Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=2)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
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: Cc1ccccc1
Solvent: CCO
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 71.2 %

Procedure:
The mixture of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (110 mg, 0.22 mmol) and 3-trifluoromethylphenylboronic acid (83 mg, 0.44 mmol) was heated in a mixture of toluene (2 ml), ethanol (2 ml) and saturated sodium bicarbonate (2 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (20 mg) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 5-(4,6-bis-benzyloxy-3′-trifluoromethyl-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (90 mg, 72%). 400 MHz 1H NMR (CDCl3) δ: 7.84 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.39-7.22 (m, 10H), 6.77 (s, 1H), 5.11 (s, 2H), 5.10 (s, 2H), 4.33 (t, J=7.6 Hz, 2H), 3.25 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.10-2.09 (m, 2H); LCMS: 575 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[N:12]#[C:13][NH2:14].[Na].[CH2:16](O)C>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[N:12][C:13]#[N:14])[S:11][CH3:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCO
Reactant: N#CN
Reactant: N#Cc1ccc(N=C=S)cc1
Agent: [Na]
Product: CSC(=NC#N)Nc1ccc(C#N)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 32 g (0.2 mole) of 4-cyanophenyl isothiocyanate and 12.8 g (0.2 mole) of monosodium cyanamide in 100 cm3 of absolute ethanol is kept at the boiling point for 2 hours. After cooling, the resulting precipitate is filtered and washed with 200 cm3 of absolute ethanol. The solid is then suspended in a solution of dimethyl sulfate (25 g, that is, 0.2 mole) in 500 cm3 of ethanol; the mixture is heated for 2 hours at the boiling temperature. The final precipitate is filtered, washed with 2×100 cm3 of water and with 2×100 cm3 of ethanol, then dried in vacuo. 32.8 g (yield 70%) of a white solid with a melting point of 220°-225° C. are obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].O>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cc(S(C)(=O)=O)ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of 1.0 M boron tribromide (44.0 ml, 44.0 mmol) in DCM (20 ml) was cooled to 0° C. 2-methoxy-4-(methylsulfonyl)benzoic acid (4.0 g, 17.4 mmol) dispergated in DCM (120 ml) was slowly added to the tribromide-solution during 20 minutes. The reaction mixture was vigorously stirred for 1.5 h at 0° C. Water was added and the organic phase was separated. The aqueous phase was extracted with DCM and EtOAc. The combined organic phases was dried (Na2SO4) and evaporated under reduced pressure to give a white powder (3.6 g). 1H-NMR (400 MHz, MeOH): δ 8.07 (1H, d, J 8.0 Hz), 7.42 (1H, d, J 2.0 Hz), δ 7.38 (1H, dd, J1 8.4 Hz, J2 1.6 Hz), δ 3.11 (3H, s).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:17]([OH:26])=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=1[OH:22].O[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:23]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]#[N:40])=[CH:33][CH:34]=2)=[C:16]([Cl:15])[C:17]=1[OH:26])(=[O:25])[CH3:24]
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Add diisopropylazodicarboxylate (DIAD, 5.418 g, 26.80 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (5.000 g, 26.80 mmol), 3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (8.666 g, 26.80 mmol), and triphenylphosphine (7.028 g, 26.80 mmol) in tetrahydrofuran (0.200M) at 0° C. Stir for 2 hours while warming to room temperature. Add silica gel and evaporate solvent. Chromatograph with Biotage Flash 75, eluting with 50-90% ethyl acetate/hexanes to afford the title compound as a white solid (13.00 g, 26.42 mmol, 98%): MS (m/z): 490 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([Cl:22])=[O:21]>O1CCOCC1>[ClH:22].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C@H:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CCOCC1>CCOCC.C1COCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:45]1[C:13](=[O:14])[C@@H:12]([N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1
Reactant: O=C(CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC[C@@H](C(=O)N1[C@H](C(=O)NCCc2ccccc2)CCCN1C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of (S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid 5-benzyl ester (580 mg, 1.59 mmol) in ether (25 mL) at 0° C., is added PCl5 (920 mg, 4.38 mmol) in one portion. After stirring at 25° C. for 40 minutes, ether is removed by evaporation, and the residue is dissolved in 20 mL of THF, and is added to a solution of (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) and N-methylmorpholine (0.74 mL, 6.77 mmol) in THF (10 mL) at 0° C. slowly. After stirring at room temperature for 2 hours, the reaction mixture is diluted with 100 mL of ether and washed with 2×20 mL of water. The combined organic layers is dried over Na2SO4 and concentrated, and purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (1.13 g, 99.2%) as pale solid. (NMR and MS data confirmed, U-3133-62).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
A suspension of 5-bromo-1-indanone (15 g, 71 mmol) in concentrated sulfuric acid (75 mL) was cooled to 0° C. Sodium azide (6.5 g, 100 mmol) was added portionwise over 1 hour. The reaction was allowed to warm to room temperature and stirred for 24 hours. The mixture was poured onto ice, neutralised with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by dry flash chromatography using 50-100% ethyl acetate/isohexane to give 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1.1 g, 7%). δH (500 MHz, CDCl3): 7.92 (1H, d, J=8.3 Hz), 7.49 (1H, dd, J=1.4, 8.3 Hz), 7.39 (1H, d, J=0.9 Hz), 6.46 (1H, s), 3.57-3.55 (2H, m), 2.98 (2H, t, J=6.6 Hz).
