Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[C:15]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:14]=[C:13]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:12]=1[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH2:38]([O:37][C:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[C:27]([OH:29])=[O:28])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C(=O)O)c(OCc2ccccc2)c(C(=O)O)c1

Procedure:
2-Benzyloxy-benzene-1,3,5-tricarboxylic acid tribenzyl ester (14) (52 g, 88 mmol) was hydrolyzed with NaOH (20 g, 0.5 mol) in 4:1 methanol-water (1 L). The solvents were removed under reduced pressure after the completion of hydrolysis, and the residue was dissolved in saline and extracted with recycling methylene chloride to remove the benzyl alcohol. 2-benzyloxy benzene-1,3,5-tricarboxylic acid (15) deposited after acidification of the solution. It was collected by filtration and dried under vacuum, yield 25.6 g, 92%.
Reaction SMILES: [CH:1]1([CH2:4]Cl)[CH2:3][CH2:2]1.[Mg].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(OCC)C>[CH2:2]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:1][CH3:4]
Reactant: ClCC1CC1
Reactant: C1CCOC1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCOCCCC

Procedure:
In another method, the organosilicon compound catalyst system component (C) is obtained by the reaction of a monocycloalkyltrialkoxysilane (i.e., mono(cyclopropyl)methyl-, mono(cyclobutyl)methyl-, mono(cyclopentyl)methyl-, mono(cyclohexyl)methyl-, mono(cycloheptyl)methyl-trialkoxysilane) with a (cycloalkyl)methyl Grignard reagent. For example, (cyclopropyl)chloromethane is first reacted with magnesium in the presence of a solvent, e.g., an ether such as tetrahydrofuran, diethyl ether, or di-n-butyl ether, to yield a (cyclopropyl)methyl Grignard reagent ((cyclopropyl)methyl magnesium chloride). This reaction may be carried out at a temperature from about room temperature to about 60° C. The (cyclopropyl)methyl Grignard reagent is then reacted with (cyclopropyl)methyl trimethoxysilane to obtain bis{(cyclopropyl)methyl}dimethoxysilane; this reaction may be conducted in the presence of an ether such as tetrahydrofuran, diethyl ether, or di-n-butyl ether, or in the presence of an aliphatic hydrocarbon solvent such as hexane or heptane or an aromatic hydrocarbon solvent such as toluene, benzene, or xylene. This reaction may be carried out at a temperature from about 50° C. to about 200° C., preferably at a temperature from about 100° C. to about 200° C. or at a temperature from about 100° C. to about 200° C. under boiling or refluxing of the solvent.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH2:28][NH:4][CH2:1][CH2:2][CH3:3])=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CCCN
Product: CCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from propylamine and 4-(4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 190-205° C.; LC-MS: 414 (MH+); HPLC RT: 4.15 minutes.
Reaction SMILES: [C:1]([N:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]2[NH:14][C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([CH3:18])[N:17]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)C)(=O)C.Cl>O.C(O)C>[Cl:12][C:11]1[C:6]([NH:4][CH3:1])=[CH:7][C:8]([O:25][CH3:26])=[C:9]([C:13]2[NH:14][C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([CH3:18])[N:17]=2)[CH:10]=1
Reactant: COc1cc(N(C)C(C)=O)c(Cl)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of 2-[4-(N-acetyl-N-methylamino)-5-chloro-2-methoxyphenyl]-4-methyl-5-(3-pyridyl)imidazole (0.70 g) and conc. hydrochloric acid (7 ml) in a mixture of water (7 ml) and ethanol (7 ml) was refluxed for 7 hours with stirring. After allowed to cool to ambient temperature, the mixture was evaporated under reduced pressure. The resulting oil was poured into water (20 ml). After neutrallized with aqueous potassium bicarbonate the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off to give 2-(5-chloro-4-methylamino-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.58 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[NH:23]1[CH:24]=[CH:25][N:26]=[C:22]1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: Ic1ncc[nH]1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ncc[nH]2)c1)c1ccccc1
Yield: 29 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 2-iodo-1H-imidazole were reacted to give the title compound as a white solid (15 mg, 29%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[C:11]([N:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2/[CH:42]=[CH:43]\[CH2:44]O)(=[O:34])=[O:33])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][CH2:17][C:16]1[O:20][CH:21]=[CH:22][C:15]2=1)=[O:9].[CH:46]([N:49](C(C)C)CC)(C)[CH3:47].C(N)C>C(Cl)Cl>[CH2:46]([NH:49][CH2:44]/[CH:43]=[CH:42]\[C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[S:32]([N:23]([C:11]1[C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:19]2[C:14]([C:15]3[CH:22]=[CH:21][O:20][C:16]=3[CH2:17][O:18]2)=[CH:13][CH:12]=1)[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])(=[O:33])=[O:34])[CH3:47]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (0.100 g) was added to an ice-cooled, stirred solution of methyl-7-{N-[4-fluoro-2-((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 48, 0.413 g) and diisopropylethylamine (0.226 g) in DCM (7 mL). The reaction mixture was stirred with ice cooling for 30 minutes. Ethylamine (2M in THF, 2 mL) was added and the reaction mixture was stirred at room temperature for 5 hours. It was diluted with DCM and washed with water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with DMAW 350, followed by DMAW 240 and then DMAW 120. The resultant product was azeotroped with toluene and ethanol to give methyl 7-{N-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.401 g) as a dark yellow gum.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:24]([F:27])([F:26])[F:25])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>ClCCl>[Si:1]([O:8][CH:9]([C:24]([F:25])([F:27])[F:26])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[CH:30][N:31]([CH3:33])[CH3:32])(=[O:21])=[O:22])([CH3:13])[CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccc1S(N)(=O)=O
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]benzenesulfonamide (750 mg, 1.76 mmol) in 25 mL of dry dichloromethane, followed by the addition of N,N-dimethylformamide dimethyl acetal (420 mg, 3.53 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under high vacuum to afford 820 mg (100%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]-N-[1-dimethylaminomethylidene]benzenesulfonamide. MS (ES+) m/z 481 [M+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]=1[OH:35])[C:19]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:20].[CH:43]1(O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]=1[O:35][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:20]
Reactant: OC1CCCCC1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(OC3CCCCC3)c2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCCC3)c(OC3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.2 %

