Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH2:28])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(C)(=O)=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Triethylamine (1.1 g, 10.6 mmol) was added with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (˜150 mL). Methanesulfonyl chloride (892 mg, 7.79 mmol) was added and the reaction was stirred under nitrogen overnight. The reaction mixture was washed with aqueous 1% sodium bicarbonate solution (3×50 mL). The aqueous washes were extracted with dichloromethane (2×20 mL). The organics were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1.89 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:10]1
Reactant: OCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reaction time: 1 h

Procedure:
A mixture of trans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol (1.51 g, 6.9 mmol) is dissolved in a solution of methylene chloride (25 mL) containing polymer supported triphenylphosphine (2.87 g, approx 8.6 mmol). The mixture is cooled in an ice water bath, and carbon tetrabromide (2.3 g, 7.0 mmol) is added. The reaction is stirred for 1 hour, and the polymeric material was removed by filtration. The filtrate is concentrated and chromatographed on silica gel using a 2:1 mixture of chloroform and ethyl acetate (EtOAc) as the solvent to give trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][SH:6].Br[C:10]1[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=1>C1COCC1>[C:16]([C:11]1[C:10]([S:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:17]
Reactant: N#Cc1ncccc1Br
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ncccc1SCC(F)(F)F
Temperature: 50 °C

Procedure:
A suspension of sodium hydride (60% oil dispersion, 180 mg, 4.52 mmol) in dry THF (17 mL) under N2 was treated with trifluoroethanethiol (0.40 mL, 4.52 mmol) and the mixture was heated to 50° C. When gas evolution ceased (ca. 1 h), 3-bromo-2-cyanopyridine was added and the mixture was heated to reflux for 4 h. The solvent wag removed in vacuo and the residue was taken up in CH2Cl2 and filtered to remove precipitated sodium bromide. The filtrate was concentrated at reduced pressure to afford the title compound as an orange oil:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(C)=O.O>[C:18]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
8.2 g of potassium carbonate was added to a suspension of 3.0 g of 4-amino-3-methylbenzoic acid in 60 ml of acetone and 60 ml of water. Thereto was dropwise added, with ice-cooling, a solution of 4.0 g of cinnamoyl chloride in 30 ml of acetone. The mixture was stirred at the same temperature for 30 minutes to give rise to a reaction. The reaction mixture was poured into ice water, and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 2.9 g of 4-cinnamoylamino-3-methylbenzoic acid as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([O:24][Si:25]([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)O[Si](C)(C)C(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:4]([N:6]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=3)[CH:17]=[CH:16][N:15]=2)C(=O)OC(C)(C)C)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][C:26]1[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH:19]=2)=[N:22][CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(N(C(=O)OC(C)(C)C)C(=O)C2CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 98.5 %

Procedure:
Add tert-butyl N-(cyclopropanecarbonyl)-N-[4-[(3-methyl-5-nitro-2-pyridyl)oxy]-2-pyridyl]carbamate (350 mg, 0.84 mmol) in DCM (10 mL), add trifluoroacetic acid (2 mL). Stir the reaction at room temperature for 2 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the title compound (260 mg, 98%). MS: (M+1): 315.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.N1C=CC=CC=1.[C:17]1([CH:23]([N:25]2[CH2:29][CH2:28][CH:27]3[CH2:30][NH:31][CH2:32][CH:26]23)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([N:31]2[CH2:30][C@@H:27]3[C@@H:26]([N:25]([CH:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:24])[CH2:29][CH2:28]3)[CH2:32]2)[N:3]=[C:4]([NH2:10])[N:5]=1)[CH3:9]
Reactant: CCc1cc(Cl)nc(N)n1
Reactant: CC(c1ccccc1)N1CCC2CNCC21
Solvent: c1ccncc1
Solvent: CCO
Product: CCc1cc(N2C[C@H]3CCN(C(C)c4ccccc4)[C@H]3C2)nc(N)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-chloro-6-ethyl-pyrimidin-2-ylamine (200 mg, 1.27 mmol) in EtOH (2.4 mL) was added pyridine (210 μL, 2.54 mmol) and 1-(1-phenyl-ethyl)-octahydro-pyrrolo[3,4-b]pyrrole (360 mg, 1.65 mmol). The solution was stirred for 2 h at 90° C. The compound was purified directly with reversed-phase HPLC to yield 115 mg (28%) of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1nnc(Cl)nc1Cl
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetralis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: [O:1]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2.[CH3:7][C:8]1[C:9]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[N:10][C:11](=[O:14])[NH:12][CH:13]=1>O1CCCC1.CS(C)=O.[Pd]>[OH:1][CH:3]1[CH2:4][CH:5]([N:12]2[CH:13]=[C:8]([CH3:7])[C:9]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:10][C:11]2=[O:14])[CH:6]=[CH:2]1
Reactant: C1CC2=C(C1)O2
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.8 %