Reaction SMILES: C([O-])(=O)C.[Na+].[Br:6][CH:7](Br)[C:8](=O)[C:9]([F:12])([F:11])[F:10].[BrH:15].Br.[NH2:17][CH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Na+]>O.CO>[Br:15][C:18]1[C:19]([NH2:21])=[N:20][C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([Br:6])[N:17]=1
Reactant: Br
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: N=C(N)CN
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(C(F)(F)F)c(Br)nc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To a solution of 22.5 g sodium acetate in 230 ml water was added 21.5 g 3,3-dibromo-1,1,1-trifluoropropanone at reflux and the mixture was refluxed for 10 min. The resulting solution was cooled to 0° C. in an acetone ice bath and added dropwise to a suspension of 19.5 g aminoacetamidine dihydrobromide in 250 ml methanol at −30° C. (dry ice acetone cooling) so that the temperature did not rise above −30° C. during the addition. To the resulting solution was added dropwise a solution of 12.285 g sodium hydroxide in 100 ml water. The mixture was then allowed to warm to room temperature (warm water bath) and then stirred at room temperature for 3 h. The dark reaction mixture was concentrated under aspirator vacuum to remove methanol and extracted with ethyl acetate (4 times). The phases were separated and the organic phase was washed with brine, treated with charcoal and dried with sodium sulfate and evaporated. To the concentrated yellow solution was added heptane and the mixture was seeded whereby crystallization was initiated. The mixture was stirred at room temperature to complete crystallization. The solid was collected by filtration to yield 8.81 g of the title compound as light yellow crystals. The aqueous layers were kept at room temperature for 72 h and then extracted (2 times) with ethyl acetate. The combined organic layers were treated with charcoal and sodium sulfate and evaporated. The residue was taken up in dichloromethane and heptane was added. The mixture was concentrated again until crystallization occurred. The solid was collected by filtration to yield another 2.06 g of the title compound as light yellow crystals. MS (M−H) at 162.1.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH:1]1([CH2:7][NH:8][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: NCC1CC=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC1CC=CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Cyclohex-3-enylmethylamine (10 g, 90 mmol) was dissolved in 200 mL of dichloromethane and cooled in an ice bath. Triethylamine (16.8 mL, 120 mmol) was added, followed by drop-wise addition of ethyl chloroformate (10.9 g, 0.100 mol). The mixture was stirred overnight at ambient temperature, then washed with water, dilute HCl, dilute aqueous sodium hydroxide, and brine (50 mL each). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude carbamate (14 g, 85%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:15]1[CH2:16][CH2:17][O:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][S:7][C:4]2[S:3][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:6][CH:5]=2)[CH2:14]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(CSc1ccc(-c2ccncc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The resultant product (500 mg) of Example 31 and 4-pyridylboronic acid (250 mg) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (25 mL) and water (5 mL), sodium hydrogen carbonate (500 mg) and tetrakistriphenylphosphine palladium (60 mg) were added, and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent, and the obtained residue was recrystallized from ethyl acetate to give the title compound (90 mg) as a pale-brown powder.
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40](F)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([F:32])=[CH:29][C:30]=1[F:31]>C(OCC)C>[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40]([N:5]4[CH2:6][CH:3]([OH:2])[CH2:4]4)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([F:32])=[CH:29][C:30]=1[F:31]
Reactant: OC1CNC1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1c(N2CC(O)C2)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
70 mg of 3-hydroxyazetidine monochloride, 200 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and 200 mg of pyridine were stirred at 80° C., and to this mixture was added 150 mg of 1-(3-amino-4,6-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The mixture was stirred at 90° C. for 10 minutes. Diethylether was added to the reaction solution, and the solution was decanted. 1 ml of ethanol was added to the residue and the solid precipitate was collected by filtration and dried to obtain 70 mg of the title compound.
