Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH:1]([C:3]1[S:7][C:6]([C:8](=[N:13][OH:14])[O:10][CH3:11])=[CH:5][CH:4]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COC(=NO)c1ccc(C=O)s1
Yield: 72 %

Procedure:
A solution of methyl 5-formyl-2-thiophenecarboxylate, prepared according to Example 10, (6.26 g, 36.78 mmoles), hydroxylamine hydrochloride (3.07 g, 44.14 mmoles) and pyridine (3.49 g, 44.14 mmoles) in 200 ml of ethanol was refluxed for 2 hours. The ethanol was removed in vacuo, the residue dissolved in ether and washed with water. The organic layer was dried (magnesium sulfate) and evaporated to a yellow solid. Trituration with a small amount of ether furnished the title compound as a white solid (4.93 g, 72%), m.p. 164°-7° C. Oxime Z:E ratio:(82:18).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: N#CCC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1cccc(Br)c1
Temperature: 70 °C
Yield: 102.4 %

Procedure:
To a stirred solution of acetic acid (30 mL) at RT was added hexamethyldisilazane (13.09 mL, 62.8 mmol) dropwise over 10 min, maintaining temperature below 40° C. The resulting solution was then added dropwise to a solution of 1-(3-bromophenyl)ethanone (6.68 mL, 50.2 mmol) and malononitrile (6.33 mL, 100 mmol) in acetic acid (30 mL) and the mixture heated to 70° C. under nitrogen overnight. The reaction mixture cooled to RT and partitioned between water and toluene (ca. 150 mL each). The aqueous layer was separated and re-extracted with toluene (ca. 100 mL). The combined organic layer was dried over MgSO4 and solvent removed in vacuo, to afford the title compound (12.7 g) which was carried over to next step without further purification. LCMS (A) m/z: 247/249 [M+1]+, Rt 1.18 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: ClCCl.[CH:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([CH2:27][OH:28])[O:25][CH3:26])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([O:28][CH2:27][CH:24]([O:25][CH3:26])[CH2:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(CO)COCCCCCCCCCCCCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Yield: 79.1 %

Procedure:
To 100 ml of dichloromethane are added 10.8 g of 1-(12-cyclohexyldodecyl)-2-methylglycerine and 4.42 ml of triethylamine, to which 3.64 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. Then, the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is removed by distillation to leave 10.42 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:17][CH:16]4[N:18](C(OC(C)(C)C)=O)[CH:13]([CH2:14][CH2:15]4)[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[CH:16]12[NH:18][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:9]1[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]=3[N:6]=[CH:7][N:8]=1)[CH2:17]2
Reactant: Cc1c[nH]c2ncnc(N3CC4CCC(C3)N4C(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c[nH]c2ncnc(N3CC4CCC(C3)N4)c12
Reaction time: 1 h
Yield: 91 %

Procedure:
Boc-protected diazabicyclo[3.2.1]octane from step A was dissolved in 4M HCl in dioxane (4 ml). The reaction was stirred for 1 hour and concentrated under vacuum to afford 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (30 mg, 0.093 mmol, 91%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>C(O)C>[OH:15][NH:14][C:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[NH:12]
Reactant: NO
Reactant: N#Cc1cccc2cnccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2cnccc12
Temperature: 65 °C
Reaction time: 12 h
Yield: 119.2 %

Procedure:
5-Isoquinolinecarbonitrile (2 g, 13 mmol; available from Fulcrum Scientific Product List), hydroxylamine.hydrochloride (7.21 g, 104 mmol) and sodium bicarbonate (10.9 g, 130 mmol), were added to a 0.5 L round bottomed flask containing ethanol (250 ml). The reaction mixture was heated at 65° C. for 3 hours and stirred for 12 hours. The cooled reaction mixture was evaporated to a smaller volume under reduced pressure and chromatographed over a 4×6 inch silica column eluting with ethanol to provide the title compound as a yellow solid (2.9 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCOCC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 19 ml of morpholine, a reaction similar to that conducted in Example 142 was carried out. As a result, 3.19 g of N-(trans-4-methylcyclohexyl)-4-(2-morpholinoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.O1CCCC1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:8][CH2:7][CH:6]1[O:1][C:2]2=[CH:11][S:10][CH:9]=[C:3]2[O:4][CH2:5]1)[CH3:25]
Reactant: OCC1COc2cscc2O1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COCC1COc2cscc2O1
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL), blanketed by nitrogen. Sodium hydride (1.9 g) was added in portions after which the reaction mixture was stirred for another 30 min. Then ethyl bromoacetate (5.3 mL) was added dropwise and stirring was continued for another hour at 25° C. The reaction mixture was then poured into ethyl acetate, washed with 1M hydrochloric acid, washed with a 1M aqueous solution of sodium hydrogen carbonate and concentrated. This resulted in quantitative formation of pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid ethyl ester as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.Cl.C(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)ccc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
8.00 kg 2-chloro-5-bromobenzoic acid was suspended in 80.00 L methylene chloride (KF of methylene chloride<0.1% H2O) and 0.02 L of DMF added at 20° C. 5.18 Kg oxalyl chloride were slowly added and the internal temperature maintained below 25° C. The addition was slightly exothermic; gas evolution of HCl and CO2 occurred. The reaction was run at 20-25° C. overnight; a clear solution was obtained. The mixture was concentrated in vacuum to an oily residue and degased at 40° C. in vacuum. Yield of 2-chloro-5-bromobenzoic acid chloride: 8.63 kg (33.98 mol, yield 100.0%)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[O:20]=[C:19]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:22][CH3:23]
Reactant: CS(=O)(=O)Nc1ccccc1
Reactant: CCC(C(=O)O)c1ccccc1
Solvent: O
Product: CCC(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Temperature: 0 °C
Yield: 23 %

