Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[CH2:12][CH:13](CO)[N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:4]=2[CH:3]=1.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>Cl(O)(=O)(=O)=O>[ClH:1].[Cl:1][C:2]1[S:11][C:10]2[N:9]3[CH2:12][CH:13]([CH2:25][C:24]([OH:27])=[O:26])[N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CN2C(=N1)CN=C(c1ccccc1F)c1cc(Cl)sc12
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cl
Product: O=C(O)CC1CN2C(=N1)CN=C(c1ccccc1F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
31 drops of perchloric acid (70%) were added to a suspension of 1.5 g of 2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno-[3,2-f][1,4]diazepine-8-methanol in 31 ml of acetic anhydride until the starting product was completely in solution. After stirring at room temperature for 20 min. the solution was poured into sodium carbonate/ice/dichloromethane and stirred at room temperature for 1 h. After extraction the dichloromethane extracts were dried with sodium sulphate, filtered and evaporated to dryness in a vacuum. The residue was dried in a high vacuum for 2 h., dissolved in 30 ml of acetone, treated with 52 g of 1.6% hydrochloric acid gas in diethyl ether, evaporated in a vacuum (223 mbar) and crystallized from acetone. After crystallization from acetone there was obtained 1 g of methyl[2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-yl-acetate-hydrochloride of m.p. 126-129° C. (dec., strongly hygroscopic).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.C(Cl)(=O)OCC.Cl.[NH2:47][CH2:48][CH2:49]Cl>O.O1CCCC1.C(N(CC)CC)C>[O:28]1[CH2:49][CH2:48][N:47]=[C:26]1/[CH:25]=[CH:24]/[C:23]1[C:19]([O:18][CH2:17][C:16]2[CH:35]=[CH:36][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:39])=[C:14]([O:37][CH3:38])[CH:15]=2)=[N:20][N:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: NCCCl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C2=NCCO2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.67 h
Yield: 35 %

Procedure:
To a mixture of (2E)-{3-{3-[(4-([2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), triethylamine (0.14 g) and tetrahydrofuran (30 mL) was added ethyl chlorocarbonate (0.15 g) at −30° C. The reaction mixture was stirred at the same temperature for 40 min and added to a mixture of 1-amino-2-chloroethane hydrochloride (0.66 g), triethylamine (0.58 g) and tetrahydrofuran (20 mL) at −30° C. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, potassium carbonate (0.19 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-({4-[({4-[(E)-2-(4,5-dihydro-1,3-oxazol-2-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-2-(2-furyl)-5-methyl-1,3-oxazole as pale-yellow crystals (0.22 g, yield 35%) from a fraction eluted with ethyl acetate-methanol (50:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 162-163° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1C=CC=CC=1.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=C1C=O>>[CH3:35][N:2]([CH3:1])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=1
Reactant: Cn1ccnc1C=O
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: CN(C)C(=O)OC(c1nccn1C)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using 1-methyl-2-imidazolecarboxaldehyde in place of benzaldehyde. Pale yellow oil (33 mg, 46%);
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[NH:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]=2[CH:7]=[CH:6]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClC(Cl)C>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:6]2[S:5][C:9]3[NH:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]=3[CH:7]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2cc(C(=O)c3ccc(Cl)cc3)sc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
Under a N2 atmosphere and at 0° C., to a 40-mL scintillation vial fitted with a magnetic stir bar was added solid aluminum chloride (0.7 g 5.28 mmol) and a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.61 g, 3.14 mmol, 0.9 equiv) in solution in 10 mL dichloroethane (DCE). 4-Chlorobenzoyl chloride (0.92 g, 5.28 mmol) was then added at 0° C. and stirring was continued for 2 h as the reaction was allowed to warm to rt. The reaction was cooled and was added to an ice-filled beaker. The aqueous mixture was extracted ×3 with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified via ISCO Companion (0-30% gradient EtOAc/heptane over 30 min) to give ethyl 2-(4-chlorobenzoyl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.34 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.13 Hz, 3H) 4.43 (q, J=7.13 Hz, 2H) 7.17 (d, J=1.81 Hz, 1H) 7.50 (d, J=8.44 Hz, 2H) 7.59 (s, 1H) 7.77-7.86 (m, 2H) 10.03 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 19.5 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-fluorophenylboronic acid (21 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-fluoro-phenyl)-thiazole-5-carboxylic acid (7.8 mg, 20%) as a white solid. MS 400 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:23]1([NH:22][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:11]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred mixture of aniline (0.306 g) and sodium bicarbonate (0.51 g) in tetrahydrofuran (2 ml) and water (5 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was washed with ethanol to give yellow crystals of N-phenyl3-(2,4-difluorophenylthio)-4-nitrobenzamide (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:19][C:5]1[C:6]([O:7][C:8]2[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:18][C:2]([NH:1][C:30](=[O:31])[CH2:29][Cl:28])=[C:3]([F:20])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-(5-amino-2-chloro-4-fluorophenoxy)-3-trifluoromethylpyridine (1.32 g) and triethylamine (0.8 ml) in toluene (20 ml) was stirred at 0° C. while a solution of chloroacetyl chloride (0.4 ml) in toluene (10 ml) was added. The mixture was stirred over night at room temperature and processed. Column chromatography on silica gel using methylene chloride as eluent gave a white solid (1.4 g), mp 146-9° C. 1H NMR (CDCl3, TMS): 4.20(2H, s), 7.12(1H, dd, J=5,8 Hz), 7.30(1H, d, J=9 Hz), 8.01(1H, m), 8.22(1H, m), 8.34(1H, d, J=7 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[C:22]([O:27]CC)(=O)[C:23]([CH3:25])=O>C(O)(=O)C>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]2[N:19]([C:18]3[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=3)[C:22](=[O:27])[C:23]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:25]2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)=O
Solvent: CC(=O)O
Product: O=C1C(Nc2ccc(F)cc2)=CC(c2cccc(OC(F)(F)F)c2)N1c1ccc(F)cc1
Yield: 59.6 %