Reaction SMILES: [C:1](OCCC[Si](OC)(OC)OC)(=O)[C:2]([CH3:4])=[CH2:3].CO[C:19]1[CH:25]=[CH:24][C:22](O)=[CH:21][CH:20]=1>>[CH2:21]1[CH:1]2[CH:2]3[CH:4]=[CH:22][CH:24]([CH:25]2[CH:19]=[CH:20]1)[CH2:3]3
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reactant: COc1ccc(O)cc1
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 87.5 °C
Reaction time: 33 h
Yield: 70 %

Procedure:
59.1 g (0.20 mol) 3-methacryloyloxypropyltrimethoxy silane and some hydroquinone monomethyl ether (MEHQ) are placed in a sulphonation flask which is connected via a distillation bridge to a cracking apparatus. After flushing with argon, cyclopentadiene is fed into the reaction vessel, with simultaneous stirring and warming to 85 to 90° C. After 33 hours the reaction has finished and formed dicyclopentadiene is distilled off at 0.05 mbar. Following subsequent fractional distillation in a high vacuum, the norbornene silane (1) (bp: 98°-100° C./7.0 mPa) is obtained as a colourless liquid in 70% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC=C)(=O)[CH3:27]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH:26]=[CH2:27])=[CH:10][CH:9]=2)[CH:18]=1
Reactant: OCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=COCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
To a solution of 3-(4-(5-bromo-2-chlorobenzyl)phenyl)propan-1-ol (0.88 g, 2.59 mmol), [IrCl(cod)]2 (17 mg, 0.026 mmol) and sodium carbonate (0.17 g, 1.56 mmol) in toluene (5 mL) was added vinyl acetate (0.48 mL, 5.18 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 5 h. The solution was allowed to cool to room temperature, and then diluted with 60 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:30:0.01) to provide 0.75 g of white solid. 1H NMR (CDCl3, 400 MHz): δ 7.29˜7.24 (m, 3H), 7.15 (d, 2H), 7.11 (d, 2H), 6.50 (dd, J=14.4 and 6.8 Hz, 1H), 4.18 (dd, J=14.4 and 2.0 Hz, 1H), 4.04 (s, 2H), 4.00 (dd, J=6.8 and 2.0 Hz, 1H), 3.71 (t, J=6.4 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.06˜1.96 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=2[C:11]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1cc(O)ccc1-c1sc2cc(O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Yield: 27.5 %

Procedure:
By the method described in Example 2, the product of Example 15 (1.0 g, 1.94 mmol), ethanethiol (0.71 mL, 9.75 mmol), and aluminum chloride (1.81 g, 13.57 mmol) were stirred in anhydrous CH2Cl2 (40 mL). Purification by chromatography (silica gel, 5-10% MeOH in CH2Cl2), provided 260 mg (27%) of the title product as a dark yellow foam: 1H NMR d 1.47 (m, 2H), 1.61 (m, 4H), 2.13 (s, 3H), 2.55 (m, 4H), 2.77 (t, J=5.5 Hz, 2H), 4.09 (t, J=5.5 Hz, 2H), 4.87 (s, 2H), 6.45 (m, 2H), 6.77 (d, J=8.7 Hz, 2H), 6.87 (dd, J=2.2, 8.8 Hz, 1H), 7.01 (d, J=9.1 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H); MS (FD) m/e 488 (MH+); HRMS (FAB) m/e calc'd. for C29H30N1O4S1 : 488.1896, found: 488.1911.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([N:7]([N:5]1[CH:6]=[C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[N:3]=[CH:4]1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:16]
Reactant: CCN(C(=O)OC(C)(C)C)n1cnc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
tert-Butyl (4-bromo-1H-imidazol-1-yl)(ethyl)carbamate (253.7 mg, 0.874 mmol), pyridin-3-ylboronic acid (113 mg, 0.918 mmol), potassium carbonate (329 mg, 2.39 mmol), water (0.870 mL), absolute ethanol (1.74 mL), and toluene (3.50 mL) were placed into a 10 mL round bottomed flask equipped with condenser and magnetic stirrer. The atmosphere was flushed with nitrogen and tetrakis triphenylphosphine palladium (30.0 mg, 0.026 mmol) was added. The mixture was heated to 110° C. and stirred for 16 hours. The reaction was cooled, the organic layer set aside, and the aqueous layer was extracted with ethyl acetate. All organics were combined, dried over sodium sulfate, and concentrated. The residue was purified using silica gel chromatography (0-25% methanol/dichloromethane) to afford the title compound (81 mg, 0.28 mmol, 32%) as a yellow oil: 1H NMR (400 MHz, CD3CN) δ 9.00 (d, J=2.5 Hz, 1H), 8.46 (d, J=4.8 Hz, 1H), 8.11 (m, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.36 (m, 1H), 3.76 (q, J=7.1 Hz, 2H), 1.45 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 289 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([O:13][CH3:14])=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O.N>O1CCCC1.O>[CH2:10]([C:8]1[C:7]([O:13][CH3:14])=[CH:6][C:3]2[CH2:4][O:5][C:16](=[O:18])[NH:1][C:2]=2[CH:9]=1)[CH:11]=[CH2:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCc1cc(N)c(CO)cc1OC
Agent: N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1cc2c(cc1OC)COC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 126.2 %

Procedure:
677 mg of 2-amino-5-methoxy-4-(2-propenyl)benzylalcohol was dissolved in 20 ml of tetrahydrofuran under nitrogen atmosphere. Thereafter, 0.52 g of triphosgene and 1.46 ml of triethylamine were added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, while cooling on ice, water and ammonia water were added to the reaction solution until foaming was terminated. The reaction solution was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and then reprecipitated from ethyl acetate, so as to obtain 485 mg of the subject compound.