Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2ccc[n+]([O-])c21
Temperature: 0 °C

Procedure:
To a mixture of 25.1 grams (0.103 mole) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 175 ml of dry methylene chloride at 0° C. under an argon atmosphere was added dropwise over 70 minutes a solution of 24.12 grams of 3-chloroperoxybenzoic acid in 150 ml of methylene chloride. After the addition the solution was stirred for 1/2 hour after which the ice bath was removed. After two days the reaction was poured into 1.0 N aqueous sodium hydroxide and extracted with methylene chloride. The organic portions were combined, washed once with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The resultant product was triturated with isopropyl ether and filtered to provide 25.8 grams (96%) yield of the title compound.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[N:19]=[C:6]2[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:4]=1[CH3:39])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])[N:19]=[C:6]2[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=2)[C:4]=1[CH3:39])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
Under an atmosphere of argon protective gas, tert-butyl N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycinate (18.0 mg, 34 μmol) was dissolved in dry dichloromethane (3.1 ml). At room temperature, trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred for 45 min. More trifluoroacetic acid (2 ml) was then added, and the mixture was stirred for a further 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (15.2 mg, 94% of theory).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C[O-].[Na+].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>O1CCOCC1>[F:13][C:14]([F:21])([F:20])[C:15]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)=[O:16]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(F)(F)F

Procedure:
25 g of trans-4-aminocyclohexanol hydrochloride were suspended in 250 mL of dry dioxane and 30 mL of sodium methylate solution (30% in methanol, 1 equivalent) were added. 39.3 mL of ethyl trifluoroacetate were added and the reaction mixture was allowed to stir until the reaction was complete. The reaction mixture was evaporated, taken up in 50 mL of 0.1 N HCl and extracted several times with dichloromethane:isopropanol 3:1. The combined organic layer was extracted once with 0.1 N HCl and brine, dried over sodium sulfate and evaporated to dryness to yield 29.0 g of 148. Rt=0.69 min (Method C). Detected mass: 212.2 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([C:11]1([CH2:51][CH2:52][CH2:53][CH3:54])[C:23]2[CH:22]=[C:21]([CH2:24][C:25](C)(O)C#C)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:30]#[C:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:33]=1)=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH3:10]>C1(C)C=CC=CC=1.CC(O)C>[CH2:51]([C:11]1([CH2:7][CH2:8][CH2:9][CH3:10])[C:12]2[CH:13]=[C:14]([C:30]#[C:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:37]=3)[CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=2)[CH2:52][CH2:53][CH3:54]
Reactant: C#CC(C)(O)Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#Cc3ccc(N(CCCCCC)CCCCCC)cc3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#Cc3ccc(N(CCCCCC)CCCCCC)cc3)ccc1-2
Yield: 87 %

Procedure:
Potash powder (0.07 g) is added to a solution of 5a (0.798 g, 1.24 mmol) in 8.75 mL of toluene/i-PrOH (6/1). The mixture is heated in a reverse-flow boiler for 1 h. After cooling, the potash is filtered and the solvents are evaporated. The raw product is purified by silica gel column chromatography (heptane/CH2Cl2 90:10) to yield 0.632 g (87%) of 5b.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc4c(ccn4Cc4ccccc4Cl)c3)c3c(N)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc3c(ccn3Cc3ccccc3Cl)c1)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of EXAMPLE 201B (1.28 g, 2.3 mmol) in anhydrous CH2Cl2 (30 ml) was cooled in an ice bath and TFA (7.5 ml) was added dropwise under inert atmosphere. After stirring 15 min the ice bath was removed and the reaction allowed to warm to ambient temperature while stirring 1 hr. The reaction was concentrated and the residue dissolved in 1M-HCl. The solution washed with EtOAc, basified with 1M-Na2CO3 (pH 9-10) and extracted with 5% MeOH/CH2Cl2 (3×100 ml). The combined extracts were dried over Na2SO4, filtered, concentrated and dried to give the title compound as a tan foam (70%). MS (ESI+) m/e 458 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 8.22 (s, 1H), 7.88 (s, 1H), 7.55 (m, 3H), 7.42 (d, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 6.24 (vbr s, 3H), 5.59 (s, 2H), 4.73 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 2.04 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:17]=2[CH3:34])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N1CCCCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCCCC1
Reaction time: 4 h

