Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][O:24][CH3:25])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[CH2:40].Cl>O1CCOCC1.O>[F:16][C:14]([F:17])([F:15])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[CH2:40])[CH:46]=2)=[C:8]([CH2:26][CH2:27][CH3:28])[CH:9]=1)([O:22][CH2:23][O:24][CH3:25])[C:18]([F:20])([F:19])[F:21]
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Yield: 81.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenyl trifluoromethanesulfonate (238 mg, 497 μmol) in 1,4-dioxan, potassium phosphate (401 mg), 3-vinylphenylboronic acid (88 mg), and tetrakis triphenylphosphine palladium complex (57 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl aceate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (175 mg, yield 81%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a solution of 2-fluoroaniline (25.0 g, 225 mmol) and potassium carbonate (47 g, 337 mmol) in water (112 mL) and acetone (45 mL) at 0° C. was added cinnamoyl chloride (37.0 g, 225 mmol, 1 eq) in acetone (45 mL) over 2 h. The reaction was stirred for 1 h at 0° C., and quenched into 200 mL of ice-water. The white crystalline solid was filtered and washed with water. The solid was air dried for 2 h, then washed with 400 mL of hexanes. The solid was dried under vacuum overnight to afford N-(2-fluorophenyl)cinnamamide (56 g, 103% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (br t, J=7.8 Hz, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.57 (m, 3H), 7.41 (m, 3H), 7.17 (m, 3H), 6.61 (d, J=15.6 Hz, 1H). Mass Spectrum (ESI) m/e=242.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)ccc1-c1ccn[nH]1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 1.9 mmol) in EtOH (10 ml) was treated with 4.0 eq of LiOH and stirred and monitored for two hours the reaction was complete. Reaction was made to pH=5, and then the solution concentrated under reduced pressure, during which time a ppt formed. The solution was concentrated to minimum volume and cooled in ice, filtered and washed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid (172 mg, 44%). 1H NMR (400 MHz, DMSO-d6): 13.03 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6, 2.9 Hz, 2H), 6.44 (d, J=2.2 Hz, 1H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@@H]1Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2CN1
Yield: 87 %

Procedure:
Prepared as in Example 12-1c from (S)-methyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-1c) and tert-butylchlorodimethylsilane. Yield 87%, yellow oil. MS 322 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:29][N:24]1[C:25]([C:26](=[O:27])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[N:16]=[C:10]3[CH:11]=2)=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=[N:23]1
Reactant: Nc1ccn2nc(-c3cccnc3)nc2c1
Reactant: COC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
A mixture of 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (468 mg, 2.22 mmol), 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (490 mg, 2.66 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.26 ml, 5.54 mmol) and N,N-diisopropylethylamine (1.51 ml, 8.86 mmol) in tetrahydrofurane (15 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording methyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (564 mg, 67.5%) as a light brown solid. mp.: 228-231° C. MS: m/z=378.5 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Nc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a solution of 4-hydroxydiphenylamine (200 mg, 1.08 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (80 mg, 2 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (387 mg, 1.09 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (289 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A 0° C. solution of 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.191 g, 0.608 mmol) in THF (3 mL) and MeOH (3 mL) was treated with NH4Cl (1.3 g, 24.31 mmol) followed by the slow addition of zinc dust (0.397 g, 6.08 mmol), the mixture allowed to warm to RT and stirred for 2 h. The mixture was treated with THF, the solids removed via filtration through diatomaceous earth, washed well with THF, the filtrate treated with EtOAc, washed with 1:1 brine/satd. NaHCO3, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (164 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=5.8 Hz, 1 H), 8.28 (s, 1 H), 7.82 (d, J=2.9 Hz, 1 H), 7.50 (d, J=2.4 Hz, 1 H), 7.29 (dd, J=8.9, 3.0 Hz, 1 H), 6.67 (dd, J=5.8, 2.4 Hz, 1 H), 6.51 (d, J=8.9 Hz, 1 H), 6.03 (s, 2 H), 2.64 (s, 3 H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=C\C(C)C)/[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-:33].[Na+]>CO>[CH2:10]([O:33][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 8 h

