Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[CH:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCCC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a degassed (Ar) solution of 1-iodo-3-trifluoromethoxy-benzene (0.54 ml, 3 mmol) in acetonitrile (30 ml) was added pent-4-ynoic acid benzyl ester (719 mg, 4 mmol; A. Rosowsky, R. A. Forsch, F. S. Queener, J. Med. Chem. 2003, 46, 1726-1736), PdCl2(Ph3P)2 (122 mg, 0.17 mmol), cuprous iodide (33 mg, 0.17 mmol) and triethylamine (1.45 ml, 10 mmol). The reaction mixture was stirred for 2.5 h at ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 1.13 g (3.2 mmol, 93%) of the title compound as yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:9](O)(=O)[C:10](C)([CH3:12])[CH3:11].[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>[N+]([O-])([O-])=O.[Ag+]>[C:10]([C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: N#Cc1cnccn1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Product: CC(C)(C)c1cnc(C#N)cn1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To an aqueous (1.5 L) solution of 2-cyanopyrazine (60 g), pivalic acid (56 mL) and ammonium peroxodisulfate (100 g) were added, then silver nitrate (146 g) was added, and the resultant was stirred at 80° C. for 2.5 hours. The reaction solution was extracted with ethyl acetate. Ethyl acetate was further added to the extract, and the suspension was filtered. Saturated saline was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→50/50) to obtain the title compound (54 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22](ON2C(=O)CCC2=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(#N)C.O>[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Reactant: NC1(C(=O)O)CC1
Solvent: CC#N
Solvent: O
Product: CC(C)C(OC(=O)NC1(C(=O)O)CC1)OC(=O)C1CCCCC1
Yield: 25.6 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.533 g, 5.27 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl cyclohexanecarboxylate (1.5 g, 4.39 mmol) were reacted in the acetonitrile/water mixture to provide 0.368 g (27% yield) of the title compound (11) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 156-158.5° C. 1H NMR (CDCl3, 400 MHz): δ=6.59 (d, 1H), 6.05 (br s, 0.3H), 5.41 (s, 0.7H), 2.38 (m, 1H), 2.13 (m, 1H), 1.96 (d, 2H), 1.78 (m, 2H), 1.6 (m, 3H), 1.44 (m, 2H), 1.23 (m, 5H), 0.99 (m, 6H). MS (ESI) m/z 350.05 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:40][C:39]5[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-(trifluoromethyl)benzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 2H), 2.20-2.33 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.66 (s, 2H), 4.77-4.83 (m, 1H), 7.58-7.64 (m, 4H), 7.70-7.72 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=532.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][CH3:31])[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][CH3:31])[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCN(CC)c1cccc2ccccc12
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCN(CCCc1c(C(=O)O)[nH]c2c(-c3ccccc3Cl)cccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of EXAMPLE 531B (192 mg) and 2-chlorophenylboronic acid (76 mg) in tetrahydrofuran (6 ml) was added tris(dibenzylideneacetone)dipalladium(0) (19 mg), tri-t-butyl-phosphonium tetrafluoroborate (12 mg) and cesium fluoride (200 mg). The mixture was purged with argon and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water, and brine and dried over Na2SO4. Concentration of the mixture and column purification of the crude material (5% ethyl acetate in hexane) provided the title compound. A portion of this material (50 mg) was dissolved in 1:1 tetrahydrofuran/methanol with a few drops of water and hydrolyzed with LiOH. Subsequent purification via RP HPLC afforded the title compound. 1H NMR (300 MHz, DMSO-d6) 10.80 (m, 1H), 8.27 (m, 1H), 7.90 (m, 1H), 7.55 (m, 1H), 7.53 (m, 1H), 7.42 (m, 3H), 7.34 (m, 3H), 7.21 (m, 2H), 7.03 (m, 1H), 6.98 (m, 2H), 3.21 (m, 4H), 3.08 (t, 2H), 1.79 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([F:18])[C:11]([F:17])=[CH:12][CH:13]=2)[C:8]=1[F:19])(=O)=O.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCCC1>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([F:18])[C:11]([F:17])=[CH:12][CH:13]=3)[C:8]=2[F:19])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: O=S(=O)(Oc1ccc2ccc(F)c(F)c2c1F)C(F)(F)F
