Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+].O[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:7][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][CH:16]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(OC2CCNCC2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
25 g of 4,4′-dimethylbenzophenone was dissolved in ethanol-tetrahydrofuran (180 ml-60 ml); 2.23 g of sodium borohydride was added under ice cooling conditions, followed by stirring at room temperature for 24 hours. The mixture was concentrated under reduced pressure; ice water was added to the residue; the crystal precipitated was collected and dried; the crystal obtained (30.5 g) was dissolved in 800 ml of toluene; 11.9 g of 4-hydroxypiperidine and 24.9 g of p-toluenesulfonic acid monohydrate were added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; 100 ml of ice water and 140 ml of a 1 N aqueous solution of sodium hydroxide were added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90;10:1). The desired fraction was collected to yield 32.8 g of 4-[bis(4-methylphenyl)methoxy]piperidine as an oily substance. 16.4 g of 4-[bis(4-methylphenyl)methoxylpiperidine was dissolved in 100 ml of N,N-dimethylformamide; 14.2 g of N-(3-bromopropyl)phthalimide and 8.15 g of potassium carbonate were added, followed by stirring at room temperature for 16 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:2). The desired fraction was collected to yield 21.2 g of N-[3-[4-[bis(4-methylphenyl)methoxy]piperidino]propyl]phthalimide as an oily substance. 20.5 g of this oily substance was dissolved in 150 ml of ethanol; 2.18 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethanol was added to the residue; the crystal precipitated was collected, dissolved in 40 ml of a 1 N aqueous solution of sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure to yield 10.5 g of the title compound as an oily substance.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1.Br[CH2:30][CH2:31][O:32][CH3:33]>CN(C)C=O.CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1
Reactant: COCCBr
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Sodium hydride (17 mg, 60%) was added slowly to an ice-cooled solution of 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (150 mg) in 2 mL N,N-dimethylformamide (DMF). After stirred for 30 min, 1-Bromo-2-methoxy-ethane (59 mg) in 1 mL DMF was added cautiously by syringe. The mixture was warmed to room temperature and stirred overnight, then diluted with 1 mL methanol and directly sent to prep-HPLC. The product [1-(2,4-difluoro-phenyl)-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (40 mg) was obtained as a yellow solid. LC-MS m/e 411(MH+). 1H NMR (400 MHz, DMSO) 9.12(s, 1H), 7.81(s, 1H), 7.61(m, 1H), 7.43(t, 1H), 7.34(d, 1H), 7.25(t, 1H), 7.10(d, 1H), 6.85(d, 1H), 5.81(s, 1H), 4.23(m, 2H), 3.71(m, 2H), 3.32(s, 3H), 2.20(s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[F:13].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:13])=[C:6]([F:12])[C:7]2[N:11]=[C:18]([C:17]3[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:24])[NH:10][C:8]=2[CH:9]=1)=[O:14]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1F
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: COC(=O)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,5-diamino-2,3-difluorobenzoic acid methyl ester (404 mg, 2.0 mmol) and 2,6-dichlorobenzaldehyde in DMSO (15 mL) was added Yb(OTf)3 (248 mg, 20%) and the solution was stirred at ambient temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid methyl ester as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14]CC)=O>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH2:11][C:10]([NH:4][C:3]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:18]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: Cc1ccc(C)c(NC(=O)CC(=O)Nc2cc(C)ccc2C)c1
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 2,5-dimethylaniline and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol,≡6.6 mL) on a stream of nitrogen. N1,N3-di(2,5-dimethyl-phenyl)-malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 14.9 g N1,N3-di(2,5-dimethyl-phenyl)-malonamide was obtained (yield 96.0%, purity 98.5%)
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]([C:12]([C:14]1([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]1)=[O:13])[NH2:11].[CH2:26]([O:33][N:34]1[C:40](=[O:41])[N:39]2[CH2:42][C@H:35]1[CH2:36][CH2:37][CH:38]2[C:43](O)=[O:44])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C:14]1([C:12]([NH:10][NH:11][C:43]([CH:38]2[CH2:37][CH2:36][C@@H:35]3[CH2:42][N:39]2[C:40](=[O:41])[N:34]3[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:44])=[O:13])[CH2:16][CH2:15]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1(C(=O)NNC(=O)C2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a solution of tert-butyl (1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (10.0 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol), and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was stirred at rt for 2 hrs. The mixture was diluted with CH2Cl2 (500 mL), washed with H2O (300 mL), dried over Na2SO4, and concentrated. The crude product was washed with EtOAc (200 mL), and filtrated to afford tert-butyl(1-(2-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopropyl)methylcarbamate (15 g, 85%) as a white solid. ESI-MS (EI+, m/z): 488.