Procedure:
(E)-Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (52 mg, 0.123 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) and treated with 1 M NaOH (5 mL) at 100° C. After stirring overnight, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:36].[OH-].[NH4+:38].CCO>O>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:36]
Reactant: [NH4+]
Reactant: CC#CC1CN(S(=O)(=O)c2cnc(Cl)c(F)c2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC#CC1CN(S(=O)(=O)c2cnc(N)c(F)c2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 37 %

Procedure:
A 20-mL microwave vial was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (165 mg, 0.30 mmol), aq. ammonium hydroxide (3 mL, 30% solution, 15.4 mmol, J. T. Baker, Phillipsburg, N.J.) and EtOH (3 mL). The is reaction vessel was sealed and the mixture heated to 150° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give an oil that was purified via column chromatography on silica gel (0-10% MeOH in CH2Cl2) to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (60 mg) as a mixture of two isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])([F:10])[F:9])=[C:4]([N+:19]([O-])=O)[CH:3]=1>CCOC(C)=O.CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])([F:9])[F:10])=[C:4]([NH2:19])[CH:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available 4-iodo-3-nitrotoluene was reacted with diethyl bromodifluoromethylphosphonate under Cd coupling conditions using Example 25 to yield diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate (500 mg, 1.55 mmol) was dissolved in EtOAc (10 mL) and EtOH (10 mL). Five percent Pd—C (approximately 20 mg) was added and the mixture placed under H2 (1 atm.) and stirred at room temperature overnight. The mixture was then filtered and concentrated in vacuo to give diethyl (4-methyl-2-aminophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-amino-phenyl)difluoromethylphosphonate was converted to diethyl (2-iodo-4-methylphenyl)-difluoromethylphosphonate using Example 86. Compound 95 was synthesized from this corresponding diethyl phosphonate using procedures similar to those of Example 40. MS (ES−): m/z 347.1 (M−H). 1H NMR: (CD3OD, 400 MHz) δ 7.90 (s, 1H), 7.49 (dd, J=0.8, 8.2, 1H), 7.27 (d, J=8.2, 1H), 2.31 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](O)(=[O:13])[C:10]#[C:11][CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[C:10]#[C:11][CH3:12]
Reactant: CC#CC(=O)O
Reactant: Nc1ccccc1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC#CC(=O)Nc1ccccc1I
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 2-iodo-phenylamine (10 g, 45.7 mmol) and but-2-ynoic acid (4.6 g, 54.8 mmol) in dichloromethane (50 ml) was cooled to 0° C. Then 1,3-dicyclohexylcarbodiimide (14 g, 68.6 mmol) was added. After stirring for 3 hours at room temperature, the mixture was washed with water (20 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product but-2-ynoic acid (2-iodo-phenyl)-amide (13.0 g, 100%) as a yellow solid which was used in next step without purification. MS calcd. for C10H8INO 285.1, obsd. (ESI+) [(M+H)+] 286.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:18])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CO
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Product: COc1ccc(C(=O)Cc2ccccc2)c(O)c1
Yield: 87.9 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethanone (7.08 g, 31.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.60 g (88%) of the title compound was obtained as a white solid: mp 87-88° C. (lit. 92° C.); IR (KBr) 1635, 1620, 1589, 1437, 1350, 1291, 1230, 1206, 1127, 1021, 958, 802, 739, 729, 551 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.71 (br s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.31-7.34 (m, 2H), 7.23-7.26 (m, 3H), 6.40-6.44 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.38, 166.61. 166.30, 134.82, 132.47, 129.76, 129.16, 127.50, 113.58, 108,27, 101.44, 56.00, 45.27.