Reactant: CCCc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc3ccc(F)c(F)c3c2F)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
1,7,8-Trifluoronaphthalene-2-yl trifluoromethanesulfonate (15 g), 4-propylphenylboric acid (11.2 g), potassium carbonate (18.8 g), tetrakis(triphenylphosphine)palladium(0) (1 g), toluene (50 ml), tetrahydrofuran (50 ml), and water (20 ml) were added in an autoclave and stirred for 4 hours at 90° C. under pressurized nitrogen (2 kg/cm2). The reaction solution was poured into water. The organic layer was removed, and the aqueous layer was extracted with toluene. The organic layers were combined, washed with 10% hydrochloric acid and brine, and concentrated. The residue was purified by column chromatography (silica gel, hexane), and 2-(4-propylphenyl)-1,7,8-trifluoronaphthalene was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O.C1COCC1>[CH2:31]([O:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]2[CH:12]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: Oc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 25 °C
Yield: 58 %

Procedure:
2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-ol (Example 24. 0.5 g, 1.63 mmol) was dissolved in dimethylformamide (10 mL) and potassium tert butoxide (2.5 mL of a 1 M solution in THF, 2.5 mmol) was added dropwise to the stirred solution. After 10 minutes iodobutane (2 mmol) was added and the reaction stirred at room temperature. Second additions of iodobutane (0.88 mmol) and 1M potassium tertbutoxide (2.5 mL, 1 mmol) were made after 4 h and reaction stirred further until complete by TLC. Water (100 mL) was added and the resulting aqueous solution was extracted with with dichloromethane (4×100 mL), the combined organic solution was dried (MgSO4), filtered and concentrated to give the crude product. This was purified either by silica gel chromatography to give the title compound (58%). 1H NMR (d6-DMSO) δ 0.93 (t, J=7.3 Hz, 3H), 1.43 (quintet, J=7.3 Hz, 2H), 1.74 (quintet, J=7.3 Hz, 2H), 4.13 (t, J=6.9 Hz, 2H), 6.84 (dd, J=2.4, 7.5 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.53 (dd, J=0.5, 8.8 Hz, 2H), 7.73 (d, J=6.4 Hz, 2H), 8.65 (d, J=6.4 Hz, 2H), 8.74 (d, J 7.5 Hz, 1H); APESI-MS m/z 362 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([CH:15]([OH:21])[C:16](=[NH:20])[O:17]CC)[CH:14]=1.[O:25]1CCC[CH2:26]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([CH:15]2[O:21][C:26](=[O:25])[NH:17][C:16]2=[O:20])[CH:14]=1
Reactant: CCOC(=N)C(O)c1cc(Cl)ccc1OCC
Reactant: C1CCOC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cl)cc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
By the procedure of Example 54, but using only 2.3 equivalents of triethylamine, ethyl 1-(5-chloro-2-ethoxyphenyl)-1-hydroxymethanecarboximidate (8.0 g., 0.029 mole) in 300 ml. of tetrahydrofuran was reacted with phosgene. After stirring for 2 hours at room temperature, isolation was also according to Example 54, substituting chloroform for ethyl acetate, resulting in toluene recrystallized 5-(5-chloro-2-ethoxyphenyl)oxazolidine-2,4-dione (2.7 g., m.p. 197°-199° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].B.C(O)(=O)C.