Procedure:
5-Bromo-2-(piperidin-1-yl)pyridin-3-amine (0.0537 g, 0.210 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.0632 g, 0.217 mmol), and hydrochloric acid, 4.0M in 1,4-dioxane (0.05 mL, 0.200 mmol) were stirred in NMP (0.50 mL) then microwaved at 150° C. After an additional 4 h, the reaction was diluted with EtOAc and washed once with satd aq. sodium bicarbonate and once with brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the brown residue was purified with silica gel chromatography (0-40% EtOAc in hexanes) to yield mostly N-(5-bromo-2-(piperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=510.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.[Br:29]N1C(=O)CCC1=O.O>CC(O)=O>[Br:29][C:11]1[C:12]2[O:21][CH:20]3[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:15]3[C:13]=2[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 82 %

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (5.360 g, 12.750 mmol) was dissolved in 160 mL CH3COOH. N-Bromosuccinimide (4.539 g, 25.500 mmol) was added. The reaction mixture was stirred under N2 at rt for 27 h. The reaction mixture was poured into a mixture of 300 g ice and 100 mL water. The aqueous mixture was extracted with EtOAc (3×). The combined organic layers were washed with 5M NaOH (2×250 mL), 25% KOH (2×200 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was chromatographed (SiO2, 15% EtOAc:hexane), and tert-butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in 82% yield (5.250 g, 10.516 mmol). MS (ESI+) for C22H22BrCl2NO3 m/z 499.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[C:21](F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH:42]1(CBr)C[CH2:43]1>C(Cl)(Cl)Cl>[F:38][C:36]([F:39])([F:37])[C:34]1[CH:33]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH:21]4[CH2:43][CH2:42]4)[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:4]=[C:3]([C:2]([F:41])([F:1])[F:40])[CH:35]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C(=O)C(F)(F)F)CC2)C(c2ccc(Cl)cc2)C1
Reactant: BrCC1CC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(CC3CC3)CC2)C(c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=574.1 (M+H+), [α]58920=−18.46, [α]54620=−27.04, (c=0.3846, chloroform), was prepared in accordance with the general method of example 102 from (−)-1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and cyclopropylmethylbromide.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 3-(3-phenyl-1-trityl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.50 g, 2.4 mmol), TFA (5 mL), and CH2Cl2 (15 mL) was stirred overnight at room temperature. The reaction mixture was alkalinized with 1 M NaOH aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from MeOH to give the title compound (751 mg, 82% yield) as a white solid: mp 206-208° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.58 (1H, d, J=7.9 Hz), 7.37-7.67 (9H, m), 8.33 (0.35H, brs), 8.65 (0.65H, brs), 8.91 (1H, d, J=7.9 Hz), 13.17-13.46 (1H, m). LC-MS (ESI) m/z 383 [M+H]+. Anal. Calcd for C20H13F3N4O.0.35H2O: C, 61.81; H, 3.55; N, 14.42. Found: C, 61.83; H, 3.61; N, 14.49.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:37](Cl)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([NH:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution of N-{5-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (199 mg, 0.38 mmol) in pyridine (2 mL) was added acetyl chloride (41 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (125 mg, 58%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])=[O:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2.0 g of 4-methoxybenzoyl chloride in 25 ml of dichlormethane were added dropwise at 0° C. while stirring within 30 min. to a solution of 3.5 g of 4-methacryloyloxybutyl (E)-3-(4-hydroxyphenyl)acrylate and 1.2 g of triethylamine in 40 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, then filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) and two-fold recrystallization from ethanol gave 4.5 g of 4-methacryloyloxybutyl (E)-3-[4-(4-methoxyphenylcarbonyloxy)phenyl]acrylate, m.p. 89°-90° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:24][O:25]C1C=CC(NN)=CC=1>>[CH3:24][O:25][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:8]3=[CH:9][NH:10][C:11]4[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:7]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4cc([N+](=O)[O-])ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 5a using 4-methoxy phenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 3.77 (3H, s), 6.89 (1H, dd, J=8.91, 2.37 Hz), 6.95 (2H, m), 7.25 (1H, d, J=2.08 Hz), 7.44 (1H, d, J=8.91 Hz), 8.05 (2H, m), 8.39 (1H, d, J=6.53 Hz). m/z 337.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][N:19]3[C:27](=[O:28])[C:26]4[NH:25][CH:24]=[N:23][C:22]=4[N:21]=[CH:20]3)[C:12]=2[F:29])[CH:9]=1)[C:5]#[N:6].[CH2:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH2:32]>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>[Cl:17][C:16]1[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([CH2:32][CH:31]=[CH2:30])[CH:9]=2)[C:5]#[N:6])=[C:12]([F:29])[C:13]([CH2:18][N:19]2[C:27](=[O:28])[C:26]3[NH:25][CH:24]=[N:23][C:22]=3[N:21]=[CH:20]2)=[CH:14][CH:15]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Temperature: 160 °C
Yield: 28 %

