Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN1CCCC1=O.F[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>O>[CH:9]1([N:8]([CH3:7])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC1CCCCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Potassium carbonate (6.0 g, 43.5 mmol) and N-methylcyclohexylamine (4.6 g, 40.6 mmol) were added to a N-methylpyrolidone (NMP) solution (20 ml) of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 7.0 g of oily yellow N-cyclohexyl-4-fluoro-2-nitro-N-methylaniline (yield: 89%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:31][C:32](=O)[CH2:33][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][CH:31]=[C:32]([CH2:33][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])[N:15]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1c[nH]c(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 30 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (112 mg, 0.306 mmol) in DMF (2.96 mL) was added sodium carbonate (162 mg, 1.53 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (95.0 mg, 0.337 mmol) and the resulting mixture was heated at 100 degrees for 4 hours. The reaction was cooled and taken up in ethyl acetate (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with water (3×5 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 47 mg (30% yield) of the title compound. LC/MS (FA) ES+ 512. 514. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (bs, 1H), 8.69-8.67 (m, 2H), 7.91-7.79 (m, 6H), 7.27-7.24 (m, 3H), 7.11-7.08 (m, 2H), 4.77 (s, 2H), 4.45 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 37.2 %

Procedure:
To a suspension of 4-hydroxyindole (5.65 g, 42.4 mmol) in chloroform (200 mL) are added imidazole (4.33 g, 63.6 mmol) and tert-butylchlorodimethylsilane (7.03 g, 46.6 mmol), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is washed with a mixture of a saturated brine and water (1:1, 100 mL), and the organic layer is dried over anhydrous potassium carbonate, filtered, and the filtrate is concentrated to about 50 mL under reduced pressure. The resultant is purified by silica gel column (300 g, ethyl acetate:hexane=1:5→1:1) to give the title compound as a white solid (3.90 g, yield: 37%), and the starting compound (2.62g, recovery rate: 46%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[O:36]1[CH2:26][CH:25]1[C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:29])([F:30])[F:28])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 0.09 g, 0.220 mmol) in dichloromethane (5 mL) was added 3-chlorobenzoperoxoic acid (0.109 g, 0.441 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. Next, 3 mL of 10% sodium sulfite solution was added to the reaction mixture at room temperature and the contents were stirred for 10 min. The reaction mixture was concentrated and partitioned between ethyl acetate (10 mL) and sat. aq. sodium bicarbonate (2×10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield a pale yellow solid. LC/MS M+1=425.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)[CH3:23]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:10]([O:12][CH3:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CSC
Solvent: C1CCOC1
Product: CCC(O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid in anhydrous THF at 0° C. under a nitrogen atmosphere was added slowly a solution of BH3.Me2S in THF (2 M, 2 eq.). The mixture was stirred for 5 min at 0° C. and 3 hr at 55° C. The reaction was quenched with MeOH and partitioned between EtOAc and sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The obtained product was used in the next step without purification. MS (ES) C16H31NO5 requires: 317, found: 318 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (20 g) and 2-bromopyridine (12.64 g) were stirred at 125° C. for 31/2 days. The cooled reaction mixture was subjected to column chromatography on silica ((chloroform:methanol 10:1) to afford the title compound as an oil. This was treated with maleic acid in ethanol to give, on addition of diethyl ether, as a white solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyridine dimaleate (11.40 g), m.p. 116°-167° C. (recrystallised from isopropanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[O:8].[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH2:19])[S:16][N:15]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.CCOC(C)=O>[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH:19][C:7]([NH:6][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:16][N:15]=1
Reactant: Nc1nc(CCl)ns1
Reactant: O=C=NCc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C
Yield: 72 %

Procedure:
3-Fluorobenzyl isocyanate (1.3 g, 8 mmol) was added into a mixture of Intermediate 38: 3-chloromethyl-[1,2,4]thiadiazol-5-ylamine (0.83 g, 5.5 mmol), and DMAP (22 mg, 0.14 mmol) in NMP (11 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 100 C and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (30 mL×2). The aqueous phase was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography to afford 1-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-3-(3-fluoro-benzyl)-urea as an off-white solid (1.2 g, 72%). LC-MS (m/z): 303.0 (M+H)
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=3[CH3:27])[N:17]=2)[CH:9]=[CH:10][CH:11]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].NCCC(O)=O.O>CC(O)=O>[C:2]([OH:3])(=[O:1])[CH3:6].[O:34]=[C:29]1[NH:30][C:31](=[O:33])/[C:32](=[CH:2]/[C:6]2[CH:7]=[C:8]([NH:12][C:13]3[S:14][CH:15]=[C:16]([C:18]4[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=4[CH3:27])[N:17]=3)[CH:9]=[CH:10][CH:11]=2)/[S:28]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(C4OCCO4)c3)n2)s1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(/C=C4\SC(=O)NC4=O)c3)n2)s1
Temperature: 100 °C
Yield: 9 %

