Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].[O:29]1CCO[CH2:31][CH2:30]1>>[CH2:1]([O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([C:30](=[O:29])[CH3:31])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(C(=O)OCc2ccccc2)c1
Reactant: C1COCCO1
Agent: [Sn]
Product: CC(=O)c1ccc(C(=O)OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In dioxane was placed 4-bromo-1,3-benzenedicarboxylate dibenzyl ester (1.78 g, 4.2 mmol), tri-n-butyl(1-ethoxyvinyl), tin (1.70 g, 4.7 mmol), and bis-triphenylphosphine palladium (II) dichloride (175 mg, 0.25 mmol). The mixture was warmed to 100° C. and stirred for 24 hours. The dark solution was evaporated at reduced pressure to give an oil. The oil was purified by MPLC (90 g silica gel, 3:1 [hexane:ethyl acetate]). This gave 0.91 g of the ethoxyvinyl intermediate. This was then placed into a solution of acetic acid (25 mL) and water (5%) and stirred for 1 hour. The mixture was evaporated in vacuo to give an oil which was purified by MPLC (90 g silica gel, 8:2 [hexane: ethyl acetate]). This gave 699 mg (43%) of a white solid. MS: M+1=389.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24]O)=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:19]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][CH:16]=[C:9]1[C:8](=[O:24])[NH:7]2)(=O)[CH3:2].C(O)(=O)C>[OH-].[OH-].[Pd+2].[H][H]>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][CH:16]=[C:9]1[C:8](=[O:24])[NH:7]2)[CH3:2]
Reactant: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(C(C)=O)ccc3n12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(CC)ccc3n12

Procedure:
A mixture of ethyl 3-(7-acetyl-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxalin-1-yl)propanoate as synthesized in above Example 183, 131 mg, Pearlman's catalyst 100 mg and acetic acid 5 mL was stirred in hydrogen atmosphere at room temperature for 43 hours. Then 75 mg of Pearlman's catalyst was added and the reaction liquid was mildly heated. Twenty-two hours later, the reaction liquid was filtered through Celite, and 30 mL of water was added to the filtrate. The precipitate was recovered by filtration, washed with water and dried in flowing air under heating to provide 65 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:15][CH:16](O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH:16]([CH3:17])[CH3:15]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 25.8 mmol methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol 2-propanol and 29.6 mmol triphenylphosphine in 100 ml THF was added 28.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 237.1 (M+H+, 100%)
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11]C)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[C:15](#[N:17])[CH3:16]>>[CH2:1]([C:3]1([C:9](=[O:11])[CH2:16][C:15]#[N:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)[CH3:2]
Reactant: CC#N
Reactant: CCC1(C(=O)OC)CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CCC1(C(=O)CC#N)CCCCC1

Procedure:
Acetonitrile was reacted with 1-ethyl-1-methoxycarbonylcyclohexane in the presence of sodium hydride to provide 1-ethyl-1-(2-cyanoacetyl)cyclohexane. A 55 g portion of the latter compound was dissolved in 200 ml of diethyl ether containing 20.5 g of absolute methanol, and the solution was stirred and cooled to about 5° C. Hydrogen chloride gas was next bubbled through the reaction mixture for forty-five minutes, after which time the reaction mixture was stored at 0° C. for twelve hours. Removal of the reaction solvent by evaporation under reduced pressure provided a yellow solid, which was dissolved in 300 ml of fresh absolute methanol and treated with 97 g of triethylamine and 22 g of hydroxylamine hydrochloride. The reaction mixture was heated at 50° C. for three hours, and then cooled to room temperature and diluted with 25 ml of concentrated hydrochloric acid. The acidic reaction mixture was heated at 50° C. for twelve hours, and then cooled to room temperature and concentrated to dryness by evaporation of the solvent under reduced pressure. The residue thus obtained was dissolved in water, and the aqueous mixture was made alkaline by the addition of 20% sodium hydroxide. The product was extracted into diethyl ether, which was then washed with water, dried, and the solvent was removed by evaporation. Distillation of the product afforded 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole. B.P. 135°-140° C. at 0.1-0.05 torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:20])[CH3:19]>C(OCC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([O:20][CH2:18][CH3:19])=[NH:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CCCN1C(=O)OCc1ccccc1
Reactant: CCO
Solvent: CCOCC
Product: CCOC(=N)C1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 107.7 %

