Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC=CCCCC(CCC/C=C\CCCCC)C(CCCC=CCCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (0.4 g, 0.9 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.2 g, 1.3 mmol), EDCI hydrochloride (0.25 g, 1.3 mmol), diisopropylethylamine (0.4 mL, 2.6 mmol) in anhydrous dichloromethane (10 mL) was added dimethylaminopyridine (5 mg). The solution was refluxed for 2 hours then stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to dryness and purified by column chromatography (100% ethyl acetate) to afford 6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 4-(dimethylamino)butanoate 9 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.30 (m, 4H), 2.22 (s, 6H), 2.03 (m, 12H), 1.88 (m, 2H), 1.66-1.18 (m, 31H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:25]2[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[C:26]=2[CH:27]=[N:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[C:25]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[C:26]=3[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3cc(Cl)c4c(c3)CCC(=O)N4C)cncc21
Yield: 65 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-8) and (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) were used to give the title compound as a white powder in 65% yield. MS: 384.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:12][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C1COCC1>>[F:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[OH:1]
Reactant: Oc1cc2ccccc2cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Product: Oc1ncc2ccccc2c1F
Temperature: 25 °C
Reaction time: 408 h

Procedure:
A mixture of 3-hydroxyisoquinoline (84.3 mg, 0.581 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (236 mg, 0.666 mmol) in THF (6.0 mL, 74 mmol) was stirred at ambient temperature for 17 d. More 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (25 mg, 0.070 mmol) was added, and the reaction mixture was heated to 50° C. for 1d. Solid material was filtered off and rinsed with THF. The filtrate was diluted with DCM (≈75 mL), washed with water (2×) and brine, dried over MgSO4, filtered, and dried in vacuo overnight. One obtained the title compound as yellow solid. It was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=11.54 (brs, 1H), 8.75 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H). MS(ES+): m/z=164.03 (100) [MH+]. HPLC: tR=2.2 min (polar—5 min, ZQ3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ncnc(N2CCNCC2)n1
Temperature: 40 °C

Procedure:
A solution of 1 mmol of 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dichloromethane was chilled and treated with 14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40° C. for 30 min. After cooling, 50 ml of 2M aqueous sodium hydroxide is added. The organic layer is separated, dried and concentrated to yield the title compound as a yellowish oil. MS (m/e): 267.0 (M+CH3COO+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[N:14]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]=3)O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[N:14]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:17]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2Cc2c[nH]c3ncc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a quartz vial, (5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-methanol (148, 0.328 g, 0.506 mmol) was combined with 20 mL of dichloromethane, triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred overnight at room temperature, then concentrated under vacuum and ethyl acetate was added. This was washed with 1 M aqueous potassium carbonate and brine, dried with sodium sulfate, and purified by silica gel column chromatography, eluting with 2-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the solid further washed with ethyl acetate and hexane to provide the desired compound. 1H NMR was consistent with compound structure.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>>[C:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CCOC(=O)OCC
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)OCC