Procedure:
A solution of N-(2-{[3-(1,3-dioxolan-2-yl)phenyl]amino}-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl)acetamide obtained in Step 1 as described above (290.00 mg; 0.72 mmol; 1.00 eq.), 2,4-thiazolidinedione (151.90 mg; 1.30 mmol; 1.80 eq.) and beta-alanine (115.55 mg; 1.30 mmol; 1.80 eq.) in AcOH (6.00 ml) are heated at 100° C. for 1 h30. Water is added and the precipitate is filtered and washed with Et2O, affording (62) as a yellow solid (35 mg; 9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]([OH:26])=[O:25])=[CH:3][CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C=O
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A −78° C. solution of Example 66A (1.5 g, 4.68 mmol) in THF (50 mL) was treated dropwise with 2.5M n-butyllithium in hexanes (4.7 mL, 11.71 mmol), stirred for 30 minutes at −78° C., then treated with excess dry ice. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature, diluted with water, adjusted to pH 3 with 2N HCl, and filtered. The filter cake was dried to provide 686 mg (51%) of the desired product. MS (CI) m/e 285 (M+); 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H); 8.29 (s, 1H); 8.09 (d, J=8.4 Hz, 2H); 7.53 (d, J=8.4 Hz, 2H); 2.28 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C:18]3([C:28]#[N:29])[CH2:26][CH2:25][C:24](=[O:27])[CH:23]=[C:19]3[CH2:20][CH2:21][O:22][C:3]=12.C1(C)C=CC=CC=1.[H][H]>C(Cl)Cl.[OH-].[OH-].[Pd+2]>[Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@@:18]3([C:28]#[N:29])[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C@@H:19]3[CH2:20][CH2:21][O:22][C:3]=12.[Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@:18]3([C:28]#[N:29])[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C@H:19]3[CH2:20][CH2:21][O:22][C:3]=12
Reactant: [H][H]
Reactant: N#CC12CCC(=O)C=C1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#C[C@@]12CCC(=O)C[C@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Product: N#C[C@]12CCC(=O)C[C@@H]1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.1 %

Procedure:
A solution of 8-bromo-9-(4-fluorophenyl)-3-oxo-2,3,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazole-12b-carbonitrile (103, R1=4-Fluorophenyl) (2.02 g, 4.47 mmol) and toluene (80 mL) was added to 20% palladium hydroxide on carbon (wet, Deguessa type, 0.314 g). The mixture was shaken under about 50 psi of hydrogen at about 55° C. After about 17 h, the reaction mixture was allowed to cool to rt then filtered through Celite® rinsing with 25% THF/toluene (4×50 mL) then 25% THF/DCM (6×25 mL). The volatiles were removed under reduced pressure to afford a light tan solid which was slurried in DCM (10 mL). The solid was collected by filtration rinsing with DCM (3×10 mL) then dried under reduced pressure to afford (4aR,12bS)-8-bromo-9-(4-fluorophenyl)-3-oxo-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazole-12b-carbonitrile; compound with (4aS,12bR)-8-bromo-9-(4-fluorophenyl)-3-oxo-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazole-12b-carbonitrile (104, R1=4-Fluorophenyl) (0.916 g, 45% yield) as an ivory solid. The mother liquor was concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][N+:13]#[C-:14])=[CH:10][CH:9]=1.C(Cl)[Cl:18]>>[Cl:18][C:14](=[N:13][CH2:12][C:11]1[CH:15]=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=1)[S:3][C:2]([F:6])([F:5])[F:1]
Reactant: ClCCl
Reactant: FC(F)(F)SCl
Reactant: [C-]#[N+]Cc1ccc(Cl)cc1
Product: FC(F)(F)SC(Cl)=NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Trifluoromethylsulfenyl chloride (4.0 g, 0.03 mol) is bubbled over 30 minutes into a solution of 4-chlorobenzylisonitrile (3.0 g, 0.02 mol) in methylene chloride, causing the formation of a white precipitate. The suspension is stirred for 16 hours at room temperature and filtered to remove solids. The white filter cake is washed with methylene chloride and solvent is removed under reduced pressure to obtain an amber oil. Bulb-to-bulb distillation of the oil (90°-100° C., 0.05 mmhg) gives the title product as a colorless oil (3.9 g, 68%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]12OCC[O:22]1)[CH3:2].C(=O)(O)[O-].[Na+].CCOCC>C(O)(=O)C.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC21OCCO1)CC(OC)=CC4
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 12 %

