Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.CCOCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C1=COCCC1
Reactant: COC(=O)C/C=C\CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C/C=C\CCOC1CCCCO1
Yield: 98.4 %

Procedure:
A solution of methyl 6-hydroxy-(Z)-3-hexenoate (0.7684 g, 5.3 mmol), 3,4-dihydropyran (0.72 mL, 7.9 mmol, 1.5 eq) and pyridinium p-toluenesulfonate (PPTS, 125 mg, 0.5 mmol) in methylene chloride (25 mL) is stirred for 4 hours at room temperature. The solution is then diluted with ether (150 mL), and the ether layer is washed with half-saturated brine (50 mL) to remove the catalyst, and dried over magnesium sulfate. Purification by flash chromatography using hexane/ethyl acetate (90:10, v/v) affords methyl 6-tetrahydropyranyloxy-(Z)-3-hexenoate (1.19 g, 99%) as a clear colorless oil: Rf=0.38, hexane/ethyl acetate (7:3, v/v), IR (film) ν2850-3000 (C=CH, alkane CH), 1740 (C=O) and H NMR (CDCl3) δ1.45-1.65 (m, 6H), 2.35 (m, 2H), 3.10 (d, J=6 Hz, 2H), 3.30-3.70 (m, 4H), 3.58 (sS, 3H), 4.55 (br s, 1H), 5.65 (br t, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([S-:4])[CH3:3].[Na+].Cl[C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1>CO>[CH3:21][C:9]1[CH:8]=[C:7]([S:4][CH:2]([CH3:3])[CH3:1])[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1
Reactant: CC(C)[S-]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SC(C)C)c2ccc3cccnc3c2n1
Yield: 80 %

Procedure:
Solid sodium 2-propanethiolate (2.35 g, 24.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MeOH/DCM, 1:80) to afford the pure product as a yellow oil (1.03 g, 80%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].N1C2C(=CC=CC=2)C=CC=1.[S]>[Pd].O1CCCC1>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: [S]
Solvent: C1CCOC1
Solvent: c1ccc2ncccc2c1
Product: O=Cc1ccc2c(c1)COC2=O
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 7 g (0.036 mole) of 5-chlorocarbonylphthalide, 50 ml of tetrahydrofuran, 0.1 ml of the quinoline/sulfur mixture and 1 g of 10% Pd/C is hydrogenated at 3.5 bar and 35÷40° C. for 3 hours. After 3 hours a stoppage of the hydrogen absorption is observed. Thus, the mixture is cooled, diluted with dichloromethane, filtered, and by a HPLC control the presence of equivalent amounts of alcohol and aldehyde is observed. The mixture is concentrated under vacuum and the residue is taken up with ethyl acetate. The crystalline product is filtered and dried to obtain 4 g of 5-formylphthalide with a purity (HPLC)=44% (yield 30%).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (181 mg, described in Example 125) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (161 mg, 51%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 8.02-8.09 (m, 2H) and 9.21 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.4 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([CH:26]=[O:27])=[C:21]([Cl:28])[N:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([C:23]2[N:24]=[C:19]([Cl:18])[N:20]=[C:21]([Cl:28])[C:22]=2[CH:26]=[O:27])[CH2:7][CH3:8])=[CH:4][CH:3]=1
Reactant: CCNc1ccc(Cl)cc1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
Solutions of 15.56 g (0.1 mole) of 4-chloro-N-ethylaniline (III) and 11.13 g (0.11 mole) of triethylamine, in each case in 50 ml of tetrahydrofuran, were successively added dropwise to a solution of 21.14 g (0.1 mole) of 2,4,6-trichloropyrimidine-5-carbaldehyde (II) in 100 ml of tetrahydrofuran. The solution was then stirred for three hours at room temperature and the triethylammoniumchloride was filtered off. The filtrate was then evaporated in vacuo and stirred with 150 ml of methanol at 0° C. 23.9 g of colorless crystals were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH2:26][CH3:27])[N:7]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(N)n3)cc2)cc1
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cccc(NS(=O)(=O)c2ccc(-c3ccc(C#N)cc3)cc2)n1
Reaction time: 6 h
Yield: 63.2 %

Procedure:
To a suspension of N-(6-Aminopyridin-2-yl)4′-cyanobiphenyl-4-sulfonamide (0.08 g, 0.23 mmol) in methanol (1 mL) was added acetaldehyde (0.02 mL, 0.34 mmol)) and molecular sieves (4 Å) were added. The resultant suspension was stirred for 30 minutes before the addition of sodium cyanoborohydride (0.043 g, 0.70 mmol). After 6 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers was washed with brine and dried over sodium sulfate. Purification by high performance flash chromatography (25% EtOAc in hexanes) gave the product (0.055g, 63%). 1H NMR (400 MHz, CDCl3), δ: 8.03 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.40 (t, J=8.3 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 5.88 (d, J=8.3 Hz, 1H), 3.10-3.21 (m, 2H) 1.23 (t, J=7.2 Hz, 3H); LRMS (ESI) m/z: 379.12; Anal. Calcd for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.80. Found: C, 63.11; H, 4.82; N, 14.63.