Procedure:
A mixture of 3-bromo-5-({6-chloro-2-fluoro-3-[(6-oxo-6,7-dihydro-1H-purin-1-yl)methyl]phenyl}oxy)benzonitrile (78 mg, 0.164 mmol), allyltri-n-butyltin (0.082 ml, 0.263 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.99 mg, 0.016 mmol) was heated in a personal microwave reactor at 160° C. for 20 min. The mixture was filtrated and was purified with reverse phase HPLC to afford a white solid 3-({6-chloro-2-fluoro-3-[(6-oxo-6,7-dihydro-1H-purin-1-yl)methyl]phenyl}oxy)-5-(2-propen-1-yl)benzonitrile (20 mg, 27.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H) 8.06-8.20 (m, 1H) 7.35-7.52 (m, 1H) 7.23-7.32 (m, 1H) 7.18 (s, 1H) 7.12 (s, 1H) 5.79-5.98 (m, 1H) 5.27 (s, 2H) 5.02 (s, 1H) 3.38 (d, 2H). LC-MS (ES+) m/z 435.50, [M+1].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:26])([F:25])[C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[NH:20][C:16]=2[CH:15]=1>C(Cl)Cl>[F:26][C:13]([F:25])([F:12])[C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21]([CH3:22])=[O:6])[NH:20][C:16]=2[CH:15]=1
Reactant: CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(C(F)(F)F)cc2[nH]1
Reaction time: 1 h

Procedure:
2.6 g (0.013 mole) of commercially available 85% strength m-chloroperoxybenzoic acid are added dropwise to a suspension, cooled to -20° C., of 3.0 g (0.013 mole) of 5-trifluoromethyl-2-methylthio-benzimidazole in 50 ml of methylene chloride in the course of 30 minutes. The mixture is then stirred for a further 60 minutes and is then extracted twice with, each time, 20 ml of an aqueous potassium carbonate solution. The solvent is stripped off in vacuo and the solid residue which remains is recrystallized from acetonitrile. 1.8 g of 5-trifluoromethyl-2-methylsulfinyl-benzimidazole of m.p. 135° C. are obtained. Deprotonation of this compound with n-butyllithium and reaction with 2-chloro-4-methoxypyridine in dry benzene yields the title compound of m.p. 166° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34](O)=[O:35])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:43][NH2:44].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]12[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]1)[CH2:14][N:13]1[C:32](=[O:33])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C:34]([NH:43][NH2:44])=[O:35])[N:11]=[C:12]21)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NN
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)O)c(OCc2ccccc2)c1=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (1 g, 2.043 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF were added and the mixture stirred at room temperature for 2 h. Solvent was then removed under reduced pressure. The crude acid chloride was then diluted with dichloromethane (10 mL)) and added to a stirred solution of hydrazine (0.641 mL, 20.43 mmol) and triethylamine (2.85 mL, 20.43 mmol) in CH2Cl2 (20 mL) and the resulting solution stirred at room temperature. After 16 h the reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil which was used in the next step without further purification. LCMS (M+H)=504.10.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 27 g (0.11 mol) of 5,9,13-trimethyl-1-tetradecanol and 10 g (0.13 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 22.1 g (0.12 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 34.4 g of (5,9,13-trimethyltetradecyl)tosylate. Under a nitrogen gas stream, 25.8 g (0.21 mol) of erythritol was dissolved in 200 ml of dry DMF, and 4.2 g (0.11 mol) of 60% NaH was added in several batches under ice cooling. After the addition, the resultant was agitated at room temperature for 1 hour, and then was heated to 50° C. A half amount of (5,9,13-trimethyltetradecyl)tosylate obtained above (17.2 g) was added dropwise thereto, and was washed with 55 ml of DMF. The resultant was heated to 80° C. and then agitated for 4 hours, the resulting reaction solution was concentrated under reduced pressure, 500 ml of ether was added to the residual solution to perform extractive dissolution twice, the product was washed twice with saturated saline, and then it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated, and purified by silica gel column chromatography to obtain 2.3 g of 1-O-(5,9,13-trimethyltetradecyl)erythritol having the following properties. As a result of HPLC analysis of the obtained product, the purity of 1-O-(5,9,13-trimethyltetradecyl)erythritol was 76.9% and that of 2-O-(5,9,13-trimethyltetradecyl)erythritol was 23.1%. The results of NMR analysis are as shown below.