Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:6]=[N:5]1.[NH2:39][CH:40]([CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C.O>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([NH:29][C:30]([NH:39][CH:40]([CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:31])[CH:6]=[N:5]1
Reactant: O=C(Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)NC(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a stirred solution of phenyl [1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (1 g) in N,N-dimethylformamide (10 ml) were added di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (631 mg) and triethylamine (0.83 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product, which was triturated with ethyl acetate-diisopropyl ether (1:3). The resulting solid was collected by filtration to give di-tert-butyl {2-[({[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1,3-propanediyl}biscarbamate (435 mg).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]>C1C=CC=CC=1>[Br:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Br)c(Br)c(Br)c(Br)c1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1c(Br)c(Br)c(Br)c(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentabromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentabromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]Br)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21].[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl diethylphosphonoacetate (75.0 g, 297.32 mmol) was added dropwise to a suspension of sodium hydride (8.03 g, 334.58 mmol) in DMF (450 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 0.5 h. 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (20.68 g, 74.34 mmol) in DMF (50 mL) was added dropwise to the reaction mixture and the reaction was heated to 60° C. and stirred for 16 h. The reaction was cooled to room temperature, poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/hexane, 3:7) to give 4-[2-tert-Butoxycarbonyl -2-(diethoxy-phosphoryl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester and unreacted t-butyl diethylphosphonoacetate. The product was 47% pure by HPLC. The product was further purified by vacuum distillation to give 77% purity. This mixture was taken on to the next reaction.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[C:14](=[N:23]O)[CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH3:39])([CH3:38])[C:30]1=[CH2:40])[CH:26]([CH3:28])[CH3:27]>C(O)C>[CH2:25]([N:29]1[C:30]2([O:22][C:15]3[C:16]4[C:21]([C:12]([C:9]5[CH:10]=[CH:11][C:6]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[CH:7][CH:8]=5)=[CH:13][C:14]=3[N:23]=[CH:40]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:31]([CH3:39])([CH3:38])[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]([CH3:28])[CH3:27]
Reactant: C=C1N(CC(C)C)c2ccccc2C1(C)C
Reactant: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Solvent: CCO
Product: CC(C)CN1c2ccccc2C(C)(C)C12C=Nc1cc(-c3ccc(N4CCCC4)cc3)c3ccccc3c1O2
Yield: 19 %

Procedure:
A solution of 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime (0.005 mol) and 1-isobutyl-3,3-dimethyl-2-methyleneindoline (0.005 mol) in anhydrous ethanol (70 cm3) was refluxed until examination of the reaction mixture by thin layer chromatography indicated that none of the 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime remained. The mixture was cooled, reduced in volume and the precipitated product collected by vacuum filtration washed with a little cold ethanol and dried. Yield=19%, m.p.=242-245° C., λmax=614 nm in PhMe upon irradiation.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.7 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of 4-n-butylphenyl isocyanate, 3.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 0.8 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (25% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 252°-254° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([N:22]([CH:36]1[CH2:38][CH2:37]1)[C:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[C:6]([C:8]1[CH:9]=[N:10][C:11]([O:14]CC2C=CC=CC=2)=[CH:12][CH:13]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:47]>CCO>[CH2:1]([O:3][C:4]([C:5]1[N:22]([CH:36]2[CH2:38][CH2:37]2)[C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[N:47][C:6]=1[C:8]1[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:39])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1ccc(OCc2ccccc2)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 1.4 g (3 mmol) of 3-(6-benzyloxy-pyridin-3-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in 5 ml of EtOH was added 1.4 g (10 mmol) of ammonium trifluoroacetate. The EtOH was evaporated and the residue heated to 110° C. for 16 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. The crude reside was re-dissolved in 10 ml of EtOH, a generous spatula of 10% palladium on activated charcoal was added, and the mixture stirred under an atmosphere of hydrogen for 1 h. The mixture was then filtered over Hyflo and concentrated. Purification by flash column chromatography [MeOH/EtOAc 4:96 to 1:9] afforded 0.8 g (70%) of the title compound as a colorless solid. MS: 434.2 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11][C:10]2([CH3:20])[CH3:19].[CH3:21][O:22]C(Cl)Cl>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:21]=[O:22])[N:13]([CH3:17])[C:12](=[O:18])[CH2:11][C:10]2([CH3:20])[CH3:19]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)C(C)(C)CC(=O)N2C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 89 mg (66 mmol) aluminum chloride and 5 ml of methylene chloride (CHCl2). The mixture was stirred at ambient temperature for 0.25 hour and then cooled to 0° C. followed by the addition of 75 mg (0.34 mmol) 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one. The reaction mixture was stirred for 10 minutes at this temperature and was then treated with 84 μl (0.93 mmol) of α,α-dichloromethyl methyl ether before allowing the reaction to slowly warm to room temperature over 16 hours. The reaction mixture was quenched with 30 ml of 2M HCl and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with saturated aqueous bicarbonate solution and brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was purified on silica gel eluting with 1:1 ethyl acetate/hexane to afford two products. The more polar material was identified as the desired product: Mass spectrum APCI m/e 248 (p+1). The less polar product was identified as 7-Dichloromethyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (Mass spectrum APCI m/e 302 (p+1)) from which the desire product was isolated after a brief stirring in pH 7 phosphate buffer. Total yield 56 mg (66%).