Procedure:
Stir 3-(trifluoromethoxy)benzaldehyde (15.0 g, 78.6 mmol), 4-fluoroaniline (22.4 mL, 236 mmol) and ethyl pyruvate (8.65 mL, 78.6 mmol) in glacial acetic acid (60 mL) at ambient temperature for 72 hours. Filter the precipitate and wash with a 3:1 heptane/MTBE mixture. Dry under vacuum to afford the titled compound (20.9 g, 60%) as an off-white powder: MS (m/z): 445 (M−1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)=[C:4]([F:18])[CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[F:8][C:7]1[CH:6]=[C:5]([CH:9]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)[C:4]([F:18])=[CH:3][C:2]=1[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Fc1cc(C2CCC3(C2)OCCO3)c(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F

Procedure:
A solution of 31.9 g (0.1 mol) of 7-(4-bromo-2,5-difluorophenyl)-1,4-dioxaspiro[4.4]nonane in 300 ml of dry tetrahydrofuran, under an argon atmosphere at -78° C., was treated with 40 ml (0.1 mol) of 2.5 M n-butyl lithium (hexane solution). The solution was warmed to -40° and poured onto 500 g of finely crushed dry ice and the mixture allowed to stand until the dry ice evaporated (18 hours). The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate/1.0 M hydrochloric acid (500 ml ea). The organic layer was washed with water, dried (MgSO4), and evaporated in vacuo to give 18.9 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[CH3:17])([O-:3])=[O:2].N1C=CC=CC=1.[OH-:24].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:32]>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[C:17]([OH:32])=[O:24])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
2-Nitro4-pentafluoroethyltoluene (56.6 g) and pyridine (170 ml) were added to a stirred solution of sodium hydroxide (10.0 g) in water (500 ml). The mixture was stirred and heated at reflux and potassium permanganate (174 g) was added portionwise. The mixture was stirred and heated at reflux for 1 hour until the purple colouration had disappeared. After cooling, the mixture was filtered and the solid was washed with water (3×100 ml) and ether (300 ml). The layers were separated and the aqueous layer was washed with ether and acidified to pH 1. It was extracted with ether (3×300 ml) and the combined extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-nitro4-pentafluoroethylbenzoic acid (51.6 g) as a white solid mp 124°-135° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(C(C)C)c2cc(-c3nnn[nH]3)cc(C(=O)O)c12
Temperature: 60 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.27 g, 0.902 mmol) in MeOH (15 mL) and tetrahydrofuran (5 mL) was added 1N NaOH (5 mL, 5.00 mmol). The reaction was heated to 60° C. and stirred for 48 hr. LCMS showed that the reaction was complete. The reaction was concentrated to near dryness under vacuum, acidified with 1 N HCl (5 mL), triturated, filtered and washed with a small volume of water, and dried under vacuum to give the product 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylic acid (0.26 g, 0.911 mmol, 101% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br. s., 1H), 8.36 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.65 (s, 1H), 4.85 (quin, J=6.6 Hz, 1H), 2.36 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 286.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N)(=[S:18])C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[S:18])=[CH:10][N:9]=1
Reactant: CC(N)=S
Reactant: N#Cc1ccc(-c2ccccc2F)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=S)c1ccc(-c2ccccc2F)nc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A mixture of 6-(2-Fluoro-phenyl)-nicotinonitrile (9.8 g, 49.4 mmol) and thioacetamide (5.94 g, 79.1 mmol) in 4.0 M HCl in dioxane (200 mL) is heated at 100° C. for 3 days, cooled to room temperature. The raction mixture is poured into old saturated sodium bicarbonate and stirred for 30 min. Solid product is collected by filtration and dried under vacuum giving the title compound (11.4 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6](=O)[C:7]1C=CC=[C:9]([CH:10]=[O:11])[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[C:9]([CH:8]=[CH:7][CH:6]=1)[CH:10]=[O:11])=[CH2:4]
Reactant: O=Cc1cccc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (27.2 g) in THF (200 mL) at 0° was added dropwise n-butyllithium (47 mL of 1.6M in hexane). The reaction mixture was stirred 30 min at 0° and cooled to -10°. The reaction mixture at -10° was transferred dropwise through a canula to a solution of isophthalaldehyde (10.0 g) in THF (300 mL) at -50°. The reaction was allowed to warm up to room temperature. After 3.5 hours at room temperature the reaction mixture was quenched with NH4OAc buffer (200 mL). The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated. Flash chromatography of the residue starting with 10% and finishing with 15% of diethyl ether in hexane afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[O:25][C:24]([F:23])([F:34])[F:35])[CH:8]=2)[N:3]=1
Reactant: COc1ccccc1CN
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COc1ccccc1CNc1ccc2cc(NCc3ccccc3OC(F)(F)F)ccc2n1

