Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[O:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-(methoxycarbonylmethoxy)-3-nitrophenol (6.0 g, 26.8 mmol), 1-(tert-butyloxycarbonyl)-4-hydroxypiperidine (13.8 g, 68.9 mmol) and triphenylphosphine (18.0 g, 68.9 mmol) in tetrahydrofuran (80 mL) at 20° C. under argon was added diisopropyl azodicarboxylate (13.9 g, 68.9 mmol), dropwise over 0.75 h. The resulting solution was stirred at 20° C. for 4 h, then evaporated in vacuo. Chromatography of the residue on silica (400 g) eluting with 5–50% ether in hexane gave the title compound (10.1 g, 93%) as a yellow oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.C(OP([CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])(=O)OCC)C.[H-].[Na+]>C1C=CC=CC=1>[CH3:39][N:37]([CH3:38])[C:36](=[O:40])[CH:35]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)C(=O)C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Di-4-biphenylyl ketone (6.68 g.) was added to a mixture of N,N-Di-methylcarbamoylmethyl phosphonic acid diethyl ester (C.A. 65, 615 g. 1966) (4.46 g.), sodium hydride (60%) (0.8 g.) and benzene (400 ml.). The mixture was boiled under reflux for 60 hours. The benzene layer, decanted and evaporated, gave an oil, from which, by column chromatography on silica gel MFC in benzene and elution by ethyl acetate, was isolated N,N-dimethyl-3, 3-di(4-biphenylyl) acrylamide, m.p. 121° C after recrystallisation from light petroleum (b.p. 80°-100° C). This, reduced with lithium aluminum hydride in ether/tetrahydrofuran at -30° C, gave 1,1-di(4-biphenylyl)- 3 -dimethylaminoprop-1-ene identical with that described in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[C:15](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O.O>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])O
Reactant: COC(=O)C(=NO)c1ccccc1O
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
1.7 g (0.0075 mol) of methyl 2-(2-hydroxyphenyl)-2-hydroxyimino-acetate (HPLC: 86.4% Z, log p=1.70) (Example VII-1d from process step 7) in 40 ml of acetonitrile are heated under reflux with 0.77 g (0.0076 mmol) of potassium bicarbonate and 1.1 g (0.0087 mol) of dimethyl sulphate for 10 hours. The reaction mixture is poured into water, the product is extracted with diethyl ether and the solvent is distilled off under reduced pressure. This gives 1.2 g of crude product which, according to HPLC, contains 46% of methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38. This crude product is chromatographed over silica gel using a mixture of 7 parts of n-hexane and 3 parts of acetone. This gives 0.8 g of a product which, according to HPLC, contains 54.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][Si](C(C)(C)C)(C)C)[CH:30]=2)[CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[CH:25]=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nnc(-c2ccncc2)cc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
600 mg 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 974 mg 1-(tert-butoxycarbonyl)-6-(tert-butyldimethylsiloxy)indole-2-boronic acid, 2.5 g cesium carbonate, and 78 mg [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) are dissolved in a mixture of 18 mL dioxane and 5.4 mL water. Argon is bubbled through the solution for 5 minutes. The mixtures is heated to reflux for 2 hours. After diluting with EtOAc, the organic phase is ished with water and brine, dried with MgSO4 and concentrated in vacuo. The crude product is dissolved in 30 mL THF. After addition of 1.51 g tetrabutylammonium fluoride trihydrate, the red solution is stirred for 2 hours. The reaction mixture is diluted with EtOAc, ished with saturated aqueous ammonium chloride, water, and brine, dried with MgSO4 and concentrated in vacuo. Purification by HPLC afforded 760 mg (95%) 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:50]>>[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH:35]([CH3:36])[CH3:37])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:50]
Reactant: CCN(Cc1cc(C(=O)OCCN(CCCl)C(C)C)cc(Br)c1N)C1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCN(CCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)C(C)C)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}-N-(2-chloroethyl)-isopropylamine analogous to Example 8. Oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]([OH:37])[C:29]=2[CH:38]([CH3:40])[CH3:39])=[O:26])[CH2:20][CH2:19]1.C(N(CC)CC)C>C1COCC1.O>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:35])[CH3:36])=[CH:32][CH:31]=[C:30]([O:37][S:2]([CH3:1])(=[O:4])=[O:3])[C:29]=2[CH:38]([CH3:40])[CH3:39])=[O:26])[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(OS(C)(=O)=O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Methanesulfonyl chloride (103 mg, 0.9 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (149 mg, 0.3 mmol) and triethylamine (91 mg, 0.9 mmol) in THF (2 ml) with ice-cooling and the mixture was stirred for 30 minutes. Then triethylamine (46 mg, 0.45 mmol) and methanesulfonyl chloride (52 mg, 0.45 mmol) were further added thereto and the mixture was stirred for 20 minutes. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, chloroform:methanol=20:1) and the resulting crude crystals were recrystallized from acetone and hexane to provide 120 mg (yield 70%) of the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:18]=[C:10]12.Cl.[Cl:34][C:35]1[CH:40]=[C:39](F)[CH:38]=[CH:37][N:36]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:19][CH:20]3[CH2:21][CH2:22][N:23]([C:39]4[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=4)[CH2:24][CH2:25]3)[N:18]=[C:10]12
