Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31]([NH:38][CH2:39][C:40](O)=[O:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:40](=[O:41])[CH2:39][NH:38][C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:11]3)[CH2:9][N:8]([C:15](=[O:16])[NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 12 h
Yield: 39.7 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (40 mg, 0.097 mmol) obtained in Example 2 was dissolved in methylene chloride (1.0 mL). Thereafter, triethylamine (27.0 μL, 0.194 mmol), N-Boc glycine (20 mg, 0.116 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (22 mg, 0.116 mmol) were added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 12 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The resultant was dried over anhydrous sodium sulfate and was then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (22.0 mg, 40%) in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:9]([CH3:15])([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:3][CH:4]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:21]=1)([CH3:24])[CH3:25]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(C(C)C)cc1
Yield: 77.1 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)-2-methylpropionate (1.00 g), which is the product of Reference example 9(b), 2-(2-bromoethoxy)tetrahydropyran (1.84 g) and potassium carbonate (1.62 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.06 g) as a syrup.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>CO.O1CCOCC1>[ClH:28].[ClH:28].[N:11]1([C:15]2[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)c1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(6-Isopropyl-quinolin-8-yl)-[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.3 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.2 g, 100%). MS (ES) m/z 270.1 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:12])[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1>CC(O)=O>[Br:1][CH:7]1[C:8](=[O:10])[CH2:9][C:4]([CH3:12])([CH3:3])[CH2:5][C:6]1=[O:11]
Reactant: BrBr
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(Br)C(=O)C1
Reaction time: 2 h

Procedure:
Bromine (0.51 mL, 10 mmol) was added dropwise to a solution of 5,5-dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. The reaction mixture was stirred for 2 h and then the product was isolated by filtration. The precipitate was washed with Et2O (2×100 mL) and then dried in vacuo give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 218.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO[CH2:30][CH2:31]OC.O>>[CH:30]([C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=2)[N:10]=[CH:9][CH:8]=1)=[CH2:31]
Reactant: COCCOC
Reactant: COc1cc(F)c2nccc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccnc2c(F)cc(OC)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of 1,1,1-trifluoromethanesulfonic acid 8-fluoro-6-methoxy-quinolin-4-yl ester (1.0 g, 3.1 mmol), potassium carbonate (1.28 g, 9.3 mmole), tetrakis-triphenylphosphine (350 mg, 0.3 mmole) in DME/H2O (20 mL, 3:1) was added 2,4,6-trivinylcycloborane-pyridine complex (460 mg, 1.5 mmole). After stirring for 3 h at 90° C., the mixture contents were cooled to room temperature and extracted with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ethyl acetate in hexane) to give the title compound as a light yellow solid (428 mg, 65%): LC/MS (ES) m/e 212 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[NH:27][CH:26]=[C:25]([C:28]([O:30]C)=[O:29])[CH:24]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[NH:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[CH:24]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(Nc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate (10 mg, 0.024 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was heated in a 60° C. bath for 16 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=5. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 2 mg.
Reaction SMILES: C([O:3][C:4](=[O:35])[C@@H:5]([NH:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C:24]2[NH:34][C:27]3[N:28]=[C:29]([NH2:33])[NH:30][C:31](=[O:32])[C:26]=3[CH:25]=2)=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO>[NH2:33][C:29]1[NH:30][C:31](=[O:32])[C:26]2[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][C:18]3[S:17][C:16]([C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:35])=[O:3])=[O:15])=[CH:20][CH:19]=3)[NH:34][C:27]=2[N:28]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc2[nH]c(CCCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 (252 mg, 0.5 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mL) and the mixture was stirred under N2 at room temperature for 16 h. TLC showed the disappearance of the starting material (Rf=0.48) and one major spot at the origin (MeOH/CHCl3 1:5). The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL), the resulting solution was cooled in an ice bath, and the pH was adjusted to 3-4 with dropwise addition of 1 N HCl. The resulting suspension was frozen in a dry ice-acetone bath, thawed to 4-5° C. in the refrigerator, and filtered. The residue was washed with a small amount of cold water and dried in vacuum using P2O5 to afford 212 mg (95%) of AAG154544 as white powder. mp 175-176° C.; 1H NMR (DMSO-d6): δ 1.88-2.10 (m, 4H), 2.31-2.34 (t, J=7.6 Hz, 2H), 2.49-2.54 (t, J=7.2 Hz, 2H), 2.78-2.81 (t, J=7.2 Hz, 2H), 4.30-4.35 (m, 1H), 5.88 (s, 1H), 5.97 (s, 2H), 6.89-6.90 (d, J=3.6 Hz, 1H), 7.68-7.69 (d, J=3.6 Hz, 1H), 8.50-8.52 (d, J=8 Hz, 1H), 10.13 (s, 1H), 10.82 (s, 1H) 12.42 (br, 2H). Anal. (C19H21N5O6S) C, H, N, S. calcd for C19H21N5O6S.1H2O; C, 49.02; H, 4.98; N, 15.05; S, 6.89. Found: C, 49.22; H, 4.80; N, 15.03; S, 6.97.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>O1CCCC1.[O-2].[Mn+4].[O-2]>[OH:15][C:12]([C:4]1[C:3]([CH:2]=[O:1])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:13])[CH3:14]
Reactant: CC(C)(O)c1nn2ccccc2c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)(O)c1nn2ccccc2c1C=O
Temperature: 65 °C
Yield: 66.7 %

