Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8].C1(O)C=CC=CC=1>>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Solvent: Oc1ccccc1
Product: C=CC(C)(C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 77.8 %

Procedure:
A mixture of 43 g (0.5 mole) of 3-methyl-2-buten-1-ol, 97 g (0.6 mole) of ethyl orthoacetate, and 7.0 g (0.075 mole) of phenol was heated at 135°-140° with stirring for 9-10 hours. Ethanol was distilled from the mixture as the reaction proceeded. When the evolution of ethanol had ceased, heating was discontinued and the mixture was allowed to cool to room temperature. The mixture was then dissolved in diethyl ether and the ethereal solution was treated with IN hydrochloric acid to decompose unreacted ethyl orthoacetate. The ethereal solution was then washed successively with a saturated aqueous solution of sodium bicarbonate and with water, then dried over magnesium sulfate. The dried solution was concentrated and distilled under reduced pressure to give 60.8 g (78% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 57°-60°/11 mm.
Reaction SMILES: OO.O.[OH-].[Li+].[CH2:6]([S:26][C@H:27]([CH2:43][CH3:44])[C:28](N1[C@@H](C)[C@@H](C2C=CC=CC=2)OC1=O)=[O:29])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].[O-:45]S([O-])=O.[Na+].[Na+].Cl>O1CCCC1.O>[CH2:6]([S:26][C@H:27]([CH2:43][CH3:44])[C:28]([OH:29])=[O:45])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25]
Reactant: O=S([O-])[O-]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS[C@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS[C@H](CC)C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22 %

Procedure:
Hydrogen peroxide (30% in water, 1.04 mL, 10.2 mmol) and lithium hydroxide monohydrate (0.21 g, 5.09 mmol) was added to a solution of (4S,5R)-3-((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)butanoyl)-4-methyl-5-phenyloxazolidin-2-one (1.40 g, 2.55 mmol) in tetrahydrofuran (15 mL) and water (5 mL) held at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 45 minutes. 10% Na2SO3 (aq) (35 mL) was added, pH was adjusted to ˜2 with 5M HCl and the mixture was extracted twice with heptane (35 mL). The combined organic extract was dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8→1:1) as eluent. Concentration of the appropriate fractions afforded 0.17 g (22% yield) of the title product as an oil. 1H-NMR (300 MHz, CDCl3): δ 1.00 (t, 3H), 1.07 (t, 3H), 1.46 (m, 2H), 1.60-1.75 (m, 3H), 1.85 (m, 1H), 2.10 (m, 4H), 2.66 (m, 2H), 2.80-2.90 (m, 8H), 3.21 (t, 1H), 5.35-5.45 (m, 10H); MS (electrospray): 389.3 [M−H]−; [α]D+50° (c=0.14, ethanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1>ClCCl.CO.[Hg]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]/[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Agent: [Hg]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)/C=C1/CCc2ccc(F)cc21
Yield: 37.6 %

Procedure:
A solution of (E)-2-(6-fluoro-1-indanylidene)acetamide (20 g, 104.6 mmol) in dichloromethane:methanol (3:1) (1000 ml) was irradiated by an Canrad-Hanovia quartz, mercury-vapor photochemical immersion lamp, 450 watts (Ace Glass, 7825-35) for 0.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was chromatographed on Silica Gel 60 using a step gradient going from ethyl acetate:hexanes (1:1) to ethyl acetate:ethanol (1:1). Fractions containing (Z)-2-(6-fluoro-1-indanylidene)acetamide were combined and concentrated by spin evaporation in vacuo. The resulting solid was slurried in hexanes to give 7.52 g (37%) of (Z)-2-(6-fluoro-1-indanylidene)acetamide as a white crystalline solid, m.p., 175-177° C.:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].FC(F)(F)S([O-])(=O)=O.[F:21][C:22]([I+]C1C=CC=CC=1)([F:27])[C:23]([F:26])([F:25])[F:24].CN(C)C=O>C(OCC)(=O)C>[F:21][C:22]([F:27])([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)[C:23]([F:26])([F:25])[F:24]
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(C(F)(F)C(F)(F)F)cc2[nH]c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of 0.5 g of 2(1H), 3(4H)-quinoxalinedione, 1.60 g of pentafluoroethylphenyliodonium trifluoromethanesulfonate and 10 ml of dimethylformamide was stirred overnight on an oil bath at 45° C. Ethyl acetate was then added to the reaction mixture and the unreacted 2(1H), 3(4H)-quinoxalinedione was removed by filtration (recovery of the starting material: 0.13 g). Water was added to the filtrate and, after rendering the mixture neutral, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. A small amount of methylene chloride was added to the residue and the precipitated crystals were collected by filtration to obtain 0.05 g of 6-pentafluoroethyl-2(1H), 3(4H)-quinoxalinedione as colorless crystals. Yield 6% (conversion yield, 8%). Melting Point (after recrystallized from acetonitrile): 317°-320° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:36]1[C:37]2[C:38]3[CH:51]=[CH:50][S:49][C:39]=3[C:40](=[O:48])[NH:41][C:42]=2[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:42]2[NH:41][C:40](=[O:48])[C:39]3[S:49][CH:50]=[CH:51][C:38]=3[C:37]=2[C:36]=1[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 68.7 %