Procedure:
Diisopropylazo dicarboxylate (63 μL, 0.32 mmol) was added dropwise to a stirring mixture of methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (65 mg, 161 μmol), cyclohexanol (34 μL, 0.32 mmol) and triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) and the resulting yellow mixture was stirred at RT for 20 h. The reaction was quenched with MeOH (5 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40 g, 0-15% EtOAc in iso-hexane) to give the desired methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg, 100%): m/z 486 [M+H]+ (ES+); 1H NMR (400-MHz, DMSO-d6) δ: 10.48 (1H, s), 7.97 (2H, d), 7.91 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 3.84 (3H, m), 1.92 (4H, m), 1.80-1.70 (4H, m), 1.60-1.40 (6H, m), 1.30-1.05 (6H, m).
Reaction SMILES: C[C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:4](NC)=[O:5].N[C@H:33]([C:36]1C=CC=CC=1)[CH2:34]O>>[OH:5][CH2:4][C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:2]1[CH:30]=[CH:36][CH:33]=[CH:34][CH:31]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@@H](CO)c2ccccc2)C1

Procedure:
Compound 70 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methylamide with (R)-2-amino-2-phenylethanol. LCMS (+ESI) m/z=431.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[N:4]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.CO>[N:26]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18]4)=[O:16])=[CH:10][CH:9]=3)[N:4]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(-c2noc(CCl)n2)cc1)N1Cc2ccccc2C1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2noc(CN3CCOCC3)n2)cc1)N1Cc2ccccc2C1
Temperature: 50 °C

