Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 95.6 %

Procedure:
Compound 3g (2.7 g, 4.2 mmol) was dissolved in dichloromethane (10 mL), TFA (14 mL, 175 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. After concentration, the residue was taken up in DCM and saturated aq. NaHCO3 was added. The aq. layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 3h (2.2 g, 96%). MS (CI) m/z 548.0, 550.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:34]CC1.CC(O)(C)C.O.C([O-])(O)=O.[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[S:21]1(=[O:23])=[O:22])[CH:15]=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.9 g, 4.3 mmol) in 1:1:1 THF/t-BuOH/H2O (60 mL) is added 1-methylmorpholine-N-oxide (551 mg, 4.74 mmol) and OsO4 (2 mL of a 2.5 wt % solution in t-BuOH, 0.17 mmol). The reaction is stirred for 4 h at ambient temperature, then diluted with water (15 mL) and treated with NaIO4 (4.5 g, 21.5 mmol) and NaHCO3 (3.6 g, 43 mmol). The mixture is stirred vigorously for 1 h, then filtered through Celite. The solution is extracted with EtOAc. The organic phase is washed with saturated NaCl. The solution is dried over MgSO4 and the solvent removed under reduced pressure, then purified via silica gel chromatography using a gradient of 0-40% EtOAc/hexanes to afford 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde as a white solid: MS (M+NH4)+=464.
Reaction SMILES: [NH2:1][C:2]1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[C:21]4[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:25][C:22]1([CH3:26])[C:21]2[C:16]([O:15][C:12]3[N:11]=[CH:10][C:9]([N:8]4[C:6](=[O:7])[C:2]5([CH2:5][CH2:4][CH2:3]5)[NH:1][C:35]4=[O:37])=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)COc2cccc(Oc3ccc(N4C(=O)NC5(CCC5)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclobutanecarboxamide (Intermediate 70, 17 mg) was dissolved in dry dichloromethane (1.8 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (39.48 μl, 0.283 mmol) was added at 0° C. Then 0.89 ml of a solution of triphosgene in dry dichloromethane was added dropwise (0.0135 mg, 4.00 mg). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. Then an additional 0.25 equivalent of triphosgene in dichloromethane (0.26 M solution) was added at 0° C. and the reaction mixture was stirred under argon an additional 30 min at room temperature. The solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 55/45. This afforded the title compound (12 mg).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([CH2:21][CH2:22][CH3:23])[C:15]([CH2:24][CH2:25][CH3:26])=[C:14]([CH2:27][CH2:28][CH3:29])[C:13]=1[CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][CH3:11].I[C:37]1[CH:42]=[CH:41][C:40](I)=[C:39]([I:44])[C:38]=1[I:45].CN1C(=O)N(C)CCC1.Cl>Cl[Cu].C1COCC1>[I:44][C:39]1[C:38]([I:45])=[CH:37][C:42]2[C:41](=[C:8]([CH2:9][CH2:10][CH3:11])[C:7]3[CH2:6][C:12]4[C:13]([CH2:30][C:31]=3[C:32]=2[CH2:33][CH2:34][CH3:35])=[C:14]([CH2:27][CH2:28][CH3:29])[C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([CH2:21][CH2:22][CH3:23])[C:17]=4[CH2:18][CH2:19][CH3:20])[CH:40]=1
Reactant: Ic1ccc(I)c(I)c1I
Reactant: CCCC#CCc1c(CC#CCCC)c(CCC)c(CCC)c(CCC)c1CCC
Agent: Cl[Cu]
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c3cc(I)c(I)cc3c1CCC)C2
Yield: 32.5 %

