Azzindani/Open_Reaction_Data huggingface dataset:
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].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38](Cl)=[O:39]>>[Cl:34][C:35]1[CH:36]=[C:37]([C:38]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:39])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3cc(Cl)cc(Cl)c3)CC2)cc1

Procedure:
(3,5-Dichloro-phenyl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3,5-dichlorobenzoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.02-2.10 (m, 4H), 3.12-3.18 (m, 1H), 3.30 (methyl sulfonyl and water peak), 3.62-3.68 (m, 1H), 4.54-4.60 (m, 1H), 5.10-5.16 (m, 1H), 7.54-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.73 (m, 1H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=546, M+Na=478.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:10]=[CH:11][C:12]([NH:14][NH2:15])=[O:13])([CH3:6])[CH3:5].[C:24](=S)=[S:25]>C(O)C>[CH3:21][C:20]([C:17]1[CH:16]=[C:9]([CH:10]=[CH:11][C:12]2[O:13][C:24](=[S:25])[NH:15][N:14]=2)[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:18]=1[OH:19])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Potassium hydroxide (0.5 g, 0.0096 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid hydrazide (2.8 g, 0.0096 mole) and carbon disulfide (1.7 g, 0.022 mole) in absolute ethanol (15.0 ml). The resulting mixture is stirred 1.5 hours at 0° C. before heating to reflux for four hours. The solution is cooled and the solvent is removed in vacuo. The residue is dissolved in water (50 ml) and washed with ether (20 ml). The aqueous layer is made acidic with aqueous 2M HCl and the product extracted with a 1:1 mixture of ethyl acetate/ether. The combined organic extracts are washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/hexane to give 1.4 g (3.2 g theor., 44%) desired product, mp 209.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]1[CH:12]([CH3:14])[S:13][C:9]1=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].[OH-].[K+].C(O)(C)(C)C.Cl>O>[Cl:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]2)=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]1[CH:12]([CH3:14])[S:13][C:9]1=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:20]
Reactant: CCOC(=O)c1c2n(c3c(Cl)c(N4CC[C@H](N(C)C)C4)c(F)cc3c1=O)C(C)S2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N(C)C)C4)c(Cl)c3n21
Temperature: 60 °C
Yield: 60.7 %

Procedure:
A mixture of 0.44 g of ethyl 8-chloro-7-((S)-3-dimethylamino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 0.33 g of 85% potassium hydroxide, 2.0 ml of tert-butanol and 6.0 ml of water was heated at 60° C. for 1 hour with stirring. After cooling, the reaction mixture was neutralized with 10% hydrochloric acid, and evaporated. To the residue, water was added and the residue was extracted with chloroform. The extract was dried and acidified with ethanolic hydrochloride. The solution was evaporated and to the residue was added small amount of methanol. The precipitate was collected by filtration and dissolved with water. The solution was neutralized with 10% aqueous sodium hydroxide and extracted with chloroform. The extract was dried, evaporated and recrystallized from a mixture of chloroform and iso-propanol to give 0.25 g of the desired compound as pale yellow crystals, m.p. 161°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: Clc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -10 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A chlorobenzene solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 g, 12.40 mmol) was cooled to −10° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 45 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and triethylamine (4.18 g, 41.31 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −10° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.92 g of the title compound (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH2:28])=[N:9]1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH:28][C:35]([C@H:32]2[CH2:31][C:30](=[O:29])[NH:34][CH2:33]2)=[O:36])=[N:9]1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2F)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2F)c1)C(F)(F)F
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared in Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29]C)=O)=[CH:4][C:3]=1[CH3:33].[OH-].[Na+].ClC(OCC)=O.CCN(CC)CC>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[C@@H:23]2[O:32][C:27](=[O:29])[CH2:26][C@@H:25]([OH:31])[CH2:24]2)=[CH:4][C:3]=1[CH3:33]
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(N2CCCC2)CC1(C)C
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(N3CCCC3)C2)ccc1F