Procedure:
Methanesulfonanilide (40 g., 0.234 mole) is added over a 10 minute period with stirring to polyphosphoric acid (400 g.) heated to 90°-100°C. Heating and stirring are continued for additional 10 minutes, at which time 2-phenylbutanoic acid (36.0 g., 0.219 mole) is added portionwise during 20 minutes. After heating and stirring for 10 minutes, the solution is poured into water (600 ml.) and ice (400 g.) with stirring. The water is decanted and ethyl ether (200 ml.) is added to the remaining oil with stirring. After cooling in ice water, the product crystallizes and is collected: 18.4 g., m.p. 143°-147°C. Recrystallization from isopropanol yields 15.7 g. (23% yield), m.p. 148°-150°C.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[S:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[SH:19]>CO>[CH3:1][S:19][C:7]1[S:6][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: Sc1nc2cnc3ccccc3c2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc2cnc3ccccc3c2s1

Procedure:
Sodium methoxide (15.8 mL of 25% in methanol, 69 mmol) and methyl iodide (3.9 mL, 63 mmol) were added to a solution of thiazolo[4,5-c]quinoline-2-thiol (13.65 g, 63 mmol) in methanol (160 mL). The reaction mixture was heated on a steam bath for 1 hour. The solvent was removed under vacuum. The resulting light green-yellow solid was slurried with water, isolated by filtration, and washed with water to provide 9.8 g of crude product. A portion (1 g) was recrystallized from methanol to provide 2-(methylthio)thiazolo[4,5-c]quinoline as a solid, m.p. 116-119° C. Analysis: Calculated for C11H8N2S2: % C, 56.87; % H, 3.47; % N, 12.06; Found: % C, 57.09; % H, 3.57; % N, 12.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH:18]=[CH2:19])(O)[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.C(OCC)C>[C:23]([S:24][CH2:19]/[CH:18]=[C:16]1\[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:11]2[S:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:9][C:10]\1=2)(=[NH:22])[NH2:25]
Reactant: NC(N)=S
Reactant: C=CC1(O)CC(C)(C)Cc2sc(-c3cccc(Br)c3)cc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1(C)C/C(=C\CSC(=N)N)c2cc(-c3cccc(Br)c3)sc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(3-Bromophenyl)-6,6-dimethyl-4-vinyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (0.39 g, 1.0 mmol) was suspended in acetic acid (2.0 mL). Thiourea (83 mg, 1.0 mmol) was added and the reaction was stirred at 25° C. for 18 hr. The mixture was diluted with diethyl ether and petroleum ether yielding a solid precipitate. The solid was filtered, washed with additional diethyl ether and dried in vacuo to afford the title compound as the acetate salt (0.3 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=O)[O:23]C(C)(C)C)[CH3:20])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].Cl.[C:32](OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:23])[CH3:32])[CH3:20])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn3)oc2c1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCOc1ccc2nc(-c3ccc(OC[C@H](C)NC(C)=O)cn3)oc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-{[6-(6-ethoxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (5.53 g), 4M hydrogen chloride/ethyl acetate (100 mL) and ethyl acetate (100 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with acetic anhydride (50 mL) and pyridine (50 mL). The obtained mixture was stirred at room temperature overnight. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (ethanol/hexane) to give the title compound as white crystals (3.48 g).
Reaction SMILES: [NH3:1].O[C:3]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]#[N:5]>O>[NH2:1][C:3]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]#[N:5]
Reactant: N
Reactant: CC(C)CC(C)(O)C#N
Solvent: O
Product: CC(C)CC(C)(N)C#N

Procedure:
To a 1-liter autoclave were added 7 moles of ammonia and then 3.5 moles of 90%-pure 2-hydroxy-2,4-dimethylpentanonitrile, and the mixture was reacted at 27° C. for 10 hours at a rate of 300 r.p.m. Thus, 2-amino-2,4-dimethylpentanonitrile was synthesized. After reaction, the reaction mixture was taken out of the autoclave, and 44 g of the water phase was separated. The residue was distilled in a wetted wall tower under the following conditions: Temperature of the heating portion 25° C.; pressure 30 mmHg; and residence time in the heating portion 1 minute or less. Low-boiling compounds were thus distilled off and purified 2-amino-2,4-dimethylpentanonitrile was withdrawn from the bottom. The yield of the purified product was 90.0 mole % based on cyanohydrin. This purified product contained 0.5% by weight of ammonia and 0.8% by weight of hydrogen cyanide, and its purity was 90%.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>CCOC(C)=O>[C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[CH:18][N:19]([CH3:21])[CH3:20])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN(C)C)c1cc(F)c(C#N)cc1C
Yield: 96.4 %