Procedure:
2-Cyano-pyrrolidine-1-carboxylic acid benzyl ester (17.0 g, 73.9 mmol) was dissolved in diethyl ether (100 mL). Ethanol (20.4 g, 444 mmol) was added and gaseous HCl was bubbled through the reaction mixture, while maintaining the temperature at −20° C. The temperature was maintained for 12 hours while stirring. The reaction mixture was concentrated under vacuo to afford 22.0 g (95%) of 2-ethoxycarbonimidoyl-pyrrolidine-1-carboxylic acid benzyl ester as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:20][CH3:21])=[CH2:19].[NH2-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[CH2:19][C:18]([O:20][CH3:21])([O:17][CH3:16])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(OC)OC
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(OC)Cc2ccc(OCc3ccccc3)cc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a 6 mL THF solution of 1-(benzyloxy)-4-bromobenzene (500 mg, 1900 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and ketene dimethyl acetal (359 μL, 3800 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added neat sodium amide (107 μL, 3800 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting mixture was heated to 80° C. and stirred for 48 hours. After the reaction was complete, it was quenched by slow addition of water. The resulting mixture was then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Solvent was removed in the presence of silica gel, and the residue was purified by column chromatography with 20% EtOAc/hexane to afford desired product H7.1 (274 mg, yield, 60%). MS ESI (pos.) m/e: 271.1 (M+H)+.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:22]=3)[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=3)[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 0.242 mmol) in TFA (2424 μL) was treated with trifluoromethanesulfonic acid (63.5 μL, 0.727 mmol) and stirred at 80° C. for 1 h. The reaction mixture was concentrated and diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, diluted with a small amount of methanol to make the solution clear, dried over sodium sulfate, and concentrated to give crude product. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 8% 2 M ammonia in MeOH/DCM to give 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (11 mg, 11.99% yield). 1H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H); 8.90 (d, J=2.35 Hz, 1H); 8.37 (d, J=2.74 Hz, 1H); 8.17 (d, J=2.35 Hz, 1H); 8.08 (dd, J=8.90, 2.64 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 3.94 (s, 3H); 3.76 (s, 2H); 3.53 (t, J=7.34 Hz, 4H); 2.53 (s, 3H); 2.28 (quin, J=7.38 Hz, 2H). m/z (ESI, +ve ion) 379.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)ccc2s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2s1
Yield: 99.1 %

Procedure:
A solution of compound 52b (510 mg, 1.9 mmol) and LiOH.H2O (319 mg, 7.6 mmol) in THF/H2O (10/10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 52c (479 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 255.0.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:8][CH:7]([N:9]([CH2:11][C@@H:12]2[C@H:16]3[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@H:15]3[C@H:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[NH2:31])[O:13]2)[CH3:10])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:6][CH:7]([N:9]([CH2:11][C@@H:12]2[C@H:16]3[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@H:15]3[C@H:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[NH2:31])[O:13]2)[CH3:10])[CH2:8]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pd/C (10 mg) was added to a solution of 9-((3aR,4R,6R,6aR)-6-(((3-(azidomethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (90 mg, 0.21 mmol) in MeOH (6 ml). The mixture was stirred at RT overnight under an atmosphere of H2. The mixture was filtered and the filtrate was concentrated to obtain the title compound which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:11])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: Oc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of tert-butyl[(2S)-1-hydroxypropan-2-yl]carbamate (1.07 g, 6.11 mmol), 4-fluoro-2-(trifluoromethyl)phenol (1.10 g, 5.55 mmol) and triphenylphosphine-resin (2.80 g, 8.40 mmol) in tetrahydrofuran (50 mL) was added drop-wise diisopropyl azodicarboxylate (DIAD, 1.37 g, 6.66 mmol). The reaction was allowed to stir at room temperature for 3 days, then filtered and rinsed with ethyl acetate. The combined filtrate was washed with 0.5 N aqueous sodium hydroxide and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (50% ethyl acetate in heptane) afforded the title compound as a clear yellow oil. Sample contained some residual diisopropyl azodicarboxylate and carried forward without further purification. Yield: 2.52 g, 134%. LCMS m/z 282.0 {[M-(2-methyl-prop-1-ene)]+1}. 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J=6.8 Hz, 3H), 1.45 (s, 9H), 3.98-4.03 (m, 2H), 4.04-4.13 (m, 1H), 6.95 (dd, J=9.2, 4.2 Hz, 1H), 7.16-7.22 (m, 1H), 7.30 (dd, J=8.3, 3.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)cc3OC)nc2n(CCC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.04 g (14.60 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.26 g (yield of Compound 24 as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc(-c2ccsc2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccnc(-c3ccsc3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-3-yl-pyridine (50 mg, 0.26 mmol), 1-methylpiperazine (100 mg, 1 mmol), 2-propanol (0.7 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[S:35][CH:36]=2)O1>>[S:35]1[CH:36]=[C:32]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:4][CH:3]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Reactant: CC1(C)OB(c2csc3ccccc23)OC1(C)C
Product: c1ccc2c(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)csc2c1