Procedure:
In a manner similar to Scheme I, 34 (0.19 g) was treated with 2N NaOH in methanol at 0°-5° C. for 18 h, followed by ethyl chloroformate (0.254 mmol) and Et3N in CH2Cl2 at 0°-5° C. Workup and purification of the residue by SiO2 using 1% Et3N in EtOAc as eluent yielded the product. mp 120°-3° C. Anal. C26H34FNO3 ·0.5 H2O: Theory C: 71,53; H: 8.08; N: 3.21; Found C: 71.60; H: 8.17; N: 3.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1csc(C(=O)O)c1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
To a solution of methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.3 g, 1.1 mmol) in THF/H2O (5 mL/0.5 mL) was added KOH (0.2 g, 3.4 mmol). The reaction mixture was heated to 50° C. for 4 h and then concentrated and diluted with H2O (2 mL). The pH was adjusted to 3 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (260 mg) which was used directly without further purification. LC-MS (ES) m/z=256 (M+H)+.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].COC1C=CC=C[N:17]=1>>[C:8]1([C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][N:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCCCCC
Reactant: COc1ccccn1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (58.5 mg, 0.0847 mmol), tridecane (345 mg, 1.875 mmol, as an internal standard), and 2-methoxypyridine (343 mg, 3.146 mmol). The Grignard reagent (1 M in THF, 6.2 mmol) was added to the above catalyst mixture under a nitrogen atmosphere at 0° C. The resulting solution was stirred for several minutes and warmed to room temperature for 15 hours. The reaction mixture was quenched with an aqueous sodium citrate solution (1 M). The resulting aqueous solution was extracted with MTBE (4×25 mL). The combined organic layer was washed with an aqueous HCl solution (2.5 M, 4×15 mL). The aqueous layer was then extracted with MTBE (1×25 mL). This solution was cooled to 0° C. and a dilute aqueous KOH solution was added until pH 8. The aqueous layer was extracted with MTBE (4×25 mL) and dried over MgSO4. The resulting solution was filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluted with MTBE) to afford 2-phenylpyridine (368 mg, 75% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:44]1[N:45]=[C:46]([NH:49]C=O)[S:47][CH:48]=1)[C:21]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.Cl>CO>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:21]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([OH:7])=[O:5]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3ccccc3C(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: COc1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3ccccc3C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 10 °C
Yield: 45 %

Procedure:
7-[2-{N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g.) was added to a mixture of trifluoroacetic acid (7 ml.) and anisole (0.35 ml.) with stirring at about 10° C., followed by stirring for 1.5 hours at 5° to 10° C. and for an additional 15 minutes at room temperature. After concentration of the reaction mixture, to the residue were added methanol (30 ml.) and conc. hydrochloric acid (2.33 ml.). The resulting mixture was stirred for 1.5 hours at room temperature and concentrated and then the residue was shaken with a mixture of an aqueous solution of sodium bicarbonate and ethyl acetate. The aqueous layer (pH 7 to 8) was separated and thereto was added ethyl acetate and 10% hydrochloric acid with stirring whereby the pH was adjusted to 2 to 3. The resulting precipitates were filtered and redissolved in an aqueous solution of sodium bicarbonate. To the aqueous solution (150 ml.) was added ethyl acetate (300 ml.) and the mixture was acidified to pH 2 to 3 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried and then concentrated. The residue was washed with diethyl ether to give the title compound (0.8 g.). mp. 220° to 230° C. (dec.)
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Mg+2].[Br-]>O1CCOCC1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 120 °C
Yield: 95.1 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.04 g, 19.87 mmol, 1.15 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in 1,4-dioxane (70 mL) respectively, then heated to 120° C. and magnesium bromide (0.22 g, 1.21 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.94 g, yield: 95.1%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: Fc1cccc(F)c1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1c(F)cccc1F)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
2,6-difluorobenzyl bromide (3.0 g, 14.5 mmol) was combined with triethylphosphite (6.2 mL, 36.2 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 80° C. for 10 hours. The final product was a slightly yellow-tinted oil (3.30 g, 86% yield). 1H NMR (400.14 MHz, DMSO) δ 7.36 (m), 7.10 (m, 2H), 3.96 (m, 4H), 3.20 (d, J=21.08 Hz, 2H), 1.16 (t, J=7.05 Hz, 6H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 161.0 (ddd, J=249.0, 7.3, 6.2 Hz, 2C), 128.4 (dt, J=10.2, 3.82 Hz), 111.0 (ddd, J=18.9, 6.0, 3.5 Hz, 2C), 108.5 (dt, J=19.8, 10.5 Hz), 62.1 (d, J=6.5 Hz, 2C), 20.6 (dt, J=142.1, 2.3 Hz), 16.0 (d, J=6.2 Hz, 2C). 31P {1H} NMR (161.97 MHz, DMSO): δ 24.68. Analysis calculated (found) %: C 50.01 (49.71), H 5.72 (5.78). MS (FAB, m/z): 265 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 265.08051 (265.08278).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
To a solution of ethyl 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (5.6 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (31.1 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, 1N hydrochloric acid (32 mL) was added, and the precipitated crystals were filtered and concentrated under reduced pressure to give the title compound (5.2 g, yield 100%) as white crystals.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:43])[CH3:42])=[N:39][N:40]=2)[N:37]=1>C1COCC1.C(Cl)Cl>[Br:1][CH:31]([C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:42])[CH3:43])=[N:39][N:40]=2)[N:37]=1)[C:30]([C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[F:22])=[O:44]
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Pyridinium tribromide (0.567 g, 1.77 mmol) was added to a solution of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.488 g, 1.54 mmol; Preparation #K.1) in THF (6 mL) and the resulting reaction mixture was stirred at ambient temperature for about 4 h. The crude mixture was diluted with DCM (20 mL) and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.61 g, 100%): LC/MS (Table 1, Method a) Rt=3.28 min; MS m/z: 396.9 (M+H)+.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[O:38]1[CH2:43][CH2:42][N:41]([C:44]2[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:47]4[CH:48]=[N:49][C:44]([N:41]5[CH2:42][CH2:43][O:38][CH2:39][CH2:40]5)=[CH:45][CH:46]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(N3CCOCC3)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (6-morpholinopyridin-3-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=583, obsd.=583).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8](C)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.CI.[CH2:22](I)[CH3:23]>>[CH3:19][N:2]([CH3:1])[C:3](=[O:18])[C:4]([CH3:17])([C:23]1[CH:22]=[CH:9][CH:8]=[CH:7][CH:11]=1)[N:5]1[CH:9]=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6]1
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Reactant: CCI
Solvent: CI
Product: CN(C)C(=O)C(C)(c1ccccc1)n1ccc(-c2ccccc2)n1

