Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:11][CH3:12].[Br:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[C:20](I)[CH:19]=1>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.[Br-].[Zn+2].[Br-].O1CCCC1>[CH2:15]([O:14][C:10]([C:11]1[N:28]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[C:21]2[C:20]([CH:12]=1)=[CH:19][C:18]([Br:17])=[C:23]([C:24]([F:27])([F:25])[F:26])[CH:22]=2)=[O:13])[CH3:16]
Reactant: CCOC(=O)CC
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)c(Br)cc2I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(Br)c(C(F)(F)F)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
N,N-diisopropylethyl amine (0.42 ml, 2.4 mmol), ethyl propionate (0.12 ml, 1.2 mmol), and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were added to an anhydrous tetrahydrofuran (THF) solution (3.2 ml) containing N-(4-bromo-2-iodo-5-trifluoromethyl-phenyl)-4-methyl-benzenesulfonamide (208 mg, 0.4 mmol) and zinc bromide (270 mg, 1.2 mmol). Then, the mixture was evacuated, and backfilled with argon. This was stirred at 80° C. for 13 hours. After cooling it to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with an aqueous solution saturated with sodium bicarbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 5-bromo-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a pale brown solid (195 mg, 50%).
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(NCC)C>CN(C)C=O>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:8]=[C:7]([N:6]2[CH:5]=[C:4]([CH3:17])[S:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC1=CN(c2cccc(C(F)(F)F)c2)CS1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and diethylamine (1.21 g, 16.5 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with the chlorotrifluoloethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was subjected to a similar post-treatment as described above, which afforded 2-chlorofluoroacetylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.19 g, 3.4 mmol, yield 67% ).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:4][C:3]1=O.Cl.CO>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:6]1
Reactant: CN1CC(c2nc3c(s2)Cc2ccccc2-3)CC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(c2nc3c(s2)Cc2ccccc2-3)C1
Yield: 38.3 %

Procedure:
To a solution of 0.11 g of 2-(1-methyl-2-oxo-4-pyrrolidinyl)-8H-indeno[1,2-d]thiazole in 4 ml of tetrahydrofuran, a 1.6 ml of a 1M solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added, followed by heating under reflux for 2 hours. After cooling, a mixed solution of 10 ml of concentrated hydrochloric acid and 10 ml of methanol was added to the reaction mixture, followed by heating under reflux for 1.5 hours. The solvent was evaporated, and ethyl acetate and water were added to the resulting residue, followed by extraction with 1N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography, whereby 0.04 g of 2-(1-methyl-3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole was obtained from the fraction eluted with chloroform-methanol-29% aqueous ammonia (300:10:1). The product was dissolved in methanol. Fumaric acid was added to the resulting solution, followed by crystallization from acetone to give a fumarate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride, water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to give 140 mg of yellow solid. 1HNMR(CDCl3) d 8.10(d,1H), 7.03(s,2H), 6.09(s,1H), 3.88(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.5–1.7(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CCO.C1COCC1.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C(C)[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a stirred solution of 15.6 (0.044 g, 0.087 mmol) in EtOH (2.00 mL, 0.087 mmol) and THF (2.00 mL, 0.087 mmol) at 23° C. was added a solution of 1M sodium hydroxide (1.00 mL, 1.0 mmol). Stirring was continued for 18 hours. The resulting reaction was concentrated in vacuo. 1N HCl was added to pH 1, the resulting mixture was extracted EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 15 (31 mg, 74% yield) as a colorless oil. MS ESI (neg.) m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:16]([Cl:15])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N(c1ccccc1)c1cccc(F)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 3 liter three-neck mechanically stirred flask under N2 containing a solution of 3-fluoro-N-phenylaniline (86 g, 460 mmol) in 1.2 L dichloromethane was cooled in an ice bath to 0° C., and then triphosgene (150 g, 505 mmol) was added. A solution of pyridine (52 mL, 640 mmol) in dichloromethane (200 mL) was added in a dropwise fashion. Initial addition resulted in a temperature spike to 25° C. after the first 10 mL had been added over 10 min. The addition was paused, and the reaction mixture was stirred for 1 h while cooling to 5° C. Addition of the pyridine solution was again commenced at a rate of 5 mL/min, at which a reaction temperature of 5-10° C. was maintained. After addition was complete (about 1 h), the reaction had proceeded to completion, and was quenched by the slow addition of ice water (500 g). Gas formation from the quench was controlled by adjusting the stirring speed, as decomposition was largely a function of the mixing of the two immiscible layers. Gas effluent was passed through a 20% sodium hydroxide trap, until all gas evolution had ceased (about 3 h). The aqueous layer was removed, and was then extracted with an additional 300 mL of dichloromethane. The organic extracts were combined, dried over MgSO4, and the solvent was removed. Clean product was readily isolated as a viscous, pink oil, which gradually formed a pale pink solid upon seeding with crystals. LCMS m/z (%)=250.0 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 7.00-7.07 (m, 1H), 7.10 (d, J=9.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.35 (d, J=7.7 Hz, 2H), 7.35-7.41 (m, 2H), 7.42-7.48 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[CH:13]1(N)C[CH2:14]1>>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([CH:9]2[CH2:14][CH2:13]2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reactant: NC1CC1
Product: CCOC(=O)c1cn(C2CC2)cn1
Temperature: 75 °C

