Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]#[N:28])[CH:21]=3)[NH:16]2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]([C:11]1[CH:10]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)[CH2:24][C:23]2([CH3:26])[CH3:25])#[N:28]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 168 h
Yield: 46.8 %

Procedure:
Propane-2-sulfonyl chloride (231 mg, 1.62 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (342 mg, 4.32 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir for 7 days. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford propane-2-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (97 mg, yield: 46.8%). MS (ESI+APCI) M+1=384.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CC(C)C(C)n1ccc(Cl)c(C=NO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)C(C)n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 100.4 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(3-methylbutan-2-yl)pyridin-2(1H)-one obtained in Step D (328 mg) in acetonitrile (3.0 mL) was added phosphorus oxychloride (0.126 mL) at room temperature. The reaction mixture was heated at 90° C. for 30 min, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (305 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([N:24]2[C:28]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:27](=[O:34])[NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:31]1[CH2:30][CH2:29][C:28]2([N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][NH:26][C:27]2=[O:34])[CH2:33][CH2:32]1)=[O:7]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (2.3 mL, 13 mmol) in dichloromethane (50 mL) was added with stirring to a mixture of 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (2.9 g, 13 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (250 mL) at room temperature. Stirring was continued for 2 h. Water (150 mL) was added, the phases were separated and the water phase was extracted twice with dichloromethane (100 mL). Organic phases were pooled, washed with brine (200 mL), dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (ethylacetate/n-hexane 1:1) yielded the desired product (5.3 g, 89%) m.p. 251° C. and MS: m/e=472.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12.C(N(CC)CC)C.S(Cl)([Cl:36])=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:36])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCCl
Yield: 81.3 %

Procedure:
To a solution of 1000 mg of 5-hydroxy-N-β-hydroxyethylbenzo[a]phenazine-6-carboxyamide in 30 ml of dry chloroform was added 300 mg of triethylamine, followed by 660 mg of thionyl chloride. The mixture was heated at reflux for 30 minutes and evaporated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried and the solvent was evaporated. The resulting residue was recrystallized from dimethylformamide to obtain 856 mg (91.8% yield) of 5-hydroxy-N-β-chloroethylbenzo[a]-phenazine-6-carboxyamide as yellow needles, m.p. 183°-186° C., Anal. Calcd. (%) for C19H14N3O2Cl: C, 64.87; H, 4.01; N, 11.94; Found: C, 64.60; H, 4.03; N, 11.66
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: NCc1cccc(Cl)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1cccc(Cl)c1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-chlorobenzylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.52-7.47 (m, 1H), 7.39-7.15 (m, 9H), 7.09-7.00 (m, 3H), 6.44 (s, 1H), 6.40 (s, 1H), 5.21-5.06 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 4.52 (t, J=8.6 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); MS (ES+) m/z 559.1 (M+23).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1O

Procedure:
ninhydrin, 4-(2-hydroxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: CS([O:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:35][CH:36]([F:39])[CH2:37]O>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][O:5][CH2:37][CH:36]([F:39])[F:35])=[O:24])[CH2:28][CH2:27]1
Reactant: OCC(F)F
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCC(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (204 mg, 0.5 mmol) obtained in Example 126a), potassium carbonate (69 mg, 0.5 mmol, 1.0 eq.) and 2,2-difluoroethanol (0.5 ml) were suspended in acetonitrile (3 ml), and the suspension was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 83%).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:1][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:39])([F:38])[F:29])=[CH:32][CH:33]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(C(F)(F)F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-trifluoromethylphenol (8.100 mg, 0.050 mmol), triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.10 mg, 38.9% yield) as a thick oil: 1H NMR δ 8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J=0.6 Hz), 7.38–7.30 (m, 4H), 7.30–7.20 (m, 3H), 6.96 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H) 2.53 (m, 2H), 2.40–1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8])(=[O:5])[CH3:4]>O>[C:7]([C:9]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:3](=[O:5])[CH:4]=1)([OH:1])=[O:8]
Reactant: [OH-]
Reactant: CC(=O)N1C(=O)C(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c2ccccc12
Yield: 77.6 %