Procedure:
To a 20 mL vial was added N-(4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)isoindoline-2-carboxamide (50 mg, 0.141 mmol) and morpholine (36.8 mg, 0.423 mmol) in DMF (470 μl). The mixture was heated to 50° C. for 30 minutes, cooled, and diluted with 2 mL methanol. Chromatography provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.9 Hz, 2H), 7.35 (ddd, J=8.8, 3.9, 2.4 Hz, 4H), 4.80 (s, 4H), 3.95 (s, 2H), 3.68-3.48 (m, 4H), 2.62-2.51 (m, 5H); MS (ESI(+)) m/e 406 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCc2c[nH]c(C(=O)O)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1nc(CCCc2ccc(O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of the ethyl ester of 13e (1.15 g, 4.0 mmol) in dry dichloromethane (50 ml) was treated with boron tribromide (16 ml, 1.0M solution in CH2Cl2, 16.0 mmol) at 0° C. After 15 min at 0° C., the mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath and quenched with a dropwise addition of water (20 ml). The resulting mixture was briefly stirred at 25° C. then filtered. The filtrate was carefully neutralised by the addition of solid NaHCO3 to afford 13f (700 mg, 71%) as a white solid: m.p. 186°-187° C. (decomp.) (recrystallised from MeOH); IR (KBr) 3500-2400, 2935, 1640, 1516, 1396, 1232; 1H NMR (d6 -DMSO) δ 9.83 (3H, bs), 7.16 (1H, s), 6.98 (2H, d, J=8.2), 6.66 (2H, d, J=8.2), 2.60-2.40 (4H, m), 1.84 (2H, m). Anal. Calcd for C13H14N2O3 : C, 63.40; H, 5.73; N, 11.38. Found: C, 62.96; H, 5.70; N, 11.27.
Reaction SMILES: Cl.[CH:2]12[CH:7]([CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)=[O:11])[CH:6]1[CH2:5][NH:4][CH2:3]2.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1>ClCCCl>[CH:30]1([CH2:33][N:4]2[CH2:5][CH:6]3[CH:2]([CH:7]3[CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:28])([F:29])[F:27])[CH:20]=3)[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)=[O:11])[CH2:3]2)[CH2:32][CH2:31]1
Reactant: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CNCC32)c1
Reactant: O=CC1CC1
Agent: Cl
Solvent: ClCCCl
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(CC4CC4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 1-Methyl-1H-imidazole-4-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-trifluoromethoxy-benzyl)-amide Hydrochloride prepared above (0.8 gm, 1.9 mmol) in 18.5 mL of DCE at room temperature was added Cyclopropanecarbaldehyde (0.1 mL, 1.6 mmol) and NaHB(OAc)3 (0.8 gm, 3.7 mmol). The reaction stirred at room temperature for 16 hours, was quenched by the addition of saturated NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 5-30% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to yield 1-Methyl-1H-imidazole-4-carboxylic acid (3-cyclopropylmethyl-3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-trifluoromethoxy-benzyl)-amide 0.5 gm. 400 MHz 1H NMR (CDCl3) δ 7.5 (s, 1H), 7.3 (m, 2H) 7.2-7.0 (m, 3H), 5.5 (brs, 1H) 4.8 (brs, 1H), 4.0 (brs, 1H), 3.7 (s, 3H), 3.3 (brs, 1H), 3.0 (m, 2H), 2.2 (m, 4H), 1.5 (brs, 1H), 1.3 (m, 2H), 0.8 (m, 1H), 0.4 (m, 2H), 0.0 (m, 2H); MS (M+1) 449.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[S:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:18]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:6]3[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:18][C:7]=3[CH2:8][CH2:9][CH2:10][S:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: COc1cc2c(cc1OC)C(COCCO)SCCC2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(COCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1)SCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol and triethylamine is added p-nitrobenzenesulfonyl chloride. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is then extracted with aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. The residue is chromatographed on silica gel to give 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl 4-nitrobenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=2)=[O:3])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C=CCOc1ccc(C(C)=O)cc1
Solvent: CCO
Product: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)c(OC)c2)cc1
Reaction time: 18 h
Yield: 92.5 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 3,4-dimethoxy-benzaldehyde were under a dry inert atmosphere (argon) dissolved in 10 ml dry ethanol and the solution was stirred for 18 h. The solution was filtered to give 3.0 g (99%) of 3,4-dimethoxy-4′-prop-2-enyloxychalcone which was recrystallized from ethanol, m.p. 74.5-75° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:36][C:33]3[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Yield: 29 %