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>O1CCCC1.C(Cl)(Cl)Cl>[Br:29][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (1.0 g in a mixture of 10 mL dry tetrahydrofuran and 10 mL dry chloroform) at 0° C. was added pyridinium bromide perbromide (1.14 g) and the reaction stirred at 0° C. After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3×) and 0.3M sodium bisulfate (3×) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) gave the title compound (1.2 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(CC=O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a stirred solution of (4-Methoxy-phenyl)-acetic acid methyl ester (18.0 g, 100 mmol) in anhydrous toluene (200 mL) cooled to −78° C. under N2 was added diisobutylaluminum hydride (DIBAL, 1.0 M in toluene, 150 mL, 150 mmol) over a period of 10-15 minutes. The mixture was stirred at −78° C. for an additional 2 h. The reaction was quenched by the slow addition of MeOH, followed by the introduction of 10% Rochelle's Salt. The suspension was diluted with EtOAc and stirred at room temperature for 1 h. The EtOAc layer was set aside and the aqueous layer was extracted with EtOAc(2×). The combined organic layers were combined and dried over Na2SO4 and filtered. The solution was concentrated under vacuum to yield 12.0 g (100%) of the title aldehyde as a yellow viscous semisolid, which was used in the next step without purification. LC/MS (APCI, ES, M+H=151).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[CH:33]1([C:36]2[C:41]([CH2:42][CH2:43][NH2:44])=[CH:40][CH:39]=[C:38]([C:45]([F:48])([F:47])[F:46])[N:37]=2)[CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:44][CH2:43][CH2:42][C:41]3[C:36]([CH:33]4[CH2:35][CH2:34]4)=[N:37][C:38]([C:45]([F:48])([F:46])[F:47])=[CH:39][CH:40]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ccc(C(F)(F)F)nc1C1CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)nc4C4CC4)cc3)c(Cl)cc21
Reaction time: 0.25 h
Yield: 19.2 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 50 mg, 0.13 mmol) was diluted with dichloromethane (2 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (73 μL, 0.15 mmol) and DMF (1 drop). After stirring for 15 minutes, 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethanamine (31 mg, 0.13 mmol) and diisopropyl ethylamine (69 μL, 0.40 mmol) were added. After stirring for 1 hour, the reaction was loaded onto silica gel and eluted with 100% ethyl acetate to yield ethyl 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (15 mg, 0.025 mmol, 19% yield). MS (es+apci, positive) m/z=589.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1.[N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]=[S:26]>CS(C)=O>[C:18]([O:17][C:16]([NH:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[Cl:23])[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[S:26])=[N:7][CH:6]=1)=[O:22])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1Cl
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)c(NC(=O)OC(C)(C)C)c2)cn1
Yield: 96.8 %

Procedure:
In the same manner as in Reference Example 30 and using tert-butyl {5-[(6-aminopyridin-3-yl)oxy]-2-chlorophenyl}carbamate (10.8 g, 32.3 mmol), ethyl isothiocyanatoformate (4.60 mL, 38.9 mmol) and DMSO (60 mL) as starting materials, the title compound (14.6 g, 97%) was obtained as a pale-yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:11]([C:31]([F:34])([F:33])[F:32])[CH:10]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl:42][C:43]1[N:44]=[C:45](Cl)[C:46]2[CH:51]=[CH:50][NH:49][C:47]=2[N:48]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[Cl:42][C:43]1[N:44]=[C:45]([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]3)=[C:11]([C:31]([F:32])([F:34])[F:33])[CH:10]=2)[C:46]2[CH:51]=[CH:50][NH:49][C:47]=2[N:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)CC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
After tert-butyl 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (266 mg), Na2CO3 (169 mg), and tetrakis(triphenylphosphine)palladium (0) (31 mg) were added to a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (1.6 mL), and water (0.6 mL), the mixture was stirred at 150° C. for 2 hours under microwave irradiation, and cooled to room temperature. After water and EtOAc were added to the reaction mixture, the mixture was stirred, filtered, and washed with EtOAc, whereby tert-butyl 4-{2-[4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (121 mg) was obtained as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11]([C:15]([CH3:17])=O)[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[CH3:17][C:15](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(=O)CC(C)C
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: CC(CC(C)C)=Nc1cc(O)c(Cl)cc1F