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3F)=[N:17][O:18][C:19]=2[CH3:20])=[O:14])[CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([N:12]2[C:26]3[C:21](=[CH:22][CH:23]=[N:24][CH:25]=3)[C:16]3=[N:17][O:18][C:19]([CH3:20])=[C:15]3[C:13]2=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC(NC(=O)c2c(-c3ccncc3F)noc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC(n2c(=O)c3c(C)onc3c3ccncc32)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dissolve 3-{[3-(3-fluoro-pyridin-4-yl)-5-methyl isoxazole-4-carbonyl]-amino}cyclo-hexanecarboxylic acid ethy ester (0.70 g, 1.87 mmol) in N,N-dimethyl-formamide (10 mL0 at ambient temperature under a nitrogen atmosphere. Add a solution of potassuim bis(trimethylsilyl)amide (0.5 M in toluene, 4.11 mL, 2.06 mmol) and stir for 20 min. at ambient temperature. Quench with water and follow by adding solid sodium chloride. Extract with ethyl acetate and wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane, allowing for the isolation of 656 mg (99%) of the desired product as a light solid. MS(ES): (M+1)+ 356.2, 357.2 m/z.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][NH:12][C:13](=O)[CH3:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC(O)=O>O1CCOCC1>[CH3:14][C:13]1[N:4]2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]2=[N:11][N:12]=1
Reactant: CC(=O)NNc1ncc([N+](=O)[O-])cc1C
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cn2c(C)nnc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a suspension of N′-(3-methyl-5-nitropyridin-2-yl)acetohydrazide (Step 67.2) (41.5 g, 198 mmol) in dioxane (180 mL) was added AcOH (35 mL) and the reaction mixture was stirred for 3 hr at 100° C. The reaction mixture was cooled RT and the crystallization was facilitated by the addition of Et2O (700 mL) over a period of 3 hr. After stirring the suspension for 3 hr at 0° C., the crystals were collected, washed with Et2O and dried to afford the title product (23.4 g, 119 mmol, 60% yield) as a light yellow solid. tR: 0.51 min (LC-MS 2); ESI-MS: 193 [M+H]+ (LC-MS 2); TLC (EtOAc/MeOH 9:1) Rf=0.35; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 2.80 (s, 3H) 7.87 (d, J=1.9 Hz, 1H) 9.45 (d, J=1.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=1.O>Cl.C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1
Reactant: CCOC(=O)c1cc(CN2C(=O)c3ccccc3C2=O)n(C)n1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(C(=O)O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of ethyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylate (8.13 g, 25.9 mmol) in hydrochloric acid (33 mL of 1 M) and acetic acid (33 mL) was heated at reflux intermittently for six hours and allowed to cool to room temperature; a precipitate formed. Water was added, and the solid was isolated by filtration, washed with water, and dried on the vacuum filter funnel for two days to provide 3.79 g of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylic acid as a brown solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1[C:20]#[N:21])([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>>[C:1]([O:4][CH2:5][C:6]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[C:20]#[N:21])([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2]
Reactant: CCC(CC)(COC(C)=O)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CCC(CC)(COC(C)=O)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215a from 2-((3-amino-2-cyanophenoxy)methyl)-2-ethylbutyl acetate (Example 232b) and sulfamoyl chloride in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (t, J=7.6 Hz, 6H), 1.37-1.43 (m, 4H), 1.98 (s, 3H), 3.87 (s, 2H), 3.96 (s, 2H), 6.98 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.54 (t, J=8.4 Hz, 1H), 9.46 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])C.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CCO>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Yield: 95.3 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (15 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (19 mg) in EtOH (0.7 mL) was microwaved at 150° C. for 2 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (19 mg). LC MS ESI+: 514 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C@@H:10]2[O:13][C@@H:11]2[CH3:12])=[CH:5][CH:4]=1.[H-].[Na+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([CH2:25][N:8]([CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9](=[O:14])[C@@H:10]1[O:13][C@@H:11]1[CH3:12])=[O:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CNC(=O)[C@@H]2O[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2O[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.21 g of (2R,3R)-2,3-epoxybutyric acid p-methoxybenzylamide in 100 ml of THF is added dropwise to a mixture, stirred at 0° under an argon atmosphere, of 550 mg of sodium hydride dispersion (55-60% in oil) and 1.52 ml of bromoacetic acid tert.-butyl ester in 25 ml of THF. The reaction mixture is heated to room temperature and stirred for a further 1 hour (reaction monitored by thin-layer chromatography). Total reaction time: 90 minutes. The insoluble portions are filtered off and washed with THF and the combined filtrates are concentrated by evaporation. The resulting crude product is purified by chromatography over 150 g of silica gel (system: toluene, toluene/ethyl acetate 80:20). Concentration of the pure fractions by evaporation yields the amorphous title compound.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[CH:13][N:12]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[Cl:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH2:10][OH:9])[CH:16]=1
