Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:25]=[C:24]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH:23]=[C:22]([F:31])[CH:21]=3)[N:13]=2)[CH2:11][CH2:10]1.[C:32]([Si:36]([CH3:43])([CH3:42])[O:37][CH2:38][C:39]([CH3:41])=[O:40])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Si:36]([O:37][CH2:38][C:39]([C:29]1[S:30][C:26]([C:24]2[CH:23]=[C:22]([F:31])[CH:21]=[C:20]([NH:19][C:14]3[N:13]=[C:12]([CH:9]4[CH2:11][CH2:10]4)[C:17]([F:18])=[CH:16][N:15]=3)[CH:25]=2)=[CH:27][N:28]=1)([OH:40])[CH3:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:43])[CH3:42]
Reactant: Fc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cncs2)c1
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
LDA (0.757 mL, 1.362 mmol) was added to tetrahydrofuran (4 mL) at −78° C. After 15 minutes at −78° C., a solution of the product of Step 4 (150 mg, 0.454 mmol) in tetrahydrofuran (4 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-{[tert-butyl(dimethyl)-silyl]oxy}acetone (0.110 mL, 0.568 mmol) in tetrahydrofuran (4 mL) was added dropwise at −78° C. The reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexanes to afford 1-{[tert-butyl(dimethyl)silyl]oxy}-2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)amino]-5-fluorophenyl}-1,3-thiazol-2-yl)propan-2-ol (150 mg, 0.29 mmol, 64%). MS ESI: [M+H]+ m/z 519.2.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:16]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>COCCOC>[C:1]1([N:7]2[C:11]([C:12]([NH2:16])=[O:14])=[CH:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cnnn1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1COCCO1
Solvent: COCCOC
Product: NC(=O)c1cnnn1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (1.0 g, 5.6 mmol) and 4-methylmorpholine (0.57 g, 5.6 mmol) in 1,2-dimethoxyethane (5 mL), isobutyl chloroformate (0.77, 5.6 mmol) was added to the mixture. After 30 minutes, ammonia in dioxane (16.8 mL, 8.4 mmol) was added to the reaction. Then it was stirred overnight. The solvent was removed and dissolved in 50 mL of ethyl acetate. The organic layer was washed with brine twice. The organic layer was dried with Na2SO4, filtered and concentrated and used without further purification. MS (m/z) 189 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[NH2:28][OH:29]>CO>[OH:29][NH:28][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:26][CH:25]=1)=[O:22]
Reactant: NO
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)NO)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate 3 (0.200 g, 0.5 mmol) in MeOH (2 mL) was added an hydroxylamine solution (1.76 M, 2 mL) in MeOH and the reaction mixture was stirred 1 h at RT under magnetic stirring. The reaction mixture was adjusted to pH=5, concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was dried with Na2SO4 and the product was crystallized by dissolving the mixture at 80° C. in CH3CN to give N-(4-(hydroxycarbamoyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 3741 (0.070 g, 35% yield) as a pale red solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]2[C:18](=[O:19])[CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15][C:14]2=[O:22])=[CH:5]1)(=O)C.CO.[OH-].[Na+].C>O>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]2[C:18](=[O:19])[CH2:17][C:16]([CH3:20])([CH3:21])[CH2:15][C:14]2=[O:22])=[CH:5]1
Reactant: CC(=O)n1cc(C2C(=O)CC(C)(C)CC2=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)C(c2c[nH]c3ccccc23)C(=O)C1
Temperature: 60 °C
Yield: 60 %