Procedure:
n-Butyl lithium (3.0 ml, 4.8 mmols, 1.6mol/l) was added to a THF solution (20 ml) of Cp2ZrCl2 (0.702 g, 2.4 mmols) at −78° C. After the mixture was stirred for an hour, 1,2-bis(2-hexynyl)-3,4,5,6-tetrapropylbenzene (0.813 g, 2.0 mmols) was added to the mixture. A cooling bath was withdrawn, and the mixture was stirred for an hour. Tetraiodobenzene (1.16 g, 2.0 mmols), DMPU (0.73 ml, 6.0 mmols) and CuCl (0.416 g, 4.2 mmols) were added to the mixture. After stirring for an hour at 50° C., 3N HCl was added to terminate the reaction. The reaction mixture was extracted with chloroform. The extract was then washed with sodium hydrogencarbonate aqueous solution and brine. After the pressure was reduced, column chromatography was performed using silica gel as the packing material to give the title compound (0.477 g) as a pink solid. The isolation yield was 33%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[CH:10]
Reactant: Cc1cccc(C)c1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of (2,6-dimethylphenylethynyl)-trimethylsilane from the previous step in THF (20 mL) was added tetrabutylammonium fluoride in THF (17 mL of 1 M solution) dropwise. After stirring 18 h, the solution was diluted with hexane and extracted with water and brine. The organic layer was dried, filtered, and solvent removed under reduced pressure. The residual oil was redissolved in hexane and filtered through a silica gel plug, then chromatographed using hexane as eluent to give 2,6-dimethylphenylacetylene.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:17]2[S:18][CH:19]=1.[N:25]([O-])=[O:26].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[C:20]([N:25]=[O:26])=[C:17]2[S:18][CH:19]=1
Reactant: O=N[O-]
Reactant: COCc1cc(OC)c(-c2csc3cc(OC)nn23)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2csc3c(N=O)c(OC)nn23)c(OC)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of water and 5N hydrochloric acid (1:4, 70 mL) was added to 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazole (2.17 g, 6.47 mmol), and then sodium nitrite (1.06 g, 15.3 mmol) was added at 0° C. and the mixture was stirred for 1 hour. Aqueous 5N sodium hydroxide and ethyl acetate were added to the mixture at room temperature. After thoroughly shaking the mixture, the organic layer was separated and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (2.34 g, 6.44 mmol).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:30][CH2:31]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: BrB(Br)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)CCO)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide (0.30 g, 0.64 mmol) in methylene chloride (6 mL) was added a solution of boron tribromide (0.12 mL, 1.29 mmol) and 2,6-lutidine (0.15 mL, 1.29 mmol) in methylene chloride (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at ambient temperature for 1 h, then cooled to 0° C. and quenched with saturated sodium bicarbonate solution (15 mL). The mixture was diluted with methylene chloride (15 mL), layers were separated, and the aqueous layer was extracted with methylene chloride (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 75% gradient of ethyl acetate in hexanes to afford the title compound as colorless solid (0.07 g, 25%): 1H NMR (300 MHz, CDCl3) δ 8.71 (br. s, 1H), 7.64-7.52 (m, 1H), 6.64-6.50 (m, 1H), 4.22-4.07 (m, 2H), 3.86-3.74 (m, 2H), 3.56 (s, 2H), 2.57 (s, 11H), 2.09-1.99 (m, 4H), 1.84-1.63 (m, 12H), 1.00-0.89 (m, 2H), 0.69-0.59 (m, 2H); MS (ES+) m/z 452.3 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:31])[F:30])=[C:20](Cl)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:30])[F:31])=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1
Reactant: Fc1ccc(C(F)(F)F)c(-c2c(Cl)nc3ncnn3c2Cl)c1
Reactant: CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2c(-c3cc(F)ccc3C(F)(F)F)c(Cl)nc3ncnn23)CC1
Yield: 57.9 %

Procedure:
A mixture of 4-methylpiperidine(1.42 mmoles), triethylamine (1.42 mmoles) and dichloromethane (10 ml) is added to a mixture of 5,7-dichloro-6-(5-fluoro-2-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-α]pyrimidine (1.42 mmol) and dichloromethane (30 ml) under stirring. The reaction mixture is stirred 48 hours at room temperature and subsequently washed with dilute hydrochloric acid (5%). The organic layer is separated, dried with anhydrous sodium sulfate and filtered. The filtrate is evaporated under reduced pressure to yield 0.34 g of white crystals having a melting point of 149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:5][CH:4]=1.Cl.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(C)C2CCNCC2(C)C)cc1
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CN(C)C2CCN(c3ccncc3)CC2(C)C)cc1
Yield: 40 %

Procedure:
N-(4-Methoxybenzyl)-N,3,3-trimethylpiperidin-4-amine (5.17 mmol, 1 eq) and 4-bromopyridine hydrochloride (1.509 g, 7.76 mmol, 1.5 eq) were dissolved in n-butanol (40 ml) and DIPEA (4.26 ml, 25.87 mmol, 5 eq) and refluxed for 16 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 40% (700 mg, 2.06 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 ml) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:10]=1.Cl.Cl.[CH3:30][C:31]1[N:35]=[C:34]([C@H:36]([NH2:38])[CH3:37])[O:33][N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([NH:38][C@@H:36]([C:34]3[O:33][N:32]=[C:31]([CH3:30])[N:35]=3)[CH3:37])=[O:20])=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:10]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)O)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
3-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (30.0 mg, 0.040 mmol, with 6 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (12.5 mg, 0.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 0.085 mmol), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.025 mmol), and N-methylmorpholine (20 μl, 0.182 mmol) were dissolved in N,N-dimethylformamide (500 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 30 min. The reaction was stopped and quenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL). The crude reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%), to afford the title compound (16.3 mg, 0.023 mmol, 58.2% yield) as a white solid. HRMS [M+1]=474.1739. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H); 7.77 (d, J=8.6 Hz, 1H); 7.66 (d, J=8.2 Hz, 2H); 7.61 (dd, J=8.5, 1.4 Hz, 1H); 7.48-7.40 (m, 1H); 7.38 (d, J=8.1 Hz, 2H); 7.10 (m, 2H); 6.79 (d, J=7.7 Hz, 1H); 5.62 (m, 1H); 2.46 (s, 3H); 2.41 (s, 3H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: OC[CH:3]([S:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19]OC(=O)C1C=CC(CCl)=CC=1>C1(C)C=CC=CC=1>[C:9]1([CH:4]2[CH2:3][S:10][C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[O:18]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:19]=1
Reactant: OCC(Sc1cc(O)ccc1O)c1ccccc1
Reactant: COC(=O)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)SCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol (0.83 g) in dry toluene (60 ml) was stirred with Amberlyst 15 (0.5 g) at 60° C. until disappearance of the starting material. After the mixture was filtered and solvent evaporated the crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7, 3.0 Hz), 5.10 (dd, 1H, J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0, 9.6 Hz), 3.06 (dd, 1H, J 13.0, 1.9 Hz).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23]O)=[CH:18][N:17]=1.Cl>C(O)(=O)C>[CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([CH2:23][C:19]2[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=2)[CH:5]=1)[CH:2]=[CH2:3]
Reactant: Nc1ncc(CO)c(N)n1
Reactant: C=CCc1ccc2cccnc2c1O
Agent: Cl
Solvent: CC(=O)O
Product: C=CCc1cc(Cc2cnc(N)nc2N)c2cccnc2c1O
Yield: 28.2 %