Procedure:
Following General Procedure E, tert-butyl 4-bromobenzylcarbamate (2.9 g, 10 mmol) was reacted with bis(pinacolato)diborane (2.8 g, 11 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.8 g, 9.0 mmol) to afford the desired product (2.7 g, 68%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [C@@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7].S(Cl)(Cl)=O.[S:13](=O)(=O)([OH:15])[OH:14].[Mn]([O-])(=O)(=O)=O.[K+].S([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:7]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[O:8][S:13]1(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: O[C@@H]1CCCC[C@H]1O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=S1(=O)OC2CCCCC2O1
Yield: 90 %

Procedure:
Ten grams (86 mmol) of trans-1,2-cyclohexanediol (CAS No. 1460-57-7) was added to toluene, and 10 g (84 mmol) of thionyl chloride was added dropwise thereto for reaction. The resulting solution was distilled. A cyclohexanediol cyclic sulfite (trans isomer) was recovered with a yield of 90%. Next, a methylene chloride solution containing 10 g (62 mmol) of cyclohexanediol cyclic sulfite was mixed with 180 g of 10% sulfuric acid aqueous solution. The mixture was mixed with 11 g (70 mmol) of potassium permanganate in an ice bath for reaction. Thereafter, the excess amount of potassium permanganate was neutralized by sodium hydrogen sulfite. The solvent was then distilled away from the organic layer. The solid product was crystallized with diethyl ether. A purified hexahydro-1,3,2-benzodioxathiol-2,2-dioxide (trans isomer) was recovered with a yield of 24%.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:27]1([C:25]#[C:26][C:2]2[C:3]([F:17])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1c(C#CC2CC2)ccc2c1cnn2C1CCCCO1
Temperature: 120 °C
Yield: 56.4 %

Procedure:
In a high pressure tube, a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8 mmol; Intermediate 18), PdCl2(PPh3)2 (3.7 g, 5.35 mmol), CuI (1.0 g, 5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cycles of vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was added under N2 atmosphere. The tube was sealed and the reaction mixture was heated at 120° C. for 63 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether) affording the title compound (4.3 g). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)/[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)=[N:12][N:11]=[C:9]12)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCn1/c(=N/NC(=O)CCCc2nc(-c3ccccc3)no2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
The mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanohydrazide (2.78 g, 6.17 mmol) in toluene (100 ml) was refluxed for 2 hours. After cooling to room temperature, the solid was filtered, washed with ethyl acetate/Hexane (1:9) and dried to give the desired product (1.97 g, 74% yield). LCMS calculated for C22H25N8O2 (M+H): 433.2. Found: 433.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C@H]2[C@H](N3C4N=CN=C(NCC5C6C(=CC=CC=6)C=CC=5)C=4N=C3)O[C@H](CO)[C@H]2O)=[O:10])[CH:6]=[C:5](OC)[CH:4]=1.NCC1SC=CC=1.C(O)(=O)C1C(=CC=CC=1)O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[OH:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(OC)cc(C(=O)N[C@@H]2[C@H](O)[C@@H](CO)O[C@H]2n2cnc3c(NCc4cccc5ccccc45)ncnc32)c1
Agent: NCc1cccs1
Agent: O=C(O)c1ccccc1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(O)c1
Yield: 73 %