Procedure:
To a solution containing 30 g of sodium hydroxide in 1.5 liter of water was added 58 g of the above-mentioned N-acetylisatin and the mixture was refluxed for 1 hour. Then the reaction mixture was cooled a certain extent, then activated carbon was added and further refluxed for 30 minutes. The activated carbon was removed from the reaction mixture by filtration while the mixture being hot, and the mother liquor was cooled, then 6N-hydrochloric acid was added to the mother liquor to adjust the pH thereof to pH 3-4. The crystals precipitated were colledted by filtration, washed with water, dried to obtain 45 g of 4-carboxycarbostyril.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=NN=N1.C(N(C(C)C)[P:42]([O:47][CH2:48][CH:49]=[CH2:50])[O:43][CH2:44][CH:45]=[CH2:46])(C)C.C([O:58]O)(C)(C)C.CCCCCCCCCC.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[P:42]([O:43][CH2:44][CH:45]=[CH2:46])([O:47][CH2:48][CH:49]=[CH2:50])([O:11][CH2:10][C@@:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:32])[CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)=[O:58]
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Reactant: Cn1c(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Reactant: CC(C)(C)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: CCCCCCCCCC
Product: C=CCOP(=O)(OCC=C)OC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)n1C)NC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (1.6928 g, 3.83 mmol) obtained in Example (43a) in dichloromethane (19 ml) were added successively 1H-tetrazole (1.7933 g, 25.60 mmol) and diallyl diisopropylphosphoramidite (2.02 ml, 7.64 mmol) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, to the reaction mixture was added a solution of t-butyl hydroperoxide in n-decane (5-6 mol/l) (2.3 ml, 11.5 mmol) with stirring under ice cooling, and the resulting mixture was stirred at the same temperature for 15 minutes. After stirring, to the reaction mixture was added an aqueous sodium sulfite solution to quench the reaction, and the resulting mixture was extracted with dichloromethane. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (1.5690 g, yield: 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[C:28](O)=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[F:33].[CH3:34]O>ClCCl>[F:22][C:23]1[C:28]([CH2:34][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[F:33]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CO
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 87 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using pentafluorophenol (30 mg, 0. 15 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 70 mg (87%) of the titled compound. ESI-MS m/z 472 (MH+), 470 (M−H−).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:1]
Reactant: COc1cc(C(C)C)ccc(CO)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)ccc(C=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (20 g, 96 mmol) was dissolved in chloroform (300 ml), to which was added active manganese dioxide (80 g, 920 mmol) in several portions, and the resultant was stirred at room temperature for 4 hours. The insoluble matter was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure and the resulting crude product was recrystallized from toluene to give 12.31 g of 7-formyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as yellow needle-like crystal (yield: 62%). Melting point of the product was 73°-75° C. 10% aqueous sodium hydroxide (50 ml) was added to the aldehyde (5 g, 24 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 10% dilute hydrochloric acid, then extracted with methylene chloride, washed with water, dried, and solvent was distilled off to give a crude crystal (4.78 g). The crude crystal was recrystallized from ethyl acetate/hexane to give 7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a colorless needle-like crystal (yield: quantitative). This compound showed melting point of 76° C., which is identical to that described in the literature (Sci. Repts. Tohoku Univ., I, 37, 367 (1953)]. The compound (1.94 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml), to which was added dropwise 2M phenyl lithium solution (5.2 ml, ca 10 mmol) in a nitrogen atmosphere while cooling to -78° C. The resultant was stirred for 10 minutes. An aqueous saturated sodium chloride was added to the reaction solution, and the resultant was extracted with methylene chloride, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 1.95 g of 7-(α-hydroxybenzyl)-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as brown oil (yield: 71%). The compound (1 g, 3.7 mmol) and 1-(4-chlorobenzhydryl)piperazine (1.27 g, 4.4 mmol) were heated and refluxed in xylene (20 ml) for 2 hours, solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [(ethyl acetate/hexane (1:2)] to give 1.71 g of 7-{1-[4-(4-chlorobenzhydryl)piperazinomethyl]-α-phenyl}-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (yield: 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][CH2:22][C:23]([CH3:34])([CH3:33])[CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:42]CCl>>[ClH:42].[ClH:42].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][CH2:22][C:23]([CH3:34])([CH3:33])[CH2:24][NH2:25])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: ClCCl
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)COc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate (0.108 g, 0.205 mmol) in 2 mL dichloromethane was added neat TFA (0.395 mL, 5.13 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, after which it was concentrated. The residue was concentrated twice from dichloromethane/hexanes to give solids, which were dried in vacuo. The solids were dissolved in several drops of methanol and minimal dichloromethane, and this solution was added to a vigorously stirring solution of 20 mL ether and 1.5 mL 2M HCl/ether, causing precipitation. The solids were stirred 5 minutes, then isolated by filtration through a medium glass fitted funnel by pushing the solvent through the funnel with nitrogen pressure, rinsed twice with ether, twice with 1:1 dichloromethane:ether, twice with ether, and dried in vacuo to give the title compound (0.042 g, 0.0841 mmol, 41.0% yield) as a pale yellow powder. MS APCI (+) m/z 426/428 (M+1)(Br isotope) detected.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1>C(#N)C>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([NH:13][C:11]([NH:10][S:7]([C:3]2[C:2]([CH3:1])=[CH:6][S:5][CH:4]=2)(=[O:8])=[O:9])=[O:12])[N:15]=1
Reactant: Cc1cscc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cscc2C)n1
Yield: 43.3 %