Reaction SMILES: [Cl-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]([CH:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH3:18])[CH:13]=[C:12]([C:23]([OH:25])=O)[CH:11]=2)=[CH:6][CH:5]=1.Cl.[CH3:27][C:28]1[N:32]=[C:31]([C@H:33]([NH2:35])[CH3:34])[O:30][N:29]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15](=[O:16])[N:14]([CH:17]([C:19]([OH:22])([CH3:20])[CH3:21])[CH3:18])[CH:13]=[C:12]([C:23]([NH:35][C@@H:33]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[N:32]=3)[CH3:34])=[O:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: CC(n1cc(C(=O)O)cc(-c2ccc(F)cc2)c1=O)C(C)(C)O
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c(=O)n(C(C)C(C)(C)O)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the sodium chloride salt of 5-(4-fluorophenyl)-1-(3-hydroxy-3-methylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (177 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride salt (110 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), 1-hydroxy-7-azabenzotriazole (6 mg, 0.05 mmol) and N-methylmorpholine (0.121 mL, 1.10 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, water was added. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. HRMS 429.1973 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][N:27]=[C:26]([N:35]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[N:25]=4)=[C:20]([C:44]([N:46]4[CH2:55][CH2:54][C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:47]4)=[O:45])[CH:19]=3)=[O:17])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=[C:26]([N:35]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[N:25]=4)=[C:20]([C:44]([N:46]4[CH2:55][CH2:54][C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:47]4)=[O:45])[CH:19]=3)=[O:17])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCCCN(CCCC)c1ncc(C(=O)OCC)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(Cl)cc4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(CCCC)c1ncc(C(=O)O)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(Cl)cc4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 55 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 4-(4-(7-chloronaphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-(dibutylamino)pyrimidine-5-carboxylate (Example 319, 23 mg, 0.03 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was added 2N NaOH (0.15 mL, 0.30 mmol). The resulting reaction mixture was stirred at 55° C. for 3 h. At 0° C., the reaction mixture was neutralized to pH 3-4 with aq. 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (14 mg, 63%). MS(ESI+) m/z 754.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[N:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C(Cl)(Cl)Cl.CO.ClCCl>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:14][C:13]=2[N:26]([CH:27]2[CH2:29][CH2:28]2)[C:35]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2nc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)CC1
Yield: 70 %

Procedure:
Following the procedure of Example K-2, the reaction of N-benzyloxy-2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxamide (Example J-2, 160 mg, 0.42 mmol) with CDI (135 mg, 0.83 mmol) in chloroform (2 mL) and purification of the reaction mixture by flash chromatography on a silica gel with 5% of MeOH/dichloromethane as eluent provided 125 mg of the title compound as powder, mp 188-189° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([C:23]2[C:24]([S:29][CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH:16]=[C:17]([CH3:19])[CH:18]=1>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([C:23]2[C:24]([S:29]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[O:6])=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc3ccccc23)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)c2cccnc2S(=O)Cc2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
m-Chloroperoxybenzoic acid (65%, 210 mg, 0.72 mmol) was added to a solution of N-(3,5-dimethylphenyl)-2-(quinolin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 1-3,200 mg, 0.50 mmol) in anhydrous dichloromethane (5.0 mL) under ice-cooling, and then the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off with chloroform (30 mL) and 1N sodium hydroxide aqueous solution (30 mL), and washed. The resulting solid was dried at 50° C. under reduced pressure to give 150 mg of the target compound as a white solid (Yield: 70%).