Procedure:
A solution of the crude NMDBA salt of 18d (3.2 g, “5.1 mmol”), salicylic acid (987 mg, 7.14 mmol), HOBt (966 mg, 7.14 mmol), and EDC (1.37 g, 7.14 mmol) in DMF (69 ml) was stirred for 1 h at 23° C. The mixture was diluted with EtOAc (700 ml) and washed (3×H2O; brine). The aqueous layers were back-extracted with EtOAc (250 ml). The combined organic layers were concentrated and chromatographed (EtOAc:cyclohexane 1:1→2:1) to give 2.18 g (73%) of the title 3-hydroxybenzamide, which was fiuther purified by preparative reverse-phase HPLC (H2O:CH3CN 70:40→25:75 over 35 min, Rt==31 min) to give 1.50 g (50%) of a white powder: m.p. 174.5-175.5° C. 1H NMR (DMSO d6) δ10.03 (s, 1H), 9.75-9.65 (br. d, 1H), 9.15 (t, J=6.0 Hz, 1H), 8.3348.29 (br. s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.42 (d, J=3.8 Hz, 1H), 727-21 (m, 4H), 7.01 (d, J=3.8 Hz, 1H), 6.91 (dt, J=7.1, 2.2 Hz), 4.59 (d, J=5.8 Hz, 2H), 2.69 (q, J=7.0 Hz, 2H), 2.04 (t, J=6.9 Hz, 2H), 1.67 (quint, J=7.1 Hz, 2H). 13C NMR (DMSO-d6) δ169.65, 167.57, 158.49, 154.79, 149.06, 142.54 (q, J=4 Hz, C—C—CF3), 136.39, 132.80, 131.61, 126.91, 124.82, 122.93 (q, J=271 Hz, CF3), 117.66, 116.22, 114.01, 112.91, 112.01 (q, J=33 Hz, C—CF3), 39.19, 36.62, 29.42, 23.35. 19F NMR DMSO-d6), δ−59.52 (s). M/Z APCI: 592 (M+1), 590 (M−1). Anal. HPLC: Rt=6.22 min (method a). C24H23F3N4O7S3 Calc.: C, 44.63%. H, 3.8%. N, 11.83%. Found: C, 44.68%, H, 3.59%, N, 11.90%.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)(Cl)=O.[CH3:16]O>C(Cl)Cl>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: CO
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
4-Vinylbenzoic acid 69 (2.222 g, 15.00 mmol) was dissolved in 5 ml of methanol at room temperature. Thionyl chloride (1.094 ml, 15.00 mmol) was added dropwise and allowed to stir for 2 hours. The mixture was then heated to reflux for 20 minutes. Upon cooling the mixture was diluted with methylene chloride. The solvent was removed under a stream of nitrogen. The residue was purified by flash chromatography on silica eluted with 95:5 methylene chloride/methanol to give 2.370 g (97.4%) of methyl-4-vinylbenzoate 70 as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:15][CH3:16])[CH:10]=2)[N:5]=1.Cl.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:15][CH3:16])[CH:10]=2)[N:5]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2cnc(Cl)nc2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.7 %

Procedure:
Sodium borohydride (0.23 g, 6.1 mmole) was added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 g, 4 mmol) in EtOH/CH2Cl2 (40 mL; 1:1; v/v) at 25° C. The mixture was stirred at 25° C. for 12 h then was poured into cold HCl aqueous solution (0.4 M, 200 mL). The resulting mixture was basicified with saturated NaHCO3 (aq) and then extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a yellowish white solid reside. Purification of the residue by flash column chromatography (gradient elution 20 to 35% EtOAc/hexanes) provided the title compound (0.33 g, 37%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (DMSO) δ 9.25 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H); 3C NMR (CDCl3) δ 159.1, 157.3, 156.1, 150.9, 150.1, 119.4, 105.9, 103.7, 56.6, 56.4; HRMS (FAB) m/z 225.0431 (M+H)+ (C10H9N2O2Cl requires 225.0431); Anal. (C10H9N2O2Cl·3/4H2O·1/4CH3OH) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[O:45][CH:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)O1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:4]3[N:5]([C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=3)[N:6]=[CH:7][C:2]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3[O:45][CH:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(-c3ncco3)cc2)OC1(C)C
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncco4)cc3)cnn12