Procedure:
To a mixture of 2-(1-acetyl-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione of Example 1e (74.8 g, 0.25 mol) and methanol (30 mL), a solution of sodium hydroxide (30 g, 0.75 mol) in water (300 mL) was added at room temperature under stirring. The reaction mixture was heated at 60° C. for 2 h under stirring, and then activated charcoal (10 g) and water (300 mL) were added. The mixture was stirred for 10 min, charcoal was filtered off, and the filtrate was acidified with hydrochloric acid to pH 2. The solid product was filtered off, washed with water and dried to give 38.3 g (60%) of the colorless solid; m.p. 173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:18](=[O:21])[NH:19][N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH:23]1([CH2:22][N:17]2[C:18](=[O:21])[NH:19][N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Nc1cccc(N2CCN(CCc3n[nH]c(=O)n3CC3CCCCC3)CC2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3n[nH]c(=O)n3CC3CCCCC3)CC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
A solution of 5-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}-4-(cyclohexylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one D10 (0.13 g, 0.34 mmol) in pyridine (2 mL) was cooled to 0° C. and acetyl chloride (0.025 mL, 0.029 g, 0.36 mmol) was added. The reaction mixture was stirred at 0° C. for 18 hrs and then evaporated to dryness. The residue was purified by flash chromatography (Silica gel 60 Å, 45 μm, 10% methanol in dichloromethane) and afforded 0.015 g (10%) N-[3-(4-{2-[4-(cyclohexylmethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]ethyl}piperazin-1-yl)phenyl]acetamide E38 as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14](O)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14]([Cl:21])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)C(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C(=O)Cl)cc(OC)c1OC

Procedure:
A stirred suspension of 3,4,5-trimethoxyphenyl-2-oxoacetic acid (1.60 g, 6.66 mmoles) in dry methylene chloride (26 mL) at room temperature was treated with 2M oxalyl chloride in methylene chloride (14 mL, 4 equiv.) and dry dimethylformamide (1 drop). After 3 h the solvents were evaporated. The residue was flushed with dry methylene chloride (3×50 mL) and dried in vacuo for 2 h during which time a solid formed. The crude acid chloride was carried on without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=1F.Cl>O1CCCC1>[CH2:3]([O:10][C:13]1[CH:14]=[C:15]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[F:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2.82 g (70.6 mmol, 2.5 eq) of sodium hydride at 60% are added to a solution of 7.6 g (70.6 mmol, 2.5 eq) of benzyl alcohol in 100 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 1½ hours and then 5.0 g (28.2 mmol, 1 eq) of 1,2,4-trifluoro-5-nitrobenzene in solution in 50 ml of tetrahydrofuran are added dropwise. The reaction medium is refluxed for 3 hours. The reaction medium is treated with 150 ml of 1M hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 90/10 heptane/ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1C=CN=C1)=[S:13].N>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:12](=[S:13])[NH2:14])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Brc1ccc2c(c1)OCCN2
Agent: N
Solvent: C1CCOC1
Product: NC(=S)N1CCOc2cc(Br)ccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
A mixture of 7-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (7.07 g, 33.00 mmol) and 1,1′-thiocarbonyldiimidazole (8.86 g, 49.70 mmol) in THF (83 mL) was heated to 120° C. under microwave irradiation, in a sealed tube, for 20 minutes, and then cooled to r.t. NH3 (110 mL, 7N solution in MeOH, 770 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, and then concentrated in vacuo. The residue was triturated with 1M aqueous HCl, then Et2O, water and again Et2O, and then dried in vacuo to give the title compound (5.31 g, 59%) as a cream solid. δH (DMSO-d6) 8.66-7.53 (2H, m), 7.39 (1H, d, J 8.7 Hz), 7.15 (1H, d, J 2.3 Hz), 7.07 (1H, dd, J 8.9 and 2.3 Hz), 4.30-4.20 (4H, m). LCMS (ES+) 272.9 and 274.9 (M+H)+, RT 3.12 minutes (Method 7).
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH2:20][N:15]2[CH2:14][CH2:13][CH:12]([N:4]3[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:2][C:3]3=[O:18])[CH2:17][CH2:16]2)=[O:22])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4NC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
In this example, 4.00 g 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 3.44 g of α-bromo-p-methoxyacetophenone, 4.2 ml of triethylamine and 60 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 4.71 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 3.79 g of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78.8 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 400 mg of ethyl 2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxylate [prepared as described in Preparation 24(iii)], 1.00 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 197 mg of potassium t-butoxide, 0.94 g of the title compound was obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[S:15][C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][C:2]1[S:15][C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH:3]=1)=[CH:11][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:8]=3
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cn2c(=O)c3ccccc3nc2s1
Product: Cc1cn2c(=O)c3cc(S(=O)(=O)Cl)ccc3nc2s1
Reaction time: 12 h