Procedure:
To a solution of 2-(3-hydroxymethyl-pyrazolo[1,5-a]pyridin-2-yl)-propan-2-ol (1.8 g, 7.42 mmol) in tetrahydrofuran (60 mL) under nitrogen atmosphere was added manganese (IV) oxide (5.22 g, 60 mmol) and the mixture was heated to 65° C. for 40 h. The mixture was filtered through a Celite pad, which was washed with excess dichloromethane. The filtrates were combined and concentrated in vacuo and the residue was purified via silica gel column chromatography (0-40% ethyl acetate in heptane) to give the title compound (1.01 g, 4.95 mmol, 67% yield) as a light yellow solid.
Reaction SMILES: O.[CH3:2][C@H:3]([OH:7])[C:4]([OH:6])=[O:5].[CH3:8]O>>[C:4]([O:6][CH3:8])(=[O:5])[CH:3]([CH3:2])[OH:7].[C:4]([OH:6])(=[O:5])[C@H:3]([CH3:2])[OH:7]
Reactant: CO
Agent: C[C@H](O)C(=O)O
Solvent: O
Product: COC(=O)C(C)O

Procedure:
2500 g of highly pure S-(−)-methyl lactate from reservoir (1), having purity 99.81% by on GC analysis as methyl lactate, obtained by reactive distillation of lactic acid and methanol followed by fractional distillation to isolate pure methyl lactate, was charged to the glass lined stirred reactor (4), having capacity of 10 L and was further charged with 2500 g of distilled water (De-ionized, glass distilled) from reservoir (2), along with 500 g of Purac Inc, USA make pure lactic (90% by wt on HPLC analysis) from reservoir (3). Temperature of reboiler was maintained continuously at 100° C. by hot oil circulator (5). The methanol vapors formed during hydrolysis reaction were allowed to rise through column (6) and condensed in cooler (7) and fractionated with proper reflux so as to get top temperature at 65° C. The methanol formed was continuously collected in reservoir (10) through cooler (8). Any trace amount of methanol or unconverted methyl lactate was recovered and recycled. After collecting desired amount of methanol in reservoir (10) through cooler (8), 1000 g of distilled water from reservoir (2) was charged to reactor (4) so as to get complete conversion of methyl lactate in to L-(+)-lactic acid. The water was removed by distillation and was collected in reservoir (9) through cooler (8) so as to get lactic acid free from methanol and methyl lactate in trace amount. After removing desired amount of water, the lactic acid in the reactor (4) was treated with 0.5% by wt of total material with pre-treated activated charcoal from reservoir (11). Where pretreatment of activated charcoal was done by washing activated charcoal with 10% solution of pure L-(+)-lactic acid in water. The pure L-(+)-lactic acid and the pre-treated activated charcoal in reactor (4) was stirred for 30 minutes, cooled to room temperature and the contents of reactor (4) were filtered on Buchner filter (12), to get highly pure L-(+)-lactic acid as the filtrate which was stored in reservoir (13). This L-(+)-lactic acid filtrate from (13) was clear and transparent and was further concentrated at 80° C. and under vacuum of 100 mm Hg till 90% by w/w of L-(+)-lactic acid solution in water was obtained. This L-(+)-lactic acid was analyzed by HPLC and showed lactic acid of 99.81% purity by wt. on water free basis and having optical purity of 99.9% as analyzed by RANDOX Enzyme Kit method. The L-(+)-lactic acid obtained was also free from any odor and color.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C(O)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(F)cc2)on1

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[S:16]([N:19]=C=O)(=[O:18])=[O:17].C1(C)C=CC=CC=1>C1C=CC=CC=1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:16](=[O:18])(=[O:17])[NH2:19])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 10.4 g (0.05 mole) of 5-hydroxy-2-nitrobenzotrifluoride, 7.8 g (0.055 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.1 g (78%) of tan solid, mp 95°-97° C. (benzene).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:9]([CH3:28])=[C:10]([CH3:27])[C:11]2[O:15][CH:14]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21])[S:13][C:12]=2[C:25]=1[CH3:26]>O1CCCC1>[OH:7][C:8]1[C:9]([CH3:28])=[C:10]([CH3:27])[C:11]2[O:15][CH:14]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][OH:21])[S:13][C:12]=2[C:25]=1[CH3:26]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCC(C)(C)C(=O)O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCC(C)(C)CO)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.3 g of lithium aluminum hydride was suspended in 30 ml of tetrahydrofuran, and a solution of 1.7 g of 5-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)-2,2-dimethylpentanoic acid (prepared as described in Example 81) in 5 ml of tetrahydrofuran was added dropwise under a stream of nitrogen and with ice-cooling to the suspension. After the dropwise addition, the reaction mixture was kept at room temperature for 1 hour and was then heated under reflux for 2 hours. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the ethyl acetate was distilled off under reduced pressure. The resulting residue was subjected to silica gel Lobar column chromatography, and the title compound was obtained by elution with a 9:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(N2CCC(Cl)=N2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1ccc(C2=NN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 150 °C
Yield: 34.9 %