Procedure:
To a solution of (4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (84 mg, 0.30 mmol) in DMF (3 mL) were added DIEA (0.103 mL, 0.6 mmol) and 5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol at rt. The reaction mixture was heated at 40° C. overnight. The reaction was quenched by adding water and the yellow precipitate was collected by filtration and washed with water. The crude product was purified by silica gel chromatography eluting with DCM/MeOH to give (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (30 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.54 (s, 1H), 7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H), 8.08 (m, 2H), 8.74 (d, 1H), 10.66 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([CH3:51])[O:44]C3CCCCO3)[CH:35]=[CH:36][CH:37]=2)[CH:18]=[CH:19][C:20]=1[CH2:21][O:22][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C1COCC1.O>[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([OH:44])[CH3:51])[CH:35]=[CH:36][CH:37]=2)[CH:18]=[CH:19][C:20]=1[CH2:21][OH:22]
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.56 ml of concentrated sulphuric acid with 2.30 g (3.37 mmol) of 2-[6-(3-{2-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 30 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 80-heptane 20), white crystals (m=475 mg; Y=38%) are obtained. m.p.=93-5° C.
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:28])/[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22]C)[C:18]([CH3:24])=[C:17]([CH3:25])[C:16]=1[O:26]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(#N)C>[C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:28])/[CH2:13][CH2:14][C:15]1[C:16](=[O:26])[C:17]([CH3:25])=[C:18]([CH3:24])[C:19](=[O:22])[C:20]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(=O)c2ccccc2)c1C
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(CC/C(C)=C/COC(=O)c2ccccc2)=C(C)C1=O
Yield: 73.7 %

Procedure:
A solution of ceric ammonium nitrate (7.2 g; 13.1 mmol) in water (30 ml) was added dropwise while cooling with ice to a solution of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl benzoate (2 g; 5.2 mmol) in acetonitrile (30 ml). After completion of the addition the mixture was diluted with water and extracted with chloroform. The extracts were washed with water, dried and freed from solvent. The residue crystallizes spontaneously and 1.35 g of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl benzoate was obtained. M.P, 74.5°-75.5° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:7]=1[NH2:8]>ClCCl>[CH3:2][C:1]([NH:8][C:7]1[C:6]([Cl:5])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[CH:9]=1)=[O:3]
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)c(Cl)cc1Cl
Temperature: 50 °C

Procedure:
Acetyl chloride (2.13 mls; 0.03 mole) is added dropwise to a suspension of 2,4,5-trichloroaniline (4.91 g; 0.025 mole) and powdered 3A molecular sieves (7.4 g) in dichloromethane (25 mls), at room temperature, under a nitrogen atmosphere. When addition is completed, the mixture is heated to 50° C. for 1.5 hours and then cooled to room temperature. The 3A sieves are separated by filtration and washed with dichloromethane. All dichloromethane solutions are combined and evaporated to obtain 4.1 grams (69% of theoretical) of the solid product; m.p. 188°-190° C. after recrystallized from toluene.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([NH:9]C(OCC1C=CC=CC=1)=O)[CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[ClH:20].[H][H]>CO.[Pd]>[ClH:20].[F:1][CH2:2][C@@H:3]([NH2:9])[CH2:4][CH2:5][C:6]([NH2:8])=[O:7]
Reactant: NC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)CC[C@H](N)CF

Procedure:
0.46 g of 21 was hydrogenated in a Parr bottle, in methanol containing a small amount of concentrated hydrochloric acid and 10% palladium-on-carbon catalyst, at 32 p.s.i.g. hydrogen pressure for 6 hours at room temperature. The resulting mixture was filtered and the filtrate was stripped of solvent. The residue was triturated with ethyl acetate and the mixture was filtered to give 22, as a brownish solid, m.p.; 165°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:33][CH:34]4[CH2:38][CH2:37][CH2:36][O:35]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCC1CCCO1
Product: O=C(NCC1CCCO1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z=530.96 (M+H+); retention time=0.78 minutes.