Procedure:
The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (17.0 g, 100 mmol) and cyclopropylamine (17.21 g, 300 mmol) was heated for 5 h at 75° C. The reaction mixture was cooled to rt and concentrated. Purification of the residue by flash chromatography (EtOAc/hexane, 5:1) gave the title compound as an orange oil. tR: 0.61 min (LC-MS 2); ESI-MS: 181.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.85 (s, 1H), 7.79 (s, 1H), 4.18 (q, 2H), 3.55 (m, 1H), 1.23 (t, 3H), 0.91-1.02 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:26]=1[O:27][CH3:28]
Reactant: NS(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nccc(Nc3ccccc3S(N)(=O)=O)n2)cc(OC)c1OC

Procedure:
The title compound is prepared from 2-(2-chloro-pyrimidin-4-ylamino)-benzenesulfonamide as described in Example 1 using 3,4,5-Trimethoxy-phenylamine instead of 6-aminoindazole in step (b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.[CH2:22]=[O:23].[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)[CH2:22][OH:23]
Reactant: O=C1Nc2c(Br)cccc2C1c1cc2c(cc1O)OCO2
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2c(Br)cccc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
To a mixture of 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (8.40 g, 24.1 mmol), para-formaldehyde (2.88 g, 96.0 mmol) and water (80 mL) was added sodium hydroxide (3.84 g, 96.0 mmol) at 0° C. The dark green solution was stirred at 0° C. for 4 h. The mixture was acidified with 3 N hydrochloride to pH 4 and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate solution was washed with 25% ammonium chloride solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was treated with toluene (300 mL) to give an off white precipitate. The precipitate was filtered and dried under reduced pressure to give 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (4.80 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ10.48 (s, 1H), 9.16 (s, 1H), 7.27 (dd, J=8.0, 1.0 Hz, 1H), 7.01 (s, 1H), 6.87-6.74 (m, 2H), 6.22 (s, 1H), 5.91 (s, 2H), 5.03 (br, 1H), 4.12 (d, J=10.0 Hz, 1H), 3.85 (d, J=10.0 Hz, 1H); MS (ES−) m/z 376 (M−1), 378 (M−1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])[N:5]=[N:6][C:7]=1[NH2:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH2:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])=[N:3][C:2]=1[NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])=[CH:24][CH:25]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2nnc(N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1[N+](=O)[O-]
Yield: 33.9 %

Procedure:
A mixture of 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (1.05 g, 3.95 mmol), (4-aminophenyl)(morpholino)methanone (1.630 g, 7.90 mmol), and N,N-diisopropylethylamine (1.243 mL, 7.11 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 2 days. The volatiles were removed under vacuum. To the residue was added water (60 mL). The precipitating material was collected by suction filtration. The filter cake was purified by ISCO (120 g silica gel, solid loading, 3-8% MeOH/CH2Cl2) to provide the desired product, (4-(6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5-ylamino)phenyl)(morpholino)methanone (0.595 g, 1.339 mmol, 33.9% yield), as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc(N)c(C(=O)O)c1
Yield: 49.3 %

Procedure:
A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (21.0 g, 70.9 mmol) in methanol (210 mL) and palladium/carbon (2 g) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a brown oil, which was stirred in ether (300 mL) overnight. The ether slurry was filtered to give 2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown solid (9.3 g, 49% yield). The product was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([N+:19]([O-])=O)[CH:11]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=3)=[O:36])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:41]([C:40]3[CH:39]=[CH:38][C:37]([C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([N:25]5[CH2:24][CH2:23][O:22][CH2:27][CH2:26]5)=[CH:33][CH:32]=4)=[O:36])=[CH:44][CH:43]=3)=[N:19][C:12]=2[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(-c4nc5ccccc5s4)ccc3[nH]2)cc1