Temperature: 60 °C
Yield: 100 %

Procedure:
A 50-ml four-neck flask equipped with a Vigreux column (2 cmφ×25 cm) and a dehydrating column (filled with molecular sieve) attached thereon was charged with 5-amino-2-chloro-4-fluorophenol (1 g), methyl isobutyl ketone and heptane (weight ratio, 4:1; 40 g), and p-toluenesulfonic acid (4 mg). The mixture was dehydrated under reflux at 60° C. under reduced pressure (constant at 150 mmHg) for 6 hours. The concentration under reduced pressure gave 1.5 g of 5-(1,3-dimethylbutylidenamino)-2-chloro-4-fluorophenol (yield, 100%), m.p., 92°-97° C.; MS (m/z): 243 (M+) 228, 186; NMR (CDCl3, δ) as a 1:4 mixture of cis and trans forms: 0.80 and 1.00 (d, 6H, J=6 Hz), 1.80 and 2.20 (s, 3H), 2.0-2.2 and 2.35-2.38 (m, 3H), 6.3 and 6.4 (d, 1H, J=7.6 Hz), 6.6-7.0 (broad, 1H), 7.04 (d, 1H, J=9.6 Hz).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:15][C:16]2[CH:21]=[C:20]([N:22]3[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]3=[O:34])[C:19]([F:35])=[CH:18][C:17]=2[Cl:36])=[N:11][CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Cl:36][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]=1[O:15][C:10]1[C:9]([OH:8])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncncc3OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncncc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A mixture of 0.959 g of 5-benzyloxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine, 10% palladium/carbon and ethyl acetate was stirred for 8 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated to obtain 0.824 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-hydroxypyrimidine.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:40]>O1CCCC1.CO>[ClH:40].[CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCCN2CCCCC2)cccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCCN2CCCCC2)cccc1-3
Temperature: 60 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (240 mg, 0.48 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 4N aqueous sodium hydroxide (2.5 ml), and the mixture was stirred at 60° C. for 2 hr. 2N Hydrochloric acid (5.1 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate:tetrahydrofuran (2:1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (1 ml) was added 4N HCl-ethyl acetate solution (2 ml). The solvent was evaporated under reduced pressure, and hexane:ethyl acetate (4:1) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:ethyl acetate (4:1) solution. The obtained solid was dried in vacuo to give 12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid hydrochloride (160 mg, yield 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged with dimethyl 5-bromoisophthalate (0.50 g, 1.8 mmol), barium hydroxide octahydrate (0.43 g, 1.4 mmol) and methanol (10 mL). The mixture was stirred at room temperature overnight. HCl (2 N ethyl ether solution, 10 mL) was added and the volatiles were removed under reduced pressure. The residue was purified via flash chromatography to afford the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): 13.70 (br, 1H), 8.42 (t, J=1.5 Hz, 1H), 8.31-8.24 (m, 2H), 3.90 (s, 3H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)nn1
Yield: 81.8 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (342 mg, 1.7 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in anhydrous toluene (8.5 mL) was treated with 3,6-dichloropyridazine (256 mg, 1.7 mmol, Aldrich Chemical Company) and triethylamine (0.24 mL, 170 mg, 1.7 mmol). The reaction mixture was heated to reflux for 16 hours, concentrated under reduced pressure, and the residue purified on SiO2 (5%MeOH/CH2Cl2/1%NH4OH) to provide the title compound (432 mg, 81% yield) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.42(s, 4.5H), 1.46(s, 4.5H), 1.91-2.05(m, 2H), 3.36-3.46 (m, 3H), 3.54-3.60 (m, 1H), 4.57(s, 0.5H), 4.70(s, 0.5H), 4.92(s, 0.5H), 5.07(s, 0.5H), 6.59(d, J=9.20 Hz, 1H), 7.34(d, J=9.56 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+, 328(M+NH4)+.
Reaction SMILES: [C:1]([C:5]1[C:25]([CH3:26])=[CH:24][C:8]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].C([O-])(O)=[O:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].C(OC)=O>C(Cl)Cl.O>[C:1]([C:5]1[C:25]([CH3:26])=[CH:24][C:8]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[O:28])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc2nc(S(=O)Cc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
5--Carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.46 g, 0.0055 mol) in H2O (10 ml) was added and the mixture was cooled to +2° C. m-chloroperbenzoic acid 69.5% (0.62 g, 0.0025 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirring was continued at +2° C. for 15 min. After separation the organic layer was extracted with an aqueous 0.2M NaOH solution (3×15 ml, 0.009 mol). After separation the aqueous solutions were combined and neutralized with methyl formate (0.56 ml, 0.009 mol) in the presence of CH2Cl2 (25 ml). After separation the organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN (10 ml) giving the title compound (0.68 g, 70%).