Procedure:
260 g (1 mol) of a technical grade oleyl alcohol were reacted with 118 g (1 mol) of diethyl carbonate in the same way as described under A. The title compound was obtained in a yield of approximately 370 g in the form of a light yellow, clear liquid having an OH value of 8.5, an acid value of 0.1, an iodine value of 76 and a number average molecular weight of 333.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1.[Cl:21][S:22](O)(=[O:24])=[O:23]>>[Cl:1][C:2]1[C:7]([S:22]([Cl:21])(=[O:24])=[O:23])=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Reactant: O=S(=O)(O)Cl
Product: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
2.9 g (9.5 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 70 g of chlorosulfonic acid, followed by heating and stirring at 100° C. for 5 hours. After cooling, the mixture was gradually dropwise added to ice water, followed by extraction with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 3.3 g (yield: 86%) of the desired product. Melting point: 77-78° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:24]=3[CH3:25])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (0.67 g) in N,N-dimethylformamide (8 ml) at 5° C. was added sodium hydride (60% in mineral oil, 0.16 g). The mixture was stirred at 5° C. for 40 minutes and then at room temperature for 15 minutes and again cooled to 5° C. 4-Chloromethyl-5-methyl-1-trityl-1H-imidazole (1.50 g) was added to the solution in small portions over two minutes. After being stirred at 5° C. for 2 hours, the reaction mixture was diluted with chilled water to give precipitates. The precipitates collected were dissolved in dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Column chromatography (silica, gel, 0.5% methanol in chloroform as an eluent) of the residue, followed by recrystallization from toluene-hexane, gave 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1 (2H)-one (1.16 g).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([NH:53][C:54](=[O:62])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])[CH2:17][C:18]([C:38]1[O:39][CH:40]=[CH:41][C:42](=[O:52])[C:43]=1[O:44]CC1C=CC=CC=1)([C:23]1[O:24][CH:25]=[CH:26][C:27](=[O:37])[C:28]=1[O:29]CC1C=CC=CC=1)[NH:19][C:20]([OH:22])=[O:21])C1C=CC=CC=1>C(O)(=O)C.Cl>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([NH:53][C:54](=[O:62])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])[CH2:17][C:18]([C:23]1[O:24][CH:25]=[CH:26][C:27](=[O:37])[C:28]=1[OH:29])([C:38]1[O:39][CH:40]=[CH:41][C:42](=[O:52])[C:43]=1[OH:44])[NH:19][C:20]([OH:22])=[O:21]
Reactant: Cc1ccccc1C(=O)NC(CC(NC(=O)O)(c1occc(=O)c1OCc1ccccc1)c1occc(=O)c1OCc1ccccc1)c1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)NC(CC(NC(=O)O)(c1occc(=O)c1O)c1occc(=O)c1O)c1occc(=O)c1O
Yield: 114.7 %

Procedure:
A solution of 4c (0.20 g, 0.20 mmol) in glacial acetic acid (2 ml) and concentrated hydrochloric acid (2 ml) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the residue azeotroped several times with methanol (10 ml) to afford the title compound 6 (130 mg, 90%) as a red-orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][C:27](Cl)=[S:28]>CC(C)=O>[CH3:9][N:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[C:27](=[S:28])[O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: CNc1cccc(C)n1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a mixture of 1.22 g of 6-methyl-2-methylaminopyridine and 1.38 g of anhydrous potassium carbonate in 20 ml of acetone was added dropwise 2.23 g of 2-naphthylchlorothioformate in 20 ml of acetone under agitation at room temperature. The reaction mixture was stirred overnight at room temperature and inorganic salts were removed by filtration. After acetone was removed by distillation under a reduced pressure, the residue was purified by the column chromatography (silica gel, developed with ethyl acetate/benzene=1/9 (V/V), to obtain 2.62 g of O-2-naphthyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate as a solid in a yield of 85%. A portion of the product was recrystallized from ethanol to give colorless crystals having a melting point of 149.5° C.-150.5° C. Elemental analysis of the crystals is given below.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([Cl:25])[C:18]=2[Cl:26])=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13].O>ClCCl>[Cl:5][C:6]1[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:25])[C:18]=2[Cl:26])=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:13])[F:14]
Reactant: COc1ccc(Cc2nn(C)c(OC(F)F)c2Cl)c(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1nc(Cc2ccc(O)c(Cl)c2Cl)c(Cl)c1OC(F)F
Temperature: 20 °C
Reaction time: 72 h

Procedure:
18.1 ml (18 mmol) of a 1-molar solution of boron tribromide in dichloromethane were added to a solution of 3.37 g (9 mmol) of 4-chloro-3-(2,3-dichloro-4-methoxybenzyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 45 ml of dichloromethane which had been cooled to (−78)° C. After 3 days of stirring at approximately 20° C., the mixture was admixed with 100 ml of water. The undissolved fraction was subsequently filtered off and washed with 100 ml of dichloromethane. The aqueous phase was extracted again with 100 ml of dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and subsequently concentrated. Yield: 1.1 g; m.p.: 127—128° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(F)cc2)n1
Yield: 30.3 %