Reactant: O=C(OCc1cc(Cl)ncn1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
(6-Chloro-4-pyrimidinyl)methyl benzoate (Intermediate 24, 394 mg, 1.584 mmol) was dissolved in methanol (16 mL), cooled to 0° C. and treated with sodium methoxide (8.56 mg, 0.158 mmol). The resulting mixture was stirred for 4 hours. A further quantity of sodium methoxide (8.56 mg, 0.158 mmol) was added and the resulting mixture was stirrred for 18 hours. The reaction mixture was cooled to 0° C. and a further quantity of sodium methoxide (8.56 mg, 0.158 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (132 mg);
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Cc2c[nH]nn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
5 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -60° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 2.4 g of cyclopentanone, and heated to 25°. Then the mixture is combined with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile.
Reaction SMILES: O[C:2]1([CH:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
7 g of crude 4-[1-hydroxycyclohept-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 50 ml of dichloromethane at 0° and stirred with 20 ml of thionyl chloride for 1 hour at 0°. Then the mixture is concentrated to dryness under an oil pump vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 30 ml of triethylamine, diluted with water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 1.9 g of 4-[1-cycloheptylidene-1-(1,2,4-triazolyl)methyl]benzonitrile as the free base, mp 79°-80°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=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.C(O)C>[C:15]1([CH:12]2[CH2:13][CH2:14][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)N1CCC(c2ccccc2)C1
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: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of (4-Bromo-phenyl)-(3-phenyl-pyrrolidin-1-yl)-methanone would be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford product.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: C=CCCBr
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and 4-bromo-1-butene, white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([N:6]([CH2:27][CH2:28][CH3:29])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17](=O)[CH2:18][C:19](OC(C)(C)C)=[O:20])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)[CH2:4][CH3:5]>CO>[CH2:3]([N:6]([CH2:27][CH2:28][CH3:29])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17]3[CH:18]=[C:19]([OH:20])[NH:2][N:1]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)[CH2:4][CH3:5]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC(=O)OC(C)(C)C)c2C1
Reactant: NN
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(-c3cc(O)[nH]n3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydrazine (1 ml, 32 mmole) was added to a solution of 500 mg (1.34 mmole) of 2-di-n-propylamino-8-t-butoxycarbonylacetyl-1,2,3,4-tetrahydronaphthalene in 25 ml methanol and stirred at room temperature for for 24 hours. The product was isolated by concentrating the reaction mixture followed by flash chromatography, eluting with 1:1 CH2Cl2 :MeOH, and finally crystallizing from MeOH/EtOAc, m.p. 214°-216° C. Analysis: Theory: C, 72.81, H, 8.68, N, 13.41; Found: C, 73.01, H, 8.81, N, 13.27.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(Cl)Cl>[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:5](=[O:6])[CH2:4][CH2:3][C:2]([OH:1])=[O:7]
Reactant: Cc1cccc(N)c1C
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a partial suspension of dihydrofuran-2,5-dione (1.0 g, 10.0 mmol) in DCM (40 mL) was added a solution 2,3-dimethylaniline (1.21 g, 10.0 mmol) in DCM (40 mL). The reaction was stirred at room temperature for 3 h and filtered. The solid was washed with CH2Cl2 to afford the title compound (1.89 g, 85% yield). LCMS, [M+H]+=222.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:28]=[CH:29][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-Chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 4-bromo-benzenesulfonamide (236 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 67%). MS (ISP) 477.0 [(M+H)+]; mp 290-293° C.