Reaction SMILES: O.[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1)#[N:3].C1N2CN3CN(C2)CN1C3.C(O)(=[O:24])C.S(=O)(=O)(O)O>O>[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:24])=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
500 g of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 2.5 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 500 g of p-cyanobenzylamine hydrate (water content: 21% by weight). 500 g of the p-cyanobenzylamine hydrate, 420 g of hexamethylenetetramine, and 2.0 kg of acetic acid were mixed and the internal temperature was elevated to 80° C. while stirring. An aqueous sulfuric acid solution of 300 g of 98% by weight sulfuric acid and 165 g of water was added dropwise thereto over 20 minutes. Further, the reaction mixture was stirred at 100° C. for 1 hour. After the internal temperature was decreased to 50° C., 300 g of 98% by weight sulfuric acid was added. The reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added 900 g of 1% by weight sulfuric acid and stirred vigorously at 100° C. for 3 hours. Thereafter, the reaction mixture was cooled to room temperature for 2 hours. The crystals which precipitated were filtered, washed with water, and dried to obtain 295 g (yield: 75%) of p-cyanobenzaldehyde. The purity was 99.5% or more. Under nitrogen atmosphere, 295 g of the p-cyanobenzaldehyde and 4.5 g of 2,2-azobisisobutyronitrile were mixed. The temperature was elevated to 105° C. and 190 g of chlorine was bubbled over 3 hours with vigorous stirring. After dry nitrogen gas was introduced into the reaction mixture for 1 hour, the solvent was distilled under reduced pressure to obtain 302 g (yield: 81%) of p-cyanobenzoyl chloride. The purity was 98.5%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>CN(C=O)C>[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18]
Reactant: Cc1nc2cnc3ccc(O)cc3c2n1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2ncc3nc(C)n(C)c3c2c1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sodium hydride (0.61 g, 15 mmol, available as a 60% dispersion in mineral oil) was added to a solution of 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol (2.5 g, 12 mmol) in DMF. The reaction mixture was stirred for 30 minutes, and ethyl bromoacetate (1.96 g, 11.7 mmol) was added. The stirring was continued for five hours, and a small volume of ethanol was added. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed three times with deionized water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow solid was recrystallized from ethyl acetate to provide 1.65 g of ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.Cl>O.CO>[I:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: II
Reactant: Cc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(I)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Methylpyridin-3-ol (3.00 g, 27.5 mmol) was dissolved in a solution of Na2CO3 (5.83 g, 55.0 mmol) in water (48 mL) and MeOH (30 mL). Iodine (6.98 g, 27.5 mmol) was added and the reaction mixture was stirred for 1 h at RT. The mixture was treated with 2 M HCl solution (14 mL) and the resultant suspension was extracted with EtOAc (2×65 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was slurried with DCM (20 mL) and the resultant solid was collected to afford 6-iodo-2-methylpyridin-3-ol (3.6 g, 55.7% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J=8.26 Hz, 1H), 6.78 (d, J=8.26 Hz, 1H), 5.03 (br s, 1H), 2.47 (s, 3H); MS (ESI) m/z: 236.0 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][N:29]=1)[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:20]>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([OH:14])=[C:8]2[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][N:29]=1)[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[O:20])#[N:4]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CN(C)CCNC(=O)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccnc(-c2c(O)[nH]c3ccc(C#N)cc23)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a suspension of sodium hydride (0.15 g, 3.70 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added a solution of 5-cyanooxindole (0.29 g, 1.84 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 30 min under a nitrogen atmosphere. 2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide (0.21 g, 0.92 mmol) dissolved in N,N-dimethylformamide (4 mL) was added dropwise and the mixture was stirred at room temperature for 30 min and then heated at 150° C. for 45 min. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. A 2 M aqueous HCl solution was added until pH 2 and the mixture was extracted with ethyl acetate. To the aqueous layer, a 45% aqueous NaOH solution was added until pH 11 and the suspension was extracted with ethyl acetate. The aqueous layer was concentrated in vacuo and the crude product was purified by preparative HPLC (column: Xterra, 19×300 mm, eluent: 0.05 M NH4OAc buffert/acetonitrile, 9:1 to 3:7) to give 15 mg (5% yield) of the title compound as a red solid: 1H NMR (DMSO-d6, 400 MHz) δ 14.88 (br s, 1 H), 11.03 (br s, 1 H), 9.10 (br s, 1 H), 8.28 (d, J=6 Hz, 1 H), 8.04-7.96 (m, 1 H), 7.95-7.83 (m, 1 H), 7.42-7.34 (m, 1 H), 7.13-7.02 (m, 2 H), 3.62-3.50 (m, 2 H), 2.86-2.69 (m,.2 H), 2.58-2.29 (m, 6 H); MS (TSP) m/z 350 (M++1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH3:23][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([O:21][CH3:23])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(C)c(-c2ccc3c(c2)CCCO3)c1C(=O)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-oxoacetic acid (42a) (1.09 g, 3.43 mmol) in methanol (10 mL) was cooled to 0° C. Trimethylsilyldiazomethane 2N in diethyl ether (6.89 mL, 13.7 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The precipitate was filtered off and washed with cooled methanol (5 mL). The filtrate was concentrated in vacuo and the residue was dissolved in a minimum of methanol. The solution was sonicated for a few seconds and the precipitate was filtered and washed with cooled methanol. The precipitates were combined to provide the desired ester (42b) (820 mg, 2.48 mmol, 72% over two steps) as a beige solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C@@H:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Using, as starting materials, 2.3 g of 3,5-bistrifluoromethyl aniline, and 1.5 g (0.01 mole) of trans-cyclohexane-1,2-dicarboxylic anhydride, the title compound was obtained in the same manner as in Example 1.