Procedure:
Compound 638 was prepared according to the procedure similar to that described in Scheme III from 1-(benzothiazol-2-yl)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H25N5O2S: 532.18; found: 532.07.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-cyanophenol: 1H NMR (300 MHz, CD3OD) δ 7.74 (d, J=8.8 Hz, 1H), 7.61 (app. d, J=8.8 Hz, 2H), 7.37 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.9, 2.4 Hz, 1H), 7.02 (app. d, J=8.8 Hz, 2H), 4.43 (q, J=8.9 Hz, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.08 (t, J=5.1 Hz, 2H).
Reaction SMILES: [C:1]([OH:18])(=O)[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].S(Cl)([Cl:21])=O>>[C:1]([Cl:21])(=[O:18])[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]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)Cl

Procedure:
Palmitic acid (1 mole) is heated with thionyl chloride (20 mole) at 75° C. for 2 hours. The thionyl chloride is removed by distillation at atmospheric pressure and the palmitoyl chloride is then separated by distillation under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](=[O:8])[NH:6][N:7]=1)[CH3:2].Cl[CH:19]([OH:22])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[OH:22][CH2:19][CH2:20][CH2:21][N:6]1[C:5](=[O:8])[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([CH2:1][CH3:2])=[N:7]1
Reactant: CCc1n[nH]c(=O)n1CCOc1ccccc1
Reactant: CCC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1nn(CCCO)c(=O)n1CCOc1ccccc1

Procedure:
The product of Example 5 "5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one" (5.0 g., 23.5 mmol), chloropropanol (2.44 g., 25.8 mmol) and potassium carbonate (9.72 g., 70.4 mmol) in 50 ml. of acetonitrile is heated to reflux for a period of 48 hr. with stirring. Water (50 ml.) is added and the mixture extracted with methylene chloride which is dried over magnesium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one (XIV, Y=H, X1 =0, n=2, R2 =C2H5). Purification is carried out by flash chromatography with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(OC(F)(F)F)cc4)ncnc32)CC1
Yield: 29.7 %

Procedure:
4-[4-(4-Trifluoromethoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (12.8 mg, 30%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 4-(trifluoromethoxy)-phenol (Avocado Research Chemicals; 16 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol). Mass spectrum MH+=480.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[C:12]=[O:13]>O1CCCC1>[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[NH:11][C:12]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:13]
Reactant: COC(=O)[C@@H](N=C=O)C(C)(C)C
Reactant: C=CCCCNC
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)(C)C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of N-methylpent-4-en-l-amine (2.0 g, 20.2 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen. To this was added methyl 3-methyl-N-(oxomethylene)-L-valinate (3.5 g, 20.2 mmol) and the resulting solution stirred 2 h. Contents of the reaction flask were evaporated and subjected to flash column chromatography eluting with hexane/ethyl acetate 60/40 to give methyl 3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate as an orange oil, 3.02 g (55% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3].[NH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]([CH2:19][NH:18][S:2]([C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3])=[O:21]
Reactant: COC(=O)CN
Reactant: COC(=O)c1sc(C(F)(F)F)cc1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CNS(=O)(=O)c1cc(C(F)(F)F)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
103.8 g of methyl 3-chlorosulfonyl-5-trifluoromethyl-thiophene-2-carboxylate are dissolved in 600 ml of chloroform, 68.05 g of freshly distilled methyl glycinate are added dropwise thereto in a manner such that the temperature does not exceed 30°, the mixture is stirred at room temperature for an additional 0.5 hour and then extracted three times with 200 ml of 1N hydrochloric acid each time. The organic phase is dried over sodium sulfate and evaporated. The oily residue is stirred with 175 ml of diisopropyl ether, and there is obtained methyl 3-[(methoxycarbonylmethyl)sulfamoyl]-5-trifluoromethyl-thiophene-2-carboxylate in the form of colorless crystals which are removed by filtration under suction and washed with diisopropyl ether. The product melts at 76°-78° after recrystallization from diisopropyl ether.
Reaction SMILES: [Cl-].[NH4+].[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)C=O.C(O[CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])C>CCO>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[C:12]1[CH:13]=[C:6]([CH2:5][CH2:4][OH:3])[CH:7]=[CH:8][CH:11]=1)[CH3:23]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1cccc(CCO)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cccc(CCO)c1
Temperature: 70 °C

Procedure:
Ammonium chloride (0.08 g) was added to a solution of 3-(2-hydroxyethyl)benzaldehyde (example 20, step b) (0.45 g) and triethoxymethane (0.55 g) in EtOH (8 mL) and the reaction mixture heated at 70° C. for 3 h. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.24 g.