Procedure:
The equivalent amount of epoxycyclopentene is slowly added at 0° C. to 3.54 g (0.020 mol) of 5-methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (prepared by reaction of thymine with 1,2,4-triazole/POCl3 /triethylamine) in a mixture of 40 ml of dry tetrahydrofuran and 20 ml of dry dimethylsulfoxide with 5 mol % of the palladium(0) catalyst prepared in situ as above, and the reaction mixture is stirred at room temperature for 12 hours. The resulting suspension is filtered, the filtrate is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 9/1. 1.34 g (25.8% of theory) of 1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one (Example 1.18.1.) of melting point 198° to 204° C. are obtained. 1H NMR (270 KHz, d6 -DMSO), δ[ppm]: 9.31 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 5.52 (m, 1H), 5.28 (d, 1H), 4.71 (m, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.47 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([SH:26])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([S:26][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc3[nH]c(S)nc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-benzimidazole-2-thiol obtained in Example 27 (750 mg), tert-butyl bromoacetate (429 mg), potassium carbonate (415 mg), and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (785 mg, 81%) as an amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 64.1 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (75 mg). m/z (M+H)+: 615
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>>[C:12]([O:11][C:7]([NH:8][NH:9][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NNC1CCCC1
Temperature: 67.5 °C
Yield: 46.3 %

Procedure:
Cyclopentanone (5.000 g, 59.44 mmol; CAS #120-92-3, purchased from Aldrich) was dissolved in hexanes (90 mL). t-Butyl carbazate (7.860 g, 59.47 mmol) was added and the mixture was heated at 65-70° C. for 1 hour. The mixture was cooled and concentrated in vacuo. The residue was taken up in isopropanol (25 mL)-ether (25 mL)-hexanes (50 mL) and chilled. The crystalline material was collected by filtration to give N′-cyclopentyl-hydrazinecarboxylic acid tert-butyl ester (5.51 g; 47%). A second crop (2.62 g, 22%) was collected from the mother liquor.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18](Cl)=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([N:21]=[N+:22]=[N-:23])=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCCCc2nc(C(=O)Cl)co2)OCCO1
Agent: N#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(CCCCc2nc(C(=O)N=[N+]=[N-])co2)OCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), this crude 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carbonyl chloride was dissolved in acetone (18.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (314 mg, 4.79 mmol) in H2O (2.0 mL) was added over 1 h. The reaction mixture was stirred at 0° C. for 1.5 h then at rt for 45 min. The mixture was concentrated under reduced pressure (coevaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.89 min [M+H]+=281.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:11]O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cncc(Br)c1
Product: COC(=O)c1cncc(Br)c1
Yield: 94 %

Procedure:
5-Bromonicotinic acid (10 g) and methanol were treated as in the above Production Example 3-3 to give the title compound (10.052 g) as colorless crystals (yield: 94.0%).
Reaction SMILES: O1CCOCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([O:42][CH2:43][CH2:44][CH2:45]Br)([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[S:48]([O-:51])([O-:50])=[O:49].[Na+:52].[Na+].[Na]>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)([O:42][CH2:43][CH2:44][CH2:45][S:48]([O-:51])(=[O:50])=[O:49])[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[Na+:52]
Reactant: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C2(OCCCS(=O)(=O)[O-])OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 50 mL 1,4-dioxane was added 3-Benzo[1,3]dioxol-5-yl-5-(3-bromo-propoxy)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)5H-furan-2-one 2.0 g (3.19 mmol). A solution of sodium sulfite, 0.88 g (7.0 mmol) in 50 mL water was added, and the mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether and water. The suspension was acidified to pH 1 with 2 N HCl, giving an oily precipitate in the aqueous phase. The ether was decanted, and the oil was extracted into ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and diluted with ethyl ether, giving a solid. The solid was filtered and dried in vacuo, giving a white solid, 1.07 g. The product was identified by 1H NMR, MS [M--H]+ =627.3 Da. Elemental analysis indicated the material to contain 1/2 sodium salt per molecule.
Reaction SMILES: C(OC([N:8]([C:53]1[N:54]=[CH:55][S:56][CH:57]=1)[S:9]([C:12]1[C:50]([F:51])=[CH:49][C:15]([O:16][C:17]2[C:18]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)[N:31]=3)=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:21][CH:22]=2)=[C:14]([Cl:52])[CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:52][C:14]1[C:15]([O:16][C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:19][C:18]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([N:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[N:31]=2)=[CH:49][C:50]([F:51])=[C:12]([S:9]([NH:8][C:53]2[N:54]=[CH:55][S:56][CH:57]=2)(=[O:11])=[O:10])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(-c4cccc(F)c4)ncc3Oc3cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c4cscn4)cc3Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Yield: 26.2 %