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cccc1F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A stirred solution of 25.0 g (0.158 mole) of 2,6-difluorobenzoic acid in 300 ml of diethyl ether was purged with nitrogen, and 20 ml of a 1 molar solution of borane in tetrahydrofuran was carefully added dropwise. The addition caused the reaction mixture to effervesce. When vigorous effervescence subsided, the reaction mixture was heated to reflux and an additional 170 ml of a 1 molar solution of borane (0.190 mole total) in tetrahydrofuran was added dropwise at a rate just sufficient to promote gentle reflux. Upon complete addition the reaction mixture was heated under reflux for an additional 1 hour, allowed to cool to ambient temperature and stand for 16 hours, then heated under reflux again for 1 hour. Acetic acid (11 ml, 0.19 mole) was added, then the reaction mixture was cooled in an ice-water bath and 100 ml of a saturated aqueous solution of ammonium chloride was added slowly. Upon complete addition the reaction mixture was stirred for 0.5 hour, then concentrated under reduced pressure to give a pasty residue. Diethyl ether was added and the mixture was washed with three portions of water, two portions of aqueous 10% sodium carbonate, two portions of water, and one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 18.9 g of (2,6-difluorophenyl)methanol as a yellow oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:12]=[C:11]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:16]=2)[OH:14])[C:10]2[C:5](=[C:6]([C:30]([F:33])([F:32])[F:31])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:12]=[C:11]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)[OH:14])[C:10]2[C:5](=[C:6]([C:30]([F:33])([F:32])[F:31])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(O)c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(C(O)c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)c1
Reaction time: 0.25 h
Yield: 24.9 %

Procedure:
A solution of 2,8-bis(trifluoromethyl)-α-(3-tert-butyldimethylsilyloxymethylphenyl)-4-quinolinemethanol (crude, 1.17 mmol) in THF (5 mL) was treated with tetrabutylammonium fluoride (1-M in UHF, 0.7 mL, 0.7 mmol), stirred for 15 min, washed with water (2×2 mL), concentrated in vacuo and the resulting oil purified by chromatography [SiO2; heptane-EtOAc (3:1-1:1)] to give the title compound (117 mg, 25%) as a white solid: mp 152-154° C.; IR νmax (Nujol)/cm−1 3359, 3206, 2924, 1458, 1378, 1308, 1184, 1155, 1136, 1115, 1083, 1032, 766 and 695; NMR δH (400 MHz, CDCl3) 3.05 (1H, br s), 6.63 (2H, s), 6.48 (1H, s), 7.10-7.40 (4H, m), 7.68 (1H, m), 8.05-8.15 (2H, m), and 8.21 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:5]2[C:4](C)(C)[C:3]1=[O:16].CN1C2=NC=C(Br)C=C2CC1=O>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:5]2[CH2:4][C:3]1=[O:16]
Reactant: CC(=O)c1cnc2c(c1)C(C)(C)C(=O)N2C
Agent: CN1C(=O)Cc2cc(Br)cnc21
Product: CC(=O)c1cnc2c(c1)CC(=O)N2C
Yield: 84 %

Procedure:
By proceeding in the same manner as for the synthesis of the compound of Example 12, but replacing the 1,3-dihydro-1,3,3-trimethyl-5-bromo-2H-pyrrolo[2,3-b]pyridin-2-one with 1,3-dihydro-1-methyl-5-bromo-2H-pyrrolo[2,3-b]pyridin-2-one, the title compound is obtained in a yield of 84%. ##STR60##
Reaction SMILES: [F:1][CH:2]([C:7]([F:10])([F:9])[F:8])[C:3]([O:5][CH3:6])=[O:4].FC(F)(F)S([O-])(=O)=O.C([B+]CCCC)CCC.C(N(C(C)C)CC)(C)C.[C:37](OCC)(=[O:39])C>ClCCl>[OH:39][CH2:37][C:2]([F:1])([C:7]([F:10])([F:9])[F:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)C(F)(F)F
Reactant: CCOC(C)=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(F)(CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl 2,3,3,3-tetrafluoropropanoate (27.0 g) was dissolved in dry dichloromethane and the solution stirred under a dry nitrogen atmosphere at 0° C. A one molar solution of di-n-butylboron trifluoromethanesulfonate in dichloromethane (190 ml) was added in portions over 15 minutes. After a further 15 minutes, the temperature was reduced to -10° C. and di-isopropylethylamine (35 ml) was added in portions, then stirring was continued for a further 2 hours. Paraformaldehyde (100 g) (previously dried under vacuum over P2 O5) was heated to 180°-200° C. and the resulting formaldehyde was passed into the reaction mixture in a stream of dry nitrogen, keeping the temperature close to -10° C. After 30 minutes, the mixture was poured into a mixture of 30% aqueous hydrogen peroxide (150 ml) pH7 phosphate buffer (600 ml) and crushed ice, and was stirred at 0° C. for 45 minutes. The mixture was extracted with dichloromethane (3×200 ml). The combined extracts were washed with sodium disulphite solution, dried (MgSO4) and concentrated under reduced pressure to leave a yellow oil, which was redissolved in ethyl acetate and filtered through a thick plug of silica gel, and then was again concentrated under reduced pressure. The crude product was purified by chromatography on silica, eluting with 25% ethyl acetate in hexane. Subsequent heating to 65° C. under aspirator vacuum (20 mmHg) gave the product as a yellow oil (4.8 g); 1H NMR (270 MHz; CDCl3) δ 3.93(3H,s), 4.05-4.30(2H,m), 2.80(1H,bt) ppm.