Procedure:
A suspension of 3-chloro-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole (114 mg, 0.43 mmol, 1.00 eq), 4-formylphenylboronic acid (97 mg, 0.65 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol, 0.03 eq), 2 M Na2CO3 (aq) (0.43 mL, 0.86 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (50 mg, 0.15 mmol, 31%).
Reaction SMILES: IC1C(O)=NC2CCN(C(=O)C(F)(F)F)CC(C)C=2C=1.C([O-])([O-])=O.[K+].[K+].CI.[I:29][C:30]1[C:47]([O:48][CH3:49])=[N:46][C:33]2[CH2:34][CH2:35][N:36](C(=O)C(F)(F)F)[CH2:37][CH:38]([CH3:39])[C:32]=2[CH:31]=1>CO.CC(C)=O>[I:29][C:30]1[C:47]([O:48][CH3:49])=[N:46][C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]([CH3:39])[C:32]=2[CH:31]=1
Reactant: COc1nc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CI
Product: COc1nc2c(cc1I)C(C)CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (100 mg, 250 μmol), K2CO3 (200 mg), MeI (2 ml) and acetone (4 ml) was stirred for 16 h at ambient temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 25.5 mg (25%) of 3-iodo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine and 41.9 mg (41%) of 3-iodo-1,5-dimethyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. 1H-NMR of O-methylated product (CDCl3) δ 7.79 (2× s, 1H), 3.95 (2× s, 3H), 3.94-3.78 (br m, 2H), 3.59 (br m, 1H), 3.56-3.36 (br m, 1H), 3.22 (m, 1H), 3.08 (br m, 2H), 1.30 (2× d, 3H) ppm. 1H-NMR N-methylated product (CDCl3) δ 7.80 (s, 1H), 3.97-3.65 (br m, 3H), 3.68 (2× s, 3H), 3.44-3.01 (m, 4H), 1.30 (2× d, 3H) ppm. A mixture of 3-iodo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (25.5 mg, 62.0 μmol), K2CO3 (17.0 mg, 124 μmol) and MeOH (7 ml) was heated for 5 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 5.90 mg (30%) of 3-iodo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 3.83 (s, 3H), 3.00-2.90 (m, 3H), 2.86-2.77 (m, 3H), 2.65 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per the procedure described in preparation 2) and 2,4-dichloro benzenesulfonylchloride.
Reaction SMILES: C([O-])(=O)C.[Li+].[CH3:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13]C(O)=O)=[CH:10][CH:9]=1.[I:19]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O.C(#N)C>[I:19][CH:13]=[CH:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C=CI)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
By referring to the synthetic method of J. Org. Chem., 1997, 62, 199, to a solution of lithium acetate (280 mg) in water (3 ml) was added acetonitrile (90 ml), the solution was stirred at room temperature, then 4-methoxycinnamic acid (7.5 g), N-iodosuccinimide (10 g) were sequentially added thereto, the solution was stirred for 2 hours at room temperature, and then neutralized with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2-iodovinyl)-4-methoxybenzene (8.0 g). By referring to the synthetic method of J. Am. Chem. Soc., 1996, 118, 2748, to a solution of 1-(2-iodovinyl)-4-methoxybenzene (7.1 g) and tributyl(4-methoxy-2-nitrophenyl)tin (10 g) in 1-methyl-2-pyrrolidone (100 ml) was added copper(I) thiophene-2-carboxylate (6.6 g) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 25 minutes at room temperature. Tetrahydrofuran was added thereto, the solution was stirred, then filtered through alumina, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.7 g).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])C=1.C(C/C(/C)=C/CC/C(/C)=C/CO)/C=C(/CCC=C(C)C)\C.C(N=C=S)CCCC>>[CH2:3]([NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: CCCCCN=C=S
Product: CCCCNC(=S)OC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Yield: 60 %

Procedure:
Similar to the preparation of 38a, the reaction of alcohol 1 with pentyl isothiocyanate afforded the desired compound 10e in 60% yield (135 mg) as a viscous oil. Column (EtOAc/Hexane); TLC Rf: 0.70 (10% EtOAc/hexanes); LCMS: MS (m/z): 406.1 (M+H).