Procedure:
Combined methyl 2-(4-cyano-5-fluoro-2-methylphenyl)acetate (5.00 g, 24.13 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (32.2 mL, 241 mmol), and lithium chloride (0.102 g, 2.413 mmol) and heated to 105° C. After 2 hours the reaction mixture was concentrated in vacuo and repeatedly diluted with EtOAc (30 mL) and concentrated to give an oil. The oil was dissolved in EtOAc (50 mL) and washed with water, 10% aqueous sodium chloride, and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a thick red oil, which was crystallized to give the title compound as a yellow solid (6.1 g, 23.26 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H) 2.34 (s, 1H) 2.54-2.81 (m, 6H) 3.50 (s, 3H) 7.20 (d, J=10.11 Hz, 1H) 7.58 (s, 1H) 7.72 (d, J=7.07 Hz, 1H). ESI-MS m/z [M+H]+ 263.2.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11](I)=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 5.58 mmol), trimethylsilylacetylene (1.24 ml, 8.94 mmol) and triethylamine (2.08 ml, 14.9 mmol) in N,N-dimethylformamide (10 ml) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (105 mg, 0.15 mmol), PPh3 (78 mg, 0.3 mmol) and CuI (9 mg, 0.05 mmol) were added. Stirring was continued at 90° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ice-water (50 mL) and extracted with ethyl acetate (3×70 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (MgSO4) and evaporated to give 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-8-trimethylsilanylethynyl-imidazo[1,5-a]pyrimidine(1.58 g, 69%) as a brown solid, which was dissolved in THF (15 ml) and MeOH (15 ml), while stirring at 0° C. potassium carbonate (51 mg, 0.37 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (50 ml) and extracted with TBME (2×80 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from diethyl ether/hexane to give 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (0.61 g, 49%) as a brown solid. MS (EI) 337.1 [(M)+]; mp 135° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:32]2[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([C:40](Cl)=[O:41])[CH:34]=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:40]([C:35]3[CH:34]=[N:33][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:36]=3[CH2:37][CH2:38][CH3:39])=[O:41])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Solvent: C1CCOC1
Product: CCCc1c(C(=O)NCCCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cnn1-c1ccccc1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 558.3 (M+H)+.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([OH:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:12]([CH3:13])[CH3:11])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: CNC
Solvent: O
Solvent: CCO
Product: CN(C)c1cc(O)nc(N)n1

Procedure:
2-Amino-4-chloro-6-hydroxypyrimidine monohydrate (5.0 g) was stirred with 30% dimethylamine in ethanol (180 mL) at 100° C. in an autoclave for 16 h. The crystalline product was filtered, washed with water, acetone, ether and dried in vacuo to afford 2-amino-4-dimethylamino-6-hydroxypyrimidine, not melting under 300° C. Yield, 4.3 g (81%). For C6H10N4O (154.17) calculated 46.34% C, 6.54% H, 36.34% N; found 46.38% C, 6.65% H, 36.68% N. 1H-NMR (CD3SOCD3): 2.89 s, 6H (N—CH3); 4.51 s, 1H (H-5); 6.18 brs, 2H (NH2); 9.75 brs, 1H (OH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:12]=[C:11]([C:26]([C:28]([F:30])([F:31])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2ccc(N3CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 428, cyclopropanesulfonyl chloride (6.0 uL, 0.06 mmol), and triethylamine (25.0 uL, 0.18 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:16]([F:29])[CH:15]=1.[I:30]I>C1COCC1>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])=[C:16]([F:29])[C:15]=1[I:30]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)c(I)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diisopropylamine (3.09 mL, 21.8 mmol) in THF (60 mL) under at 0° C. was added n-butyllithium (6.83 mL, 20.0 mmol) dropwise over 5 min. After 10 min, the reaction mixture was cooled to −78° C., and a solution of (4-chloro-2-fluorobenzyloxy)(tert-butyl)dimethylsilane (5.00 g, 18.2 mmol) in THF (15 mL) was added slowly over 5 min. After 2 h at −78° C., a solution of iodine (5.54 g, 21.8 mmol) in THF (25 mL) was added over 10 min. After a further 20 min at −78° C., the reaction mixture was warmed to RT and was quenched with sodium thiosulfate, followed by water (100 mL). The separated aqueous solution was extracted with diethyl ether (2×60 mL). The combined organic phases were washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane: hexane=10:90) gave (4-chloro-2-fluoro-3-iodobenzyloxy)(tert-butyl)dimethylsilane as colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (1H, t, J=7.5 Hz), 7.17 (1H, d, J=7.1 Hz), 4.65 (2H, s), 0.75-0.85 (9H, m), 0.01 (6 H, s)