Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](F)(F)[CH:4]([C:9]([F:12])([F:11])[F:10])[C:5](F)(F)[F:6].Cl.[C:16]([NH2:19])(=[NH:18])[CH3:17].ClC(Cl)C.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[F:6][C:5]1[C:4]([C:9]([F:12])([F:11])[F:10])=[C:3]([O:2][CH3:1])[N:19]=[C:16]([CH3:17])[N:18]=1
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Reactant: CC(=N)N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1nc(C)nc(F)c1C(F)(F)F
Temperature: 0 °C
Yield: 134.2 %

Procedure:
A reaction flask was loaded with 1,1,3,3,3-pentafluoro-2-trifluoromethylpropyl methyl ether (18.1 g), acetamidine hydrochloride (11.1 g), dichloroethane (78 ml), water (78 ml), and benzyltriethylammonium chloride (0.078 g), and cooled to 0° C. with stirring. To this mixture, a 17% aqueous solution of sodium hydroxide (93 g) was dropwise added in 1.5 hours, followed by stirring for 1 hour. Thereafter, the cooling was stopped, and an organic layer was separated from the reaction mixture at room temperature and condensed to give 4-fluoro-6-methoxy-2-methyl-5-(trifluoromethyl)-pyrimidine (22 g). By GC/MS analysis, a molecular ion peak of 210 was confirmed for this compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C(OC(=O)C)(=O)C.I.[PH2](O)=O.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]>O>[CH3:21][C:22]1[NH:23][C:24]([CH:1]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C(C)c2ccccc2)c1C
Reaction time: 48 h

Procedure:
A solution of 0.6 ml of acetophenone of 5 ml of acetic anhydride was slowly added to a stirred mixture of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid containing 548 mg of 2,4-dimethyl-3-acetyl pyrrole. The mixture was allowed to stand for two days at room temperature then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless rhombic plates (75%), mp. 146°-148.5° C. Anal. Calc. For C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.47: H, 7.78; N, 5.79.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:41]CC1.[OH-].[Na+].OO>COCCOCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:33])[CH3:34])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:12]([OH:41])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.60 g, 1.22 mmol) was partially dissolved in dry diethyleneglycol dimethyl ether (14 mL) and a solution of borane/THF complex (1M in THF, 7.29 mL, 7.29 mmol) was added dropwise. After stirring briefly at room temperature, the mixture was allowed to stand for 16 h. The mixture was then cooled in ice, and water (1.1 mL), 2M sodium hydroxide (3.6 mL) and 35% hydrogen peroxide (0.94 mL, 8.98 mmol) were added dropwise in sequence. The mixture was heated at 50° C. for 8 h, then cooled, diluted with water (approximately 30 mL) and extracted three times with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to give racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.46 g, 74%), containing approx. 20% of 4-hydroxypiperidine isomer. LCMS RT=4.48, [M+H]+=509.
Reaction SMILES: [Cl:1][C:2]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]2[O:6][CH:7]([CH2:9][N:10]=[N+]=[N-])[CH2:8][C:4]=2[CH:3]=1>[Pt]>[Cl:1][C:2]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)c3ccccc3c2O1
Agent: [Pt]
Product: NCC1Cc2cc(Cl)c3ccccc3c2O1
Yield: 43 %