Procedure:
10 mg (1.0 eq) of the obtained tert-butyl 4-(4-(5-(4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-2-(3-fluorophenyl)pyridin-4-yl)pyrimidin-2-yl)piperazin-1-carboxylate was dissolved in 0.2 oL dimethylchloride, and 0.2 mL of trifluoroacetic acid was added thereto. The mixture was reacted at room temperature for 2 hours. The solvent was removed by concentrating under reduced pressure. The residue was separated by PLC (developing solvent, dimethylchloride:methanol=15:1) to obtain 2.0 mg of 5-chloro-2-fluoro-4-((6-(3-fluorophenyl)-4-(2-(piperazin-1-yl)pyrimidin-4-yl)pyridin-3-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide.
Reaction SMILES: CC(CC(C)(C)C)C[CH2:4][CH:5](C(C)CC(C)(C)C)[CH2:6][OH:7].[CH2:20]([CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:28][OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:4]([O:29][CH2:28][CH:27]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:5]1[O:7][CH2:6]1
Reactant: CCCCCCCCCC(CO)CCCCCCC
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Product: CCCCCCCCCC(CCCCCCC)COCC1CO1
Yield: 80 %

Procedure:
The same reaction as in Reference Example 1 was carried out under the same conditions except that the 5,7,7-trimethyl-2-(1,3,3-trimethylbutyl) octanol in Reference Example 1 was replaced by 2-heptylundecanol, whereupon 65 g (yield: 80%) of 2-heptylundecyl glycidyl ether was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)([O-:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Yield: 4.5 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-nitrobenzyl bromide (0.09 g) in place of benzyl chloride and Cs2CO3 (0.2 g) in place of NaH. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12; found, m/z 383.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.07-8.05 (m, 1H), 7.91-7.87 (m, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 3H), 7.36-7.33 (m, 2H), 5.41 (s, 2H), 2.88-2.85 (m, 4H), 2.82-2.79 (m, 2H), 2.73-2.71 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:14]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1Br
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-5-methoxybenzoic acid (Aldrich 384003; 5.0 g, 21.6 mmol) in methanol (80 mL) was added concentrated hydrochloric acid (2 mL) and the mixture was heated under reflux for 18 hours. The resulting solution was cooled, the solvent was removed in vacuo, water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over MgSO4, filtered and evaporated to obtain methyl 2-bromo-5-methoxybenzoate as a light brown oil (4.50 g, 85%); NMR Spectrum δH (300 MHz, CDCl3) 7.53 (1H, d, J 8.8 Hz, 3-H), 7.32 (1H, d, J 3.0 Hz, 6-H), 6.89 (1H, dd, J 3.0, 8.8 Hz, 4-H), 3.94 (3H, s, Ar OCH3) and 3.82 (3H, s, CO2CH3) (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142); νmax/cm−1 (thin film) 2951, 1732 (C═O), 1592, 1472, 1433, 1289, 1250, 1227, 1099, 1017, 975, 823, 792 (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142); Rf (hexane-ethyl acetate 5:1) 0.58.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1>CN(C)C=O>[CH:32]1([CH2:31][N:11]([C:4]2[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:18][CH2:19]2)=[O:13])[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(CC2CC2)c2cc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100 mg, 0.26 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.2 mg, 0.26 mmol) was added, followed by stirring at room temperature for 15 min, and successively bromomethylcyclopropane(21.8 mg, 0.26 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.