Procedure:
15 parts of 2-methyl-5H-thiazolo[2,3-b]quinazolin-5-one were introduced slowly into 70 parts of chlorosulfonic acid, at 20°-30° C. Stirring was continued for 12 hours, and the 2-methyl-7-chlorosulfonyl-5H-thiazolo[2,3-b]quinazolin-5-one formed was precipitated with ice water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:22]2[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=3)[CH2:21]2)=[O:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(F)cc(F)c3)C2)c1

Procedure:
The compound of Example 6 was prepared according to the general preparation protocol A from 3,5-difluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[O:19][CH2:20][CH2:21][NH2:22])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[C:8]1([S:5]([CH2:4][CH2:3][CH2:2][NH:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[O:16][CH2:14][CH3:15])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(CCCBr)c1ccccc1
Reactant: CCOc1ccccc1OCCN
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccccc1OCCNCCCS(=O)(=O)c1ccccc1
Yield: 7.1 %

Procedure:
A mixture of [(3-bromopropyl)sulfonyl]benzene (26.3 g, 100 mmol), 2-(2-ethoxyphenoxy)ethanamine (18.1 g, 100 mmol), and potassium carbonate (55.3 g, 400 mmol) in 200 mL of methyl ethyl ketone is heated at reflux for 18 hours. The reaction mixture is cooled, filtered, and the filtrate is evaporated. The residue is dissolved in warm 2-propanol and treated with oxalic acid (9.3 g, 101 mmol). The precipitated salt is filtered and recrystallized from 2-propanol to yield 3.2 g (7%) of product, mp 184-188° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([Cl:16])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[CH3:18][C:19]1([CH3:30])[CH2:28][C:27]2[CH:26]=[C:25]([OH:29])[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:15]1[C:3]([CH2:2][O:29][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]([CH3:30])([CH3:18])[CH2:28][C:27]=3[CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Reactant: CC1(C)CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)cc2C1
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (200 mg, 0.62 mmol), 7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (109 mg, 0.62 mmol) and potassium carbonate (257 mg, 1.86 mmol) in acetone (20 mL) was stirred at 50° C. for 4 hrs. The reaction mixture was filtered, the filtrate was concentrated and purified by SGC (eluting with petroleum ether/ethyl acetate from 100/1 to 25/1) to get the desired compound (220 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C2=CCNCC2)nc1

Procedure:
A solution of tert-butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 hours. This resulted in the product with the molecular weight of 194.67 (C10H11CIN2); MS (ESI): 195 (M+H+).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:7]=1[CH:8]=[O:9].O>ClCCl>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:7]=1[CH:8]=[O:9]
Reactant: COc1cccc(F)c1C=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(O)cccc1F
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of boron tribromide in dichloromethane (1M; 20.15 ml) was added dropwise to a stirring solution of 2-fluoro-6-methoxybenzaldehyde (4.66 g, prepared as described above) in dichloromethane (40 ml) at -78° C. The mixture was allowed to warm to ambient temperature then water (150 ml) was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml) then brine (100 ml) and the solvent evaporated. Distillation of the residue at reduced pressure gave 2-fluoro-6-hydroxybenzaldehyde (2.0 g), contaminated with 7% of the starting methoxy compound, as an oil b.p. 60° C. at 4.66 mbar, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3NC(=O)c1ccccc1