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]-2-hydroxypropyl 4-methylbenzenesulfonate (4.6 g, 9.26 mmol) with palladium on carbon (5 wt. %, 0.50 g) and hydrogen chloride in isopropanol (4.0 M, 4.0 mL) generally according to the procedure described for Intermediate 4 provided (±)-3-(4-chloro-1-hydroxy-2-naphthyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphosphine (3.5 g, 13.3 mmol) followed by diisopropylazodicarboxylate (2.69 g, 13.3 mmol) generally according to the procedure described for Intermediate 5 afforded (±)-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (1.1 g, 16.4 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methyl azide as a pale brown oil. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.15 g) generally according to the procedure described for Example 2 provided 1.07 g (43%) of (±)-1-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 269-271° C.; Anal. calcd. for C13H12ClNOHCl.0.8H2O: C, 54.87; H, 5.17; N, 4.92. Found: C, 54.68; H, 4.78; N, 4.79.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=2)[N:4]=1.[CH2:17]([N:19](CC)[CH2:20]C)C.CS(Cl)(=O)=O.Cl.CNC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][N:19]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=2)[N:4]=1)[CH3:20]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1ccc2nc(CO)ccc2c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2nc(CN(C)C)ccc2c1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
The N-[2-(hydroxymethyl)-6-quinolinyl]acetamide (92.3 mg, 0.427 mmol) obtained in Reference Example 5 and triethylamine (0.0712 ml, 0.512 mmol) were dissolved in N,N-dimethylformamide (2 ml), methanesulfonyl chloride (0.0396 ml, 0.512 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction solution were added dimethylamine hydrochloride (69.6 mg, 0.854 mmol) and potassium carbonate (177 mg, 1.28 mmol), and the mixture was stirred at 60° C. for 16 hours. To the reaction solution was added an aqueous potassium carbonate solution, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate) to obtain N-[2-[(N,N-dimethylamino)methyl]-6-quinolinyl]acetamide (71.9 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[CH:3]=[CH:4]\[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:17])([F:18])/[CH:3]=[CH:4]\[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: COC(=O)c1ccc(/C=C\C(F)(F)F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C\C(F)(F)F)ccc1C(=O)O
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A mixture of (Z)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate (60.0 mg, 0.000230 mol), MeOH (10 mL), and 2 N aqueous NaOH solution (0.5 mL) was stirred at 65° C. for 5 h. After cooling the mixture, the solvent was removed under reduced pressure. The residue was treated with water, acidified with 1N HCl to pH 2-3, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the product as a syrup which became an off-white solid while standing at room temperature for a long time. LC-MS: 2.49 min, 244.8 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][CH2:27][O:26][C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OCCOc1ccc(OCCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCCOc3ccc(OCCO)cc3)ccc2c1
Yield: 79.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl)ether (10.6 g, 53.3 mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g, 48.7 mmol) and NEt3 (13 mL, 93.3 mmol) in DMF (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under vacuum and the residue was partitioned between HCl (3N, 100 mL) and CH2Cl2 (200 mL). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, Rf=0.15) and then recrystallized from ethyl ether and hexane to give the title compound as a white solid (6.01 g, 31% yield). Mp 76-78° C. 1H NMR (CDCl3) δ 7.7-7.64 (m, 3H), 7.42-7.38 (m, 1H), 7.15-7.08 (m, 2H), 6.74-6.72 (m, 4H), 4.45-4.36 (m, 2H), 4.1-3.85 (m, 7H), 3.90 (s, 3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 174.6, 157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9, 118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4. MS (API) m/z 428 (M+NH4)+. Anal. calcd. for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.01; H, 6.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: O=C1CCC(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)CCC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 24 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol), 4-N,N-dimethyaminopyridine (2.6 mg, 0.02 mmol) and succinic anhydride (47 mg, 0.47 mmol) in methylene chloride (2.53 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.17 mL, 0.98 mmol). The reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction mixture was poured onto a saturated aqueous ammonium chloride solution (100 mL) and was then extracted with a 90/10 methylene chloride/methanol solution (3×100 mL). The pH of the aqueous layer was brought to pH=2 with a few drops of a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution (1×100 mL). The combined organics were dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (12 g, 0.5-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OJ column, 30% methanol) afforded succinic acid mono-{3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl}ester (57 mg, 24%) as a light tan solid. ES+-HRMS m/e calcd for C22H18N6O8Cl2 (M+H+) 565.0636, found 565.0633.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][O:27][CH3:28])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CS(C)=O>[CH2:14]([O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]#[N:13])=[CH:9]2)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][O:27][CH3:28])[CH3:15]
Reactant: CCOC(=O)c1cc(Br)ccc1OCOC
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ccc1OCOC
Temperature: 75 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A mixture of 4-phenyl-1H-pyrrole-3-carbonitrile (0.2 g), 5-bromo-2-methoxymethoxy-benzoic acid ethyl ester (0.36 g), copper iodide (0.023 g), N,N-dimethylgrycine (0.025 g), cesium carbonate (0.39 g) and dimethylsulfoxide (3 mL) was stirred at 75° C. for 12 hours. After cooling to ambient temperature, the insoluble material was removed by filtration through Celite pad, and this filtrate was concentrated. This obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90−66/34) to give the title compound (0.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1)([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:17]3[CH:16]=[N:15][CH:14]=[C:13]([C:10]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:20])([CH3:12])[CH3:11])[CH:18]=3)=[CH:35][N:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: CC(C)(C(=O)OCc1ccccc1)c1cncc(Br)c1
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)OCc4ccccc4)c3)cnc21

Procedure:
6-[5-(1-Benzyloxycarbonyl-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method VI using 2-(5-bromo-pyridin-3-yl)-2-methyl-propionic acid benzyl ester and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (Intermediate G).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]1[N:43]=[CH:42][CH:41]=[CH:40][C:37]=1[C:38]#[N:39]>CN(C)C=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:36]3[N:43]=[CH:42][CH:41]=[CH:40][C:37]=3[C:38]#[N:39])=[CH:26][CH:27]=1)=[CH:7]2
Reactant: O=c1c2c(Cl)cccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1ccc(-c2cc3cccc(Cl)c3c(=O)n2Cc2ccc(F)cc2F)cc1
Temperature: 105 °C
Yield: 57 %