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:13]=2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1nc(-c2ccncc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccc1)c1nc(-c2ccncc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1-phenyl-1-[4-(4-pyridyl)-2-thiazolyl]methanone (675 mg, 0.0025 mol) in methanol (40 mL) was added sodium borohydride (300 mg, 0.0079 mol) in portions and the mixture allowed to stir at room temperature for one hour. The reaction mixture was concentrated, diluted with water, and extracted with ether (3×25 mL). The combined extracts were washed with brine, dried over magnesium sulfate, concentrated, and chromatographed. Recrystallization from hexane/ethyl acetate afforded 1-phenyl-1-[4-(4-pyridyl)-2-thiazolyl)methanol (300 mg, 45%). mp. 146°-147° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:4].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[NH:7][C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 77.5 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.147 mmol) in methanol (1.5 mL) was added 1 M NaOH (1.47 mL, 1.47 mmol). The reaction mixture was stirred at 75-80° C. for 2 days. The reaction mixture was diluted with H2O and the pH was adjusted with 1 M HCl until 1-2. The reaction mixture was diluted with EtOAc and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated with diethyl ether/dichloromethane and the resulting solid was collected and dried under vacuum to yield 0.033 g (69%) pure desired product as a yellow solid. MS ESI (+) m/z 327, 329 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 13.1 (br s, 1H), 11.5 (s, 1H), 10.9 (s, 1H), 8.77 (br s, 1H), 8.10 (d, 1H), 7.59 (d, 1H), 7.35 (d, 1H) 6.16 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:12](=[O:13])([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[O:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-nitrophenol (1.00 g) in dichloromethane (20 ml) were added dropwise ethyl chloroformate (0.70 ml) and pyridine (0.70 ml) under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. To the residue obtained was added ethyl acetate, and the organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, a saturated aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residual solid obtained was collected by filtration using hexane to afford ethyl 4-nitrophenyl carbonate (1.44 g, yield: 95%) as a white solid.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([NH2:10])[C:4]=1[CH3:11].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl-:1].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:2][N+:3]2[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([N:10]=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:13]([CH3:22])[CH3:12])=[CH:15][CH:16]=3)[C:4]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: Cc1n(N)c(CO)c[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)c(CO)c[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
0.89 g (5 mmol) of 1,3-diamino-4-(hydroxymethyl)-2-methylimidazolium chloride and 1.49 g (10 mmol) of 4-dimethylaminobenzaldehyde are dissolved in 20 ml of glacial acetic acid. After 22 hours the precipitated product is filtered off and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-4-(hydroxymethyl)-2-methylimidazolium chloride of melting point 237° (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCNCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (820 mg, 90%) as a white solid: LC/MS m/e calcd for C22H27N3O2 (M+H)+: 366.48, observed: 366.0.