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][C:10]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1)=[O:2].Cl([O-])=[O:28].[Na+].O.O.P([O-])(O)(O)=O.[Na+].O>CC(O)(C)C.CC(=CC)C.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][C:10]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)([OH:28])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1cc2c(nc1COc1ccc(C=O)cc1)CCCCC2
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1cc2c(nc1COc1ccc(C(=O)O)cc1)CCCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.1 %

Procedure:
Ethyl 2-(4-formylphenoxymethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.05 g, 8.63 mmol) was dissolved in a mixed solution of 2-methyl-2-propanol (33.0 ml) and 2-methyl-2-butene (10.0 ml), and to the solution was added dropwise aqueous solution (26.0 ml) of sodium chlorite (80%, 4.88 g, 43.2 mmol) and sodium dihydrogenphosphate dihydrate (4.46 g, 28.6 mmol). Chloroform was added until insoluble matter was dissolved and then the solution was stirred at room temperature for 3.5 hours. The reaction solution was diluted with chloroform, mixed with water and then extracted with chloroform-methanol mixed solution (5:1). The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain the title compound (2.84 g, 89.1%) as white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([F:13])=[CH:9][C:10]=1[O:11][CH3:12])=[O:4].[OH-].[Na+]>O1CCOCC1>[F:13][C:8]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a stirring solution of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (0.5 g, 2.3 mmol) in dioxane (8 mL, 0.3 M) was added 2N NaOH (6.0 mL, 12 mmol). After one hour at room temperature, the reaction mixture was concentrated, and 2N HCl was added. The aqueous layer was diluted with ether. The organic layer was separated, dried over Na2SO41 filtered and concentrated to afford a 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (0.55 g, 96%) as a pale yellow powder: Rf 0.18 (5% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 8.35 (d, J=9.0 Hz, 1 H), 7.55–7.52 (m, 2 H), 7.48–7.38 (m, 3 H), 6.89 (d, J=11.7 Hz, 1H), 4.12 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1.[CH3:19][C:20]1[CH:25]=[C:24]([N:26]2[C:30]([CH3:31])=[C:29]([CH3:32])[C:28]([CH3:33])=[N:27]2)[CH:23]=[CH:22][C:21]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:9]1([C:8]2[C:3]([CH2:2][O:34][C:21]3[CH:22]=[CH:23][C:24]([N:26]4[C:30]([CH3:31])=[C:29]([CH3:32])[C:28]([CH3:33])=[N:27]4)=[CH:25][C:20]=3[CH3:19])=[C:4]([N:12]3[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]3)[CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Reactant: Cn1nnn(-c2cccc(C3CC3)c2CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-bromomethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 2) δ0 g, 2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol (described in Reference Preparation example 20) 0.36 g, potassium carbonate 0.29 g and acetonitrile 15 ml was stirred with heating under reflux for seven hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was then concentrated. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 2”) δ1 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:26][CH2:25][C:5]2([CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6]2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]2([CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)C1CC2(CCC(O)CC2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCC(=O)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
To a solution of 3-ethyl 2-(phenylmethyl) 8-hydroxy-2-azaspiro[4.5]decane-2,3-dicarboxylate (112) (4.36 g, 120.05 mmol) in dry DCM (60 mL) was added Dess-Martin Periodinane (10.22 g, 24.1 mmol) and the reaction stirred at rt under nitrogen for 18 h. The reaction was poured into 10% aq sodium thiosulfate (150 mL) and sat. NaHCO3 (150 mL) and stirred for 10 min. Extracted with DCM (2×150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25-80% hexanes/EtOAc to afford the title compound as a pale yellow oil (2.89 g, 67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: OCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-(4-bromophenoxy)-1-propanol (10.0 g). To the mixture was added under ice-cooling 65% sodium hydride (2.4 g),and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise bromopropane (5.5 ml), and the mixture was stirred for 3 hours. To the mixture was added 65% sodium hydride (0.8 g), and the mixture was stirred at 70 for 1 hour and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=5/1) to give 1-bromo-4-(3-propoxypropoxy)benzene (6.7 g).