cc(OC(F)(F)F)cc(Br)c1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Through a cooled (-78° C.) solution of 2-bromo-6-(prop-2-enyl)-4-trifluormethoxyphenol (Description 15.; 5.9 g, 0.02 mol) in dichloromethane (30 ml) and methanol (30 ml) was bubbled a mixture of ozone in oxygen for 4 h. After the solution had been purged with nitrogen for 1 h., sodium borohydride (0.755 g) was added and then stirred at room temperature for 15 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water containing (2M HCl (20 ml). The organic phase was washed with saturated brine, dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed on silica gel (eluting with 20% ethyl acetate in hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ2.93 (2H, t, J 5.6 Hz), 3.98 (2H, t, J 5.4 Hz), 6.96 (1H, d, J 2.5 Hz), and 7.3 (1H, d, J 2.4 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=[CH:28][CH:27]=1.Cl>C(O)(C)C>[O:34]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:25][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:31]=2[CH:32]=[CH:33]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Nc1cccc2occc12
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4occc34)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 85 °C
Yield: 109.8 %

Procedure:
A mixture of 4chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (0.1 g), 4-aminobenzofuran (0.057 g), isopropanol (4 ml) and a solution of hydrogen chloride in isopropanol (6M, 0.06 ml) was stirred and heated to 85° C. for 3 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed in turn with a 1:1 mixture of diethyl ether and isopropanol and with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.14 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.9 (s, 3H), 3.3-4.0 (broad m, 10H), 4.05 (s, 3H), 4.35 (m, 2H), 6.9 (s, 1H), 7.4 (m, 2H), 7.45 (t, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.3 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:24][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3Cl)CC2)c(C)c1
Yield: 52.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (814 mg) described in Preparation Example 11 and oxazolidin-2-one (174 mg), the title compound (437 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[S:17][CH2:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1.[OH:19]O>C(O)(=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[S:17](=[O:19])[CH2:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: OO
Reactant: CN(C)c1ccc2cc3n(c(=O)c2c1)CCCS3
Solvent: CC(=O)O
Product: CN(C)c1ccc2cc3n(c(=O)c2c1)CCCS3=O
Reaction time: 1 h

Procedure:
A mixture of 550 mg. of 8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 10 ml. of acetic acid, and 0.41 ml. of a 35% aqueous hydrogen peroxide solution was stirred at 20°-30° C. After one hour, the reaction mixture was filtered and after adding 10 ml. of water to the filtrate, anhydrous sodium carbonate was added to it to make the filtrate basic. The precipitates formed were recovered by filtration and dried. By recrystallizing from benzene-hexane, 300 mg. of 8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:22])[O:27][N:26]=1
Reactant: NCc1cc(C(F)(F)F)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 480.0 (M)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.Cl>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 4-methoxy-phenylhydrazine×HCl according to the method described for Example 1 in 10% yield. MS: M=413.5 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[O:20][CH3:21])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[O:20][CH3:21])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3OC)c(C#N)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1Cc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-methoxy-4-(trifluoromethyl)benzyl]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 30, 33.8 mg, 0.056 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0° C. Trifluoroacetic acid (22 μL, 0.28 mmol) was added and the reaction stirred for 3 hours warming slowly to room temperature. The solvent was removed in vacuo and the residue re-dissolved in methanol (˜5 mL). Once again the solvent was removed in vacuo. The material was suspended in methanol (5 mL) and filtered through Celite™. The reaction mixture was concentrated in vacuo and purified by the B-HPLC method to afford the title compound.