Procedure:
7-Chloro-8-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 277 and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole were reacted using procedures analogous to those described in Example 276 to give the title compound, 8-(4-chlorophenyl)-7-(4-(oxazol-2-yl)phenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. HPLC: 99% at 8.42 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 549 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 5.32 (s, 2H), 7.23-7.32 (m, 2H), 7.40-7.59 (m, 4H), 7.62-7.78 (m, 4H), 7.90-8.05 (m, 2H), 8.24-8.27 (m, 1H), 8.81 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH:11]=[C:12]([O:15][C@H:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@@H:19]([NH2:26])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:26][C@@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:7][N:8]=4)[CH:11]=3)[CH2:17][CH2:18]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of Intermediate 75b (62.0 mg, 0.18 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 78.9 mg, 0.195 mmol), DIPEA (46.3 μL, 0.27 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (22 mg, 20%). LCMS (Method 5) Rt 4.30 min, m/z 605 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.79-2.15 (8H, m), 2.36 (3H, s), 3.49 (4H, m), 4.81 (1H, m), 5.51 (1H, t, J 4.5), 6.30 (1H, s), 7.03 (1H, dd, J 10.1, 2.2), 7.09 (1H, d, J 8.5), 7.25-7.40 (8H, m), 7.51 (1H, m), 7.83 (1H, m), 8.07 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC(C)C)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1>C(O)C>[CH3:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccc(C)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C)cc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 4-methylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)1,4-dihydropyridine-5-carboxylic acid 4-methylbenzyl ester of melting point 106° C (from ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11].N#N.CCOCC>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Oc1ncc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Temperature: 90 °C
Yield: 65.5 %

Procedure:
5-bromo-3-iodopyridin-2-ol (6.7 g, 22 mmol) (Heterocycles. 57, 1, pp 55), 1-ethynyl-4-fluorobenzene (4.03 g, 33.5 mmol), copper(I) iodide (0.255 g, 1.34 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.784 g, 1.12 mmol) were combined and evacuated/backfilled with N2 (3×) then diluted with triethylamine (223 mL) and heated to 90° C. for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL), brine, dried over Na2SO4, filtered, and concentrated. Trituration with Et2O afforded the expected product 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (4.2 g, 14.4 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.42 (2H, m), 8.03 (2H, dd, J=8.78, 5.27 Hz), 7.46 (1H, s), 7.39 (2H, t, J=8.91 Hz). LC-MS retention time: 2.36 min; m/z (MH+): 292, 294. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[CH3:18][Mg]Br>O1CCCC1.[Cu]I>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH3:18])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(c1ccc(OC(F)(F)F)cc1)C(C#N)C#N
Yield: 60 %

Procedure:
Using 1.19 g of (4-(trifluoromethoxy)benzylidene)malononitrile, 20 ml of tetrahydrofuran, a catalytic amount of copper (1) iodide, and 12.5 ml of a solution of methyl magnesium bromide in tetrahydrofuran (about 1 M, available from Tokyo Kasei Kogyo Co., Ltd), and according to the process described in REFERENCE PRODUCTION EXAMPLE 2, there was obtained 0.76 g of (1-(4-(trifluoromethoxy)phenyl)ethyl)malononitrile (the intermediate (10)).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.C([O-])([O-])=[O:14].[K+].[K+].S1C=CC(C(Cl)=O)=C1>C(Cl)Cl>[C:3]1([OH:14])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc2cc(O)ccc2c1
Agent: O=C(Cl)c1ccsc1
Agent: [K+]
Solvent: ClCCl
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
The hydrochloride salt of 6-aminonaphthalen-2-ol (3.93 g, 20.1 mmol) and K2CO3 (9.45 g, 68.5 mmol) were suspended in CH2Cl2 (38 ml) and 3-thiophenecarbonyl chloride (4.3 g, 29.3 mmol) was added. The reaction was stirred at room temperature for 17.5 hours and then quenched with water (50 ml) and filtered. The solid was washed with CH2Cl2 and then the solvent was removed in vacuo to provide the intermediate napthyl alcohol.