Procedure:
N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoyl chloride in a similar manner as described above to give a pale yellow solid (81% yield). 1H-NMR (CDCl3): δ 8.63 (s, 1H), 7.81-7.75 (m, 2H), 7.54-7.48 (m, 1H), 7.47-7.40 (m, 2H), 7.28 (m, 1H), 7.20 (d, 1H), 6.99 (dd, 1H), 6.40 (d, 1H), 5.36 (m, 1H), 2.75 (m, 2H), 2.44 (s, 3H), 2.31 (m, 1H), 2.02-1.91 (m, 3H); MS m/z 303 (M−1).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH3:15])=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>>[CH2:21]([O:20][C:16](=[O:19])[NH:17][N:18]=[CH:13][C:11]1[N:12]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][C:10]=1[CH3:15])[CH3:22]
Reactant: CCOC(=O)NN
Reactant: Cc1[nH]c(Cc2ccccc2)nc1C=O
Product: CCOC(=O)NN=Cc1nc(Cc2ccccc2)[nH]c1C

Procedure:
A 4.08 gm. portion of 2-benzyl-5-methyl-4-imidazolecarboxaldehyde and 2.29 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 190°-191.5° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:27]1([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:40][C:35]1[CH:34]=[C:33]([O:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: Cc1cc(OC2CCCC2)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(OC2CCCC2)cc1CBr
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
4.81 g of N-bromosuccinimide (27 mmol) and 0.6 g of benzoyl peroxide (2 mmol) are introduced into a solution of 5 g of 4-cyclopentyloxy-1-fluoro-2-methylbenzene (25.8 mmol) in carbon tetrachloride (130 ml). The mixture is heated at 80° C. for 17 hours, a further 2.29 g of N-bromosuccinimide (12.89 mmol) and 0.3 g of benzoyl peroxide (1 mmol) are then added and heating is continued for 12 hours. The mixture is then cooled to room temperature and filtered through Celite. The mother liquor is concentrated and the black oil obtained is purified by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate). 4.63 g of an orange oil are obtained:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]=[O:10])#[CH:2]
Reactant: C#Cc1cccc(C2OCCO2)c1
Agent: Cl
Solvent: O
Product: C#Cc1cccc(C=O)c1
Temperature: 60 °C
Yield: 87.8 %

Procedure:
A multinecked, round bottom flask fitted with a mechanical stirrer, reflux condenser and thermometer, was charged 50.4 g (0.289 mol) of the product of Example XI, 400 ml of distilled water and 1 g of concentrated hydrochloric acid. The mixture was heated to 60° C. and maintained at that temperature for about 4 hours and then cooled to room temperature which yielded the product as a yellow precipitate. The product was filtered, washed with distilled water and allowed to dry on the funnel overnight to yield 33 g (0.254 mol, 87.8% yield).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].CNC.C(O)(=O)CC.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH:17]=O)[CH3:14]>O>[CH3:3][C:2](=[CH:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[CH:1]=[O:4]
Reactant: CCOC(C=O)OCC
Reactant: CCC=O
Agent: CNC
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(C=C(C)C=O)OCC
Yield: 68.9 %

Procedure:
504 g of a solution of 240 g of propionaldehyde in 264 g of diethoxyacetaldehyde (glyoxal(mono)diethylacetal) are run into a mixture of 48 g of dimethylamine in 72 g of water and 80 g of propionic acid at 40° C. in the course of 30 minutes, while stirring. The reaction mixture is then stirred for a further 3 hours. After the lower aqueous phase has been separated off, fractional distillation of the organic phase gives 237 g (68.9% of theory) of 2-methyl-4,4-diethoxybut-2-enal of boiling point 67°-69° C./8 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]#[N:33])[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[NH:36][N:35]=[N:34][N:33]=4)[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:10])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(C#N)CC2)n1-c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(c3nnn[nH]3)CC2)n1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carbonitrile, NaN3 (59 mg, 0.9 mmol), and NH4Cl (50 mg, 0.9 mmol) in DMF (2 mL) was heated at 100° C. overnight. The crude product was purified by HPLC (10-99%, MeCN/H2O with 0.05% TFA) to give the title product as a white solid (45 mg, 47%). MS (EI) m/z 530.3 [M+H]+.