Reactant: Fc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3n(n2)CC(O)CC3c2ccc(F)cc2Cl)CC1
Agent: Cl
Product: OC1CC(c2ccc(F)cc2Cl)c2nc(NC3CCN(c4ccnc(Cl)c4)CC3)nn2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 4-(8-(2-chloro-4-fluorophenyl)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)piperidine-1-carboxylate (0.05 g, 0.1 mmol) was added HCl (3 mL, 4 N in dioxane) and the reaction stirred for 0.5 hour. The reaction was then concentrated to dryness, the residue redissolved in dimethylacetamide (0.5 mL), triethylamine added until the mixture was basic, followed by the addition of 2-chloro-4-fluoropyridine (0.04 g, 0.3 mmol) and the mixture heated to 80° C. for 1 hour. The reaction was evaporated to dryness, redissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate, water, brine, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate/MeOH (v/v 1:0 to 95:5) as eluent. The title compound was obtained as a light yellow gum (0.04 g, 76%), an inseparable 1:1 mixture of diasteriomers. MS ISP (m/e): 477.1 [(M+H)+].
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:48](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:17][N:18]([CH3:48])[NH:19][N:20]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC[C@H](O[C@@H]1CC[C@H]2[C@H](c3nnn[nH]3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C3=NNN(C)N3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-methoxyethoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 199; 0.05 g, 0.1 mmol), methyl iodide (0.04 g 0.02 ml, 0.3 mmol) and potassium carbonate (0.04 g, 0.3 mmol) in acetonitrile were heated at 60° C. for 1.5 hours. The mixture was quenched with water and concentrated in vacuo, the residue was partitioned between water and dichloromethane using a bond elute cartridge. The organics were collected and concentrated in vacuo and the residue purified by preparative thin layer chromatography eluting with 5% methanol/dichloromethane. The title compound was isolated as a white solid (33 mg, 58%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].I([O-])(=O)(=O)=[O:25].[Na+].CO>O.C1COCC1>[CH2:1]([S:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=1)=[O:25])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
A mixture of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.25 g), sodium periodate (0.24 g), methanol (6 ml), water (2 ml), and THF (0.8 ml) was stirred at room temperature for 20 minutes, and then heated to 50° C., and stirred with heating for further 1.5 hours. To the ice-cooled reaction mixture, water was added. The precipitated crystal was collected by filtration. The obtained crystal was dissolved in ethyl acetate, and washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, sequentially. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hexane to give 0.20 g of 2-(2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[SH:12])=[O:5])[CH3:2].Br[CH2:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([F:18])[F:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[S:12][CH2:14][CH2:15][C:16]([F:18])([F:17])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1S
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(C)nc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a solution of give 4-mercapto-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.58 g, 2.83 mmol) in acetone (10 ml) are added 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.72 g, 2.83 mmol) and potassium carbonate (0.78 g, 5.66 mmol) an the mixture is heated at 80° C. for 16 h. Acetone is evaporated, diluted with water (40 ml) and extracted with EtOAc (3×30 ml). The crude product is purified by column chromatography (silica gel, 10% EtOAc/hexane) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.6 g, 1.6 mmol, 56%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10](Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([N:24]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(=O)([O-])O.[Na+].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:1]([N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:28]2[N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:25]=[CH:26][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cn(Cc2ccccc2)nc(Cl)c1=O
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cn(Cc2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 77.7 %

Procedure:
1-Benzyl-3-chloro-5-methoxypyridazin-4(1H)-one (13.6 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (22.0 g), potassium carbonate (51.0 g) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.92 g) were suspended in toluene (330 mL) and water (33.0 mL), and the mixture was heated under reflux under a nitrogen atmosphere for 24 hr. The reaction mixture was cooled to room temperature, diluted with water and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to give the title compound (15.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:36]=[O:37])[CH:43]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3c2=O)cc1