Procedure:
A solution of 2 g of 4-methyl-3-thiophenesulfonyl isocyanate in 5 ml of dry acetonitrile was added to 1.5 g of 2amino-4,6-dimethoxypyrimidine in 20 ml of acetonitrile with stirring. The mixture was stirred for 16 hours at ambient temperature and filtered to yield 1.5 g of the desired product, m.p. 175°-178°.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C([O-])([O-])=[O:30].[Na+].[Na+].OO>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([NH2:15])=[O:30])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (1.10 g, 2.88 mmol) dissolved in ethanol (100 mL) and 3 M Na2CO3 (10 mL) was added 30% hydrogen peroxide (10 mL). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylic acid amide (0.83 g, 2.08 mmol, 72% yield). M.p. 260-261° C. 1H-NMR (200 MHz, CD2Cl2): δ8.10 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.71 (br d, J=8.1 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=7.7, 8.1 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.13 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.43 (s, 2H) CH2PhF2), 1.92 (s, 2H, NH2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:18](Cl)([OH:21])(=O)=[O:19].[CH4:23].O.Cl>N1C=CC=CC=1>[Cl:1][CH:2]1[C:8](=[S:18](=[O:21])=[O:19])[CH:7]=[CH:6][C:4]([NH:5][CH3:23])=[C:3]1[S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: C
Reactant: Nc1cccc(Cl)c1Sc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CNC1=C(Sc2ccc(Cl)cc2Cl)C(Cl)C(=S(=O)=O)C=C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-chloro-2-(2,4-dichlorophenylthio)-aniline (8.96 g) is dissolved in pyridine (300 ml). Methane sulphochloride (4.56 ml) is added dropwise to this solution and the resulting mixture is stirred for 12 hours at room temperature. Following this, the mixture is emptied onto iced water, acidified with concentrated hydrochloric acid. The resulting mixture is extracted 3 times with methylene chloride (each 200 ml). The combined organic phases are dried (Na2SO4), filtered and the filtrate is concentrated in a vacuum. The resulting residue is dissolved in methanol, mixed with a sodium methylate solution in methanol (29.7%, 50 ml) and is stirred for 12 hours. The clear solution is acidified with concentrated hydrochloric acid, brought to room temperature, diluted with water (200 ml). The result in precipitate is suction filtered, washed with water and dried. Yield: 10.69 g (95.0%).