Procedure:
A stirred mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 4.4 g of p-fluoroaniline and 4.2 g of sodium carbonate was heated under reflux for 6 hr. and filtered. Water was added to the filtrate to the precipitation point. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 4.1 g of product; mp. 97°-102°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[N:28][CH:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:27]=[N:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: N#Cc1cncc(Cl)n1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.6 g, 6.4 mmol) in anhydrous DMF (15 mL) was added cesium carbonate (5.2 g, 16.0 mmol) and 6-chloro-pyrazine-2-carbonitrile (0.89 g, 6.4 mmol). The resulting mixture was stirred at room temperature overnight then quenched with crushed ice. The pH was adjusted to 2 with 6M HCl and the mixture extracted with EtOAc (2×200 mL). The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-75% EtOAc in hexane) to give 6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.6 g, 71%). 1H NMR 400 MHz (DMSO-d6) δ 9.30 (s, 1H), 8.93 (s, 1H), 8.90 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 5.58 (m, 1H), 4.05 (q, J=7.2, 2H), 3.17 (m, 1H), 2.40 (m, 1H), 2.33 (s, 3H), 1.13 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:14]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1
Yield: 62 %

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 3-trifluoromethyl-phenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 62% yield as a pale-yellow viscous oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:8][CH3:7]
Reactant: CC(C)(C)[O-]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(CC)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (3.53 g, 9.89 mmol) in THF (30 ml) was added potassium tert-butoxide (1.11 g, 9.89 mmol) in THF (10 ml) dropwise at 0° C. and the mixture was stirred at ambient temperature for 2 hours. Then, to this mixture was added 4-(trifluoromethyl)propiophenone (Aldrich, 1.00 g, 4.95 mmol) in THF (10 ml) at 0° C. and stirred at ambient temperature for 2 hours. The reaction was quenched with small amount of water and evaporated to remove the solvent. The crude mixture was diluted with hexane. The formed precipitates were filtered and the organic layer was separated. After evaporation of solvent, residue was applied to a silica gel chromatography column and eluted with hexane to afford 1.12 g (crude 100%) of the title compound as a red oil.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: CCCCO
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 93 μL of 1-ethylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1.[CH2:25]([O:29][C:30]1[CH:31]=[C:32]([C:40]2[NH:44][C:43](=[O:45])[C:42]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[N:41]=2)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:26][CH:27]=[CH2:28]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19]([N:48]2[CH2:49][CH2:50][C:42]3([N:41]=[C:40]([C:32]4[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([O:29][CH2:25][CH2:26][CH:27]=[CH2:28])[CH:31]=4)[NH:44][C:43]3=[O:45])[CH2:46][CH2:47]2)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1
Reactant: C=CCCOc1cc(C2=NC3(CCNCC3)C(=O)N2)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCS(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Triethylamine (1.27 ml, 9.11 mmol) and 4-(2-chlorosulfonyl-ethyl)-3-methyl-benzoic acid methyl ester (1.01 g, 3.65 mmol) were added to a solution of 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (1.40 g, 3.83 mmol) in methylene chloride (35 ml) at 0° C. The mixture was stirred at room temperature for two hours, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid methyl ester (2.10 g). This compound was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH3:16]
Reactant: Oc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Yield: 78.6 %

Procedure:
4.20 g of 2-bromo-6-chloro-4-pentafluorosulfanylphenol were stirred together with 3.48 g of K2CO3 and 2.68 g of CH3I in 50 ml of anhydrous DMF at RT for 24 hours. The solvent was then removed under reduced pressure and subsequently taken up with 100 ml each of water and EA. The phases were left to separate and extraction was then effected twice more with 100 ml each time of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:1 DIP/HEP afforded 3.44 g of a colorless viscous liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:30])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26](O)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1>>[CH3:7][N:8]([CH3:30])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1
Reactant: C1COCCN1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)cn2n1

Procedure:
Using morpholine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off-white solid (117 mg, 58%). MS: m/z=399 (M+H+). Ames test negative.