Procedure:
This compound may be prepared using methods as described for Compound 120, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)amine and 4,4,5,5-tetramethyl-2-benzo[b]thiophen-3-yl-[1,3,2]dioxaborolane in step 4. LCMS: Rt 0.84 min (95%), m/z (ESI) 402 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:13][C:14]([F:31])([C:27]([F:30])([F:29])[F:28])[C:15]([N:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[O:16]>C(OCC)C>[F:13][C:14]([F:31])([C:15]1[O:16][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[N:7][C:18]([C:19]([F:21])([F:22])[F:20])([C:23]([F:26])([F:24])[F:25])[N:17]=1)[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: N#Cc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: FC(F)(F)c1cccc(C2=NC(C(F)(F)F)(C(F)(F)F)N=C(C(F)(F)C(F)(F)F)O2)c1
Reaction time: 6 h

Procedure:
3-Trifluoromethylbenzonitrile (1.69 g, 0.01 mole) and 2,2,3,3,3-pentafluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl)ethylidene}propanamide (4.67 g, 0.015 mole) were dissolved in diethyl ether, sealed in an ampoule and kept at 60° C. for six hours. The solvent was evaporated and the residue distilled at reduced pressure to give a colorless oil, 4.4 g. (90 percent). PMR (CDCl3), 7.70 t (1H), 7.95 d (1H), 8.30 s&d (2H); 19F NMR, −45.68 (2F), −5.49 (3F), −10 (6F), 14.11 (3F).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[CH:13][CH:14]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[N:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:33])([F:34])[F:32])[N:6]=1)=[S:44]
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=S)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Yield: 89.8 %

Procedure:
To a 50 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (326 mg, 644 μmmol), Lawesson's reagent (520 mg, 129 mmol) and anhydrous toluene (23 mL). The reaction solution was stirred at reflux for 1 day. The reaction solution was concentrated in vacuo, and the crude material was chromatographed through a 25 g SiO2 column using a gradient of 100% Hx to 50% EtOAc to afford 302 mg (90% yield) of the title compound. MS (ES) 523.3 [M+H]+, 545.0 (M+Na)+.
Reaction SMILES: [C:1]1([C@@H:11]([NH:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:19]=[O:20]>C(O)CCC>[C:1]1([C@@H:11]([N:13]([CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[CH2:19][O:20][CH2:10][CH2:1][CH2:2][CH3:3])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC[Si](C)(C)C)c1cccc2ccccc12
Reactant: C=O
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@@H](C)c1cccc2ccccc12

Procedure:
The title compound was prepared from (S)-(-)-N-1-(1-naphthyl)ethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (80% pure) as a pale yellow oil (5.5 g, 82%)δH [CD3)2CO] 0.1 (s, SiMe3), 0.93 (t, J 7 Hz, CH3CH2), 1.2-1.7 (m, CH3CH and (CH2)2), 2.22, 2.45 (AB quartet, J 15 Hz, NCH2Si), 3.25 (t, J 7 Hz, CH2O), 4.22, 4.35 (AB quartet, J 10 Hz, NCH2O), 4.78 (q, J 7 Hz, CH), 7.3-8.5 (m, naphthyl).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])=[N+:13]=[N-:14]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc(F)cc1
Yield: 80.9 %

Procedure:
A solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2.5 g, 11.5 mmol) in DMSO (15 mL) at 10° C. was vigorously stirred and sodium azide (0.94 g, 14.4 mmol) was added. The mixture was stirred for I hour then quenched with water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give 2-azido-1-(4-fluoro-phenyl)-ethanone (1.7 g, 9.3 mmol) as a viscous yellow-red liquid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCSc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSc2ccccc2)CC1
Yield: 27.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.00 g) as starting compound and 5-phenylthiopentyl bromide (1.54 g) were reacted and treated in the same manner as in Example 168 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylthiopentyl)piperidin-4-yl)methyl)benzamide.