Procedure:
Following the procedure of Example 95, but substituting N,N-dimethyl-α,3-diphenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and methyl iodide for ethyl iodide, there is obtained N,N,α-trimethyl-α,3-diphenylpyrazole-1-acetamide, m.p. 129°-131.5° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20](=[O:22])=[O:21]>O1CCCC1.CCCCCC.O>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C=O
Reactant: Fc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(O)c1ccncc1F

Procedure:
While a mixture of 3.54 g of diisopropylamine and 50 ml of tetrahydrofuran was cooled in a dry ice-acetone bath, 20 ml of 1.6 M hexane solution of n-butyllithium was added while stirring so that the temperature of the reaction mixture did not exceed −40° C. Thereafter, the reaction mixture was stirred for 30 minutes. Then, a mixture of 2.91 g of 3-fluoropyridine and 3 ml of tetrahydrofuran was added so that the temperature of the reaction mixture did not exceed −60° C. The mixture was further stirred for 30 minutes. After crushed dry ice was added to the reaction mixture, cooling was stopped. Then, the reaction mixture was stirred until the temperature returned to room temperature. Water was added to the reaction mixture, and most part of hexane and tetrahydrofuran was removed under reduced pressure. The residue was washed with tert-butyl methyl ether, and the aqueous layers were collected. To the collected aqueous layer, concentrated hydrochloric acid was added while ice-cooling, and pH of the mixture was made to be 3 and stirred for one hour. Precipitates were collected by filtration and dried under reduced pressure to give 3.59 g of 3-fluoroisonicotinic acid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].O>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:13]1[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCOC(=O)c1cccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A 40 ml of 2.5 M solution of n-butyllithium in hexane was transferred under argon dropwise to a solution of 14 ml of diisopropylamine in 200 ml of anhydrous THF at −20° C. over 10 minutes. The solution was stirred at −20° C. for 3 hours and at 0° C. for fifteen minutes to form a lithium diisopropylamide (LDA) solution. The LDA solution was then cooled to −78° C. and a solution of 15.65 g ethyl thiophene-2-carboxylate in 25 ml THF was added dropwise. After the solution thus obtained was stirred for 1 hour at −78° C., 30 ml of tributyltin chloride in 25 ml of THF was added dropwise. The reaction was then stirred at −78° C. for another hour and at room temperature overnight. After 200 ml of water was slowly added, the organic layer was collected, dried with Na2SO4, and concentrated and then vacuum distilled at about 650 mTorr. The fraction between 162-165° C. was collected to give 26.71 g (60.0%) of the desired product as a light yellow liquid, whose chemical structure was confirmed by NMR spectroscopy.