Procedure:
The title compound, MS: m/e=454.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 2-(trifluoromethoxy)benzylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.C1(C)C=CC=CC=1>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in toluene (5.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 905 mg (72 %).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]3[N:11]([OH:14])[N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[H][H].I[CH3:22]>CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]3[N:11]([O:14][CH3:22])[N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CI
Reactant: On1nnc2cc(Cn3ccnc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COn1nnc2cc(Cn3ccnc3)ccc21
Yield: 64.3 %

Procedure:
To a stirred mixture of 4.5 parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol and 94 parts of N,N-dimethylformamide was added portionwise 1 part of a sodium hydride dispersion 50%. Upon complete addition, stirring was continued till hydrogen evolution had ceased. 1.3 Parts of iodomethane were added at once and stirring was continued at room temperature. The N,N-dimethylformamide formamide layer was evaporated and the residue was taken up in water and a mixture of trichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume). The product was extracted with a mixture of trichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume). The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel first using trichloromethane and then a mixture of trichloromethane and methanol (90:10 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 50° C., yielding 3.1 parts (64.3%) of 5-(1H-imidazol-1-ylmethyl)-1-methoxy-1H-benzotriazole; mp. 94.3° C. (compound 221).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:40])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:39])[CH:26]=2)[CH:21]=1.N1C=CC=CC=1.O>ClCCl>[CH3:16][O:17][C:18](=[O:40])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:36][CH:37]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:39])[CH:26]=2)[CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(O)cc2)c1C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Trifluoromethanesulfonic anhydride (2.6 mL, 15.0 mmol) was added drop-wise to a -6° C. solution of [6-fluoro-4-(4-hydroxy-benzyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (3.9 g, 11.5 mmol) and pyridine (1.4 mL, 17.4 mmol) in dichloromethane (100 mL). The reaction mixture was warmed to room temperature, and stirred for 1 hour. The reaction mixture was then cooled to 4° C. Water (20 mL) was added, and the organic layer was dried over MgSO4, filtered, and concentrated. A solution of this crude product in dichloromethane was concentrated over silica gel, and the resulting silica gel-supported product was subjected to flash chromatography (Analogix SuperFlash™ column, 5%-20% ethyl acetate in hexane) to give 3.8 g (70%) of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyloxy-benzyl)-naphthalen-2-yl]-acetic acid methyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.94 (dd, J=8.9, 6.2 Hz, 1 H), 7.79 (s, 1 H), 7.70 (dd, J=12.1, 1.8 Hz, 1 H), 7.37 (d, J=8.8 Hz, 2 H), 7.29-7.38 (m, 1 H), 7.20 (d, J=8.8 Hz, 2 H), 4.53 (s, 2 H), 3.94 (s, 2 H), 3.64 (s, 3 H), 2.29 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH:39]=O>>[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39][N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(F)c(F)c2)CC1
Yield: 13.5 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 3,4-difluoro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (10.4 mg, 13.5%) as light yellow oil. MS m/e=591.2 [M+H]+.