Reactant: O=Cc1cccc(B(O)O)c1
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3cccc(C=O)c3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 6-chloro-2-(4-methoxycarbonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 3-formylphenylboronic acid.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: Ic1ccc2c(c1)CCc1ccccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Ic1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
Under an argonatmosphere, 125 g of 2-iodo-9,10-dihydrophenanthrene, 98 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and 1.2 L of 1,4-dioxane were added, and then the mixture was stirred for 24 hours under heating reflux. After having been cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography, and was then washed with methanol. Thus, 98 g of a white crystal were obtained (in 68% yield).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]#[N:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[CH3:18][OH:19].[ClH:20]>ClCCl>[ClH:20].[CH3:18][O:19][C:16](=[NH:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1
Reactant: CO
Reactant: N#CCc1ccc2c(c1)Nc1nccnc1S2
Agent: Cl
Solvent: ClCCl
Product: COC(=N)Cc1ccc2c(c1)Nc1nccnc1S2
Temperature: -20 °C

Procedure:
480 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetonitrile was suspended in a solution of dry methanol (20 ml)/dry dichloromethane and cooled to −20° C. Then dry hydrogen chloride gas was blown thereinto until saturation was attained while paying attention lest the bulk temperature exceed 0° C. Then the reaction mixture was hermetically sealed and allowed to stand under ice-cooling over day and night. Next, the solvent was distilled off under reduced pressure while maintaining the bulk temperature at room temperature or below. Then a small amount of dry methanol was added to the residue and ethyl acetate was gradually added thereto under ultrasonication. The orange crystals thus precipitated were taken up by filtration, washed with diethyl ether and dried under reduced pressure. Thus, 570 mg of the title compound was obtained.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1B(O)O>>[Cl:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(N[C@H]2COC[C@H]2O)c(CC)nc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting cis-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and 2-chloro-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3420, 2969, 2935, 2873, 1604, 1568, 1482, 1439, 1397, 1393, 1287, 1229, 1204, 1181, 1044 cm−1; OAMS supporting ions at: ESI+ 378.1; MS (EI) m/z 377 (M+); HRMS (FAB) calcd for C19H24CLN3O3+H1 378.1584, found 378.1566. Anal. Calcd for C19H24ClN3O3: C, 60.39; H, 6.40; N, 11.12. Found: C, 59.97; H, 6.46; N, 10.99.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[CH:10][C:11]=1[CH2:12][CH3:13])[C:7]([OH:9])=O)[CH3:2]>C(OC(=O)C)(=O)C>[CH2:12]([C:11]1[CH:10]=[C:6]2[C:7](=[O:9])[O:16][C:14](=[O:15])[C:5]2=[CH:4][C:3]=1[CH2:1][CH3:2])[CH3:13]
Reactant: CCc1cc(C(=O)O)c(C(=O)O)cc1CC
Solvent: CC(=O)OC(C)=O
Product: CCc1cc2c(cc1CC)C(=O)OC2=O
Yield: 22.7 %

Procedure:
The product of above-mentioned (a) (1.5 g, 6.7 mmol) was heated under reflux in acetic anhydride (10 ml) for 1 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 10% aqueous sodium hydroxide solution. The insoluble materials were collected by filtration, washed with water, and dried to give 0.31 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].[F:22][C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[C:25]([F:43])([F:42])[O:26][C:27]([F:41])([C:32]([F:40])([F:39])[O:33][C:34]([F:38])=[C:35]([F:37])[F:36])[C:28]([F:31])([F:30])[F:29]>O1CCCC1>[F:37][C:35]([F:36])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:34]([F:38])[O:33][C:32]([F:39])([F:40])[C:27]([F:41])([O:26][C:25]([F:42])([F:43])[C:24]([F:44])([F:45])[C:23]([F:22])([F:46])[F:47])[C:28]([F:31])([F:30])[F:29]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
In a dry box, tetrahydrofuran (THF, 1000 mL) and dimethyl 5-hydroxyisophthalate (42.00 g, 0.20 mol) were added to an oven dry round bottom reaction flask equipped with a stirrer to form a reaction mixture. Potassium t-butoxide (6.16 g, 0.055 mol) was added to the reaction flask. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2trifluorovinyloxy)propan-2-yloxy)propane (216 g, 0.50 mol) was then added via the addition funnel to the reaction mixture, and the reaction allowed to stir at room temperature. After 24 hour the reaction was terminated via the addition of 80 mL of 10% HCl. The reaction mixture was concentrated at reduced pressure, diluted with dichloromethane, washed with 10% HCl (2×100 mL) and then with water (2×100 mL), to form an aqueous phase and an organic phase. The separated organic phase was dried over anhydrous sodium sulfate and was then concentrated at reduced pressure to form a crude product. The crude product was purified by column chromatography to give 86.07 g (67.32%) yield of the desired material, dimethyl 5-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)isophthalate.