Procedure:
7-Allyl-8-hydroxyquinoline [H. Fiedler, Arch. Pharm., 297, 108 (1964)] (33.0 g, 0.227 mol), 2,4-diamino-5-hydroxymethylpyrimidine (32.7 g, 0.227 mole), glacial acetic acid (300 mL) and concentrated HCl (31.5 mL) were refluxed for 5 hr. The resulting precipitate was filtered off and then slurried with H2O (250 mL) and sufficient NH4OH to give a pH of 8. The dissolved solid was filtered off, washed with H2O and dried to give the title compound as yellow powder (19.7 g, 28%), mp 229°-231° dec., structure confirmed by NMR. Anal. Calcd for C17H17N5O: C, 66.43; H, 5.58; N, 22.79. Found: C, 66.41; H, 5.59; N, 22.78. Additional product (5.0 g, 7%) was obtained by evaporation of filtrates and chromatography to separate unreacted starting materials.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>Cl.CCOCC>[F:24][C:21]([F:22])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:2]1([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccccc2C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
tert-Butyl 4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidine-1-carboxylate (0.40 g, 1.0 mmol) was dissolved in a 2.0 M solution of HCl in ether (5 mL). After being stirred at room temperature overnight, the solution was diluted with ether. The white solid was filtered and washed with ether to give 170 mg of pure product. MS calculated for C12H14F3NO: (M+H)246; found 246.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NO)OCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NOC(=O)c1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzoyl chloride (13.1 mL, 102 mmol) is added slowly to a solution of benzyl hydroxycarbamate (19.0 g, 114 mmol) and triethylamine (14.4 mL, 104 mmol) in diethyl ether (500 mL) at 0° C. then stirred at room temperature for 1 h. The reaction is
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 74 %

Procedure:
As described for example 58d, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid (69 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (64 mg, 74%) which was obtained as a light yellow solid. MS: m/e=406.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2.[CH3:21]I.O>CN(C=O)C>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:21])[C:15](=[O:20])[CH:14]=[CH:13]2
Reactant: CI
Reactant: O=c1ccc2cc(OCCCCCBr)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 440 mg) was suspended in DMF(20 ml), and was cooled to 0° C. in ice water bath. 6-(5-Bromopentyloxy)-1H-quinolin-2-one(3.1 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Methyl iodide(1.9 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(2.68 g) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:4]=1.[CH3:19][O:20]C(Cl)Cl.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:10]([F:12])([F:13])[F:11])([OH:18])[C:14]([F:15])([F:16])[F:17])[CH:6]=[CH:7][C:8]=1[CH:19]=[O:20]
Reactant: COC(Cl)Cl
Reactant: COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
To a solution of 31.6 g (0.12 mole) of 1-methoxy-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzene in 200 ml dichloromethane is added 38 g (0.2 mole) of titanium tetrachloride at 0°-5° with stirring under a nitrogen atmosphere. After the resulting solution is stirred for 15 minutes, 11.5 g (0.1 mole) of α,α-dichloromethyl methyl ether is added dropwise at 0°-5° C. Stirring is continued while the temperature of the solution is allowed to reach 20°-25° during 18 hours. The solution is then added with stirring to a solution of 100 ml 6N hydrochloric acid in 500 ml of ice and water. The resulting organic phase is separated leaving an aqueous phase which is washed with three 300 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 1N hydrochloric acid and then with saturated sodium chloride solution. The dichloromethane solution is dried with anhydrous magnesium sulfate, filtered, and evaporated at reduced pressure to obtain an oily solid which is triturated with chlorobutane, filtered and recrystallized from chlorobutane to give 14.5 g of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)ethyl]benzaldehyde having a melting point of 144°-146°.