Procedure:
To a solution of 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (54 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL), was added powdered Cs2CO3 (89 mg, 0.27 mmol), followed by 2-chloronicotinonitrile (33 mg, 0.23 mmol). The resulting suspension was stirred and heated in a 105° C. oil bath. After stirring for 64 h at 105° C., HPLC analysis of the reaction mixture showed no 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, nor 2-chloronicotinonitrile remaining. The reaction was allowed to cool to ambient temperature and was diluted with H2O (15 mL), and Et2O (50 mL). The layers were separated, the organic layer was washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a yellow liquid. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 40% EtOAc/hexane. The product peak was collected to afford 2-{4-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenoxy}nicotinonitrile, a compound of formula (Id), (36 mg, 57% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.35 (1H, dd, J=5.0, 2.0 Hz), 8.05 (1H, dd, J=7.6, 1.8 Hz), 7.54-7.51 (2H, m), 7.42-7.38 (1 H, m), 7.27-7.24 (2H, m), 7.22-7.18 (2H, m), 7.15 (1H, dd, J=7.6, 5.0 Hz), 7.08-7.00 (1H, m), 6.80-6.74 (1H, m), 6.71-6.65 (1H, m), 6.46 (1H, s), 5.22 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([C:26]4[CH:31]=[CH:30][C:29]([B:32]5[O:36]C(C)(C)C(C)(C)[O:33]5)=[C:28]([C:41]#[N:42])[CH:27]=4)[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:43]4[CH2:45][CH2:44]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([C:26]4[CH:31]=[CH:30][C:29]([B:32]([OH:36])[OH:33])=[C:28]([C:41]#[N:42])[CH:27]=4)[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([CH:43]4[CH2:44][CH2:45]4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:14])[NH:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B(O)O)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
The crude 2-(4-chlorophenyl)-6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (162 mg, 0.251 mmol) was dissolved in tetrahydrofuran (6.0 mL). HCl (3.01 mL, 1.505 mmol) was added followed by addition of sodium periodate (429 mg, 2.006 mmol). The mixture was stirred at room temperature overnight. It was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with 10% aq. Na2S2O3 and brine, dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by reversed phase HPLC (10-100 MeCN/H2O with 0.05% TFA) to give product (88 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54-8.74 (br.s., 1H) 8.51 (q, J=4.49 Hz, 2H) 8.13 (s, 1H) 7.93 (d, J=8.78 Hz, 2H) 7.74-7.79 (m, 2H) 7.58-7.67 (m, 3H) 7.22 (s, 1H) 3.47 (s, 3H) 2.84 (d, J=4.68 Hz, 3H) 2.03-2.14 (m, 1H) 0.99 (br. s., 1H) 0.85 (br. s., 2H) 0.45 (br. s., 1H). LCMS (m/z, ES+)=564 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][OH:13].[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCC#Cc1ccc(Cl)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: OCCCCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 12.0 g (0.0558 mole) of 4-(2,4-dichlorophenyl)-3-butyn-1-ol and 0.4 g of platinum oxide in 280 mL of ethanol was placed in a Parr hydrogenator. Hydrogen gas was introduced into the reactor until there was no further uptake. Upon completion of the reaction, the reaction mixture was filtered to remove the platinum oxide catalyst, and then the solvent was evaporated under reduced pressure, leaving 4-(2,4-dichlorophenyl)-1-butanol as the residue. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O-:32])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(C)C(=O)O[C@@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)O[C@@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 90.0 mg (0.2854 mmol) of (−)-trans-4-({[(1R)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid 17 was reacted with 24.0 mg (0.2854 mmol) of sodium bicarbonate (NaHCO3) in 4 mL of a mixture of acetonitrile and water (1:1) to yield 96.3 mg (quant.) of the title compound 18 as a colorless powder. The enantiomeric excesses were determined with an analytical Waters 2690/ZQ LC/MS apparatus using a ChiralPak AD-RH column, an isocratic eluent consisting of 30% acetonitrile/70% water/0.05% formic acid, and a flowrate of 60 μL/min (Rf=15.0 min; e.e. =97.7%). 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=1
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Temperature: 70 °C
Reaction time: 14 h
Yield: 52.4 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-[1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazol-4-yl]-ethanone (270 mg, 719 μmol), 3-methylsulfonylphenyl boronic acid (220 mg, 1.08 mmol), PdCl2dppf (55 mg, 10 mol %), K2CO3 (300 mg, 2.16 mmol), 1,2-dimethoxyethane (11 mL) and H2O (1 mL). The reaction solution was allowed to stir at 70° C. for 14 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NR4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 75% EtOAc to afford 170 mg (52% yield) of product. MS (ES): 451 [M+H]+, 473 [M+Na]+.