Procedure:
Heat 13β-ethyl-3-methoxy-17,17-ethylenedioxy-gona-2,5(10)-diene (0.1 g.) in glacial acetic acid (2.5 cc.) and water (1 cc.) on a steam bath for 20 minutes, bring finally to boiling and allow to cool. Add aqueous sodium bicarbonate to neutralize the solution and ether extract the product. Wash, dry and evaporate the ether extracts to furnish a residue (0.065 g.); crystallize from a mixture of acetone and light petroleum to obtain the title compound (0.01 g.), m.p. 154°-5°; ultraviolet absorption peak at 239 mμ (ε15,000); infrared absorption peaks at 5.75, 5.96 μ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
p-Aminoacetophenone (87.6 g.) is heated with 1-bromohexadecane (198 g.) in dry hexamethyl phosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (20 ml.). The amber solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the product of the Example.
Reaction SMILES: [CH3:1][OH:2].[F:3][C:4]([F:8])([F:7])[CH:5]=[CH2:6].[O:9]1CCOC[CH2:10]1>Cl[Pd]Cl.[Al](O)(O)O>[CH3:10][O:9][CH:6]([O:2][CH3:1])[CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: CO
Reactant: C1COCCO1
Reactant: C=CC(F)(F)F
Agent: Cl[Pd]Cl
Agent: O[Al](O)O
Product: COC(CC(F)(F)F)OC
Temperature: 60 °C
Reaction time: 10 h

Procedure:
In a glass autoclave, a mixture of 150 g (4.69 mol) of methanol, 150 g of 1,4-dioxane, 3.0 g (0.017 mol) of PdCl2, 5.8 g (0.034 mol) of CuCl2.2H2O and 4.0 g of Al(OH)3 was kept heated at 60° C. Stirring the mixture, 3,3,3-trifluoropropene was continuously introduced into the autoclave so as to keep the gas pressure in the autoclave at 8 kg/cm2. This operation was continued for 10 hr. As the result 245.2 g (1.552 mol) of 1,1-dimethoxy-3,3,3-trifluoropropane was obtained. In this case selectivity to this acetal was 60.2%, and the remaining part of the reaction product was 3,3,3-trifluoropropanal.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1.[OH-].[Li+].Cl.CCOC(C)=O>C1COCC1.C(Cl)Cl>[C:17]([O:16][C:14]([CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[CH:11][CH:10]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)CCc1ccc(OCC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To a solution of 3-(4-tert-Butoxycarbonylmethoxy-phenyl)-propionic acid methyl ester (2.70 g, 9.17 mmol) in THF (80 ml) is added 0.2N lithium hydroxide (45.9 ml, 9.17 mmol) at 0° C. and the reaction mixture is stirred at 0° C. for 4.5 hours. 1M HCl (15 ml) is added and the product is extracted using EtOAc (×3). The organic phase is dried (Na2SO4) and concentrated in vacuo to yield a white solid. Flash chromatography (SiO2, 10% EtOAc in CH2Cl2, then 20% EtOAc in CH2Cl2) yields 3-(4-tert-Butoxycarbonylmethoxy-phenyl)-propionic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.[C:27]([C:29]1C=C2C(=[CH:37][CH:38]=1)C(=C(CC)CC)CCC2(C)C)#[CH:28]>>[CH3:26][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[C:29]([CH2:38][CH3:37])[CH2:27][CH3:28])[CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=C(CC)CC
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=C(CC)CC)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 143 mg (0.57 mmol) of 6-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound W) was converted into the title compound using 142 mg (0.51 mmol) of ethyl 4-iodobenzoate, 36 mg (0.19 mmol) of cuprous iodide and 130 mg (0.19 mmol) of bis(triphenylphosphine)palladium(II) chloride.
Reaction SMILES: [NH:1]([C:8]1[C:9](=[O:20])[C:10](=[N:13][C:14]2[CH:19]=CC=CC=2)[C:11]=1[OH:12])[C:2]1[CH:7]=CC=CC=1.C(N1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)C>>[OH-:12].[OH:12][C:11]1[C:10](=[N+:13]2[CH2:14][CH2:19][N:26]([CH2:25][CH3:24])[CH2:27][CH2:28]2)[C:9](=[O:20])[C:8]=1[N:1]1[CH2:2][CH2:7][N:1]([CH2:8][CH3:11])[CH2:2][CH2:7]1
Reactant: CCN1CCNCC1
Reactant: O=c1c(Nc2ccccc2)c(O)c1=Nc1ccccc1
Product: CCN1CCN(c2c(O)c(=[N+]3CCN(CC)CC3)c2=O)CC1
Product: [OH-]

Procedure:
A mixture of 4.0 grams of 2-anilino-3-hydroxy-4-(phenylimino)-2-cyclobuten-1-one and 3.4 grams of 1-ethylpiperazine is heated at 194°-198° C. in an atmosphere of dry nitrogen for 30 minutes. The cooled solid is comminuted, washed with anhydrous ethyl ether, and dried and the resulting solid is then extracted with 50 ml. of anhydrous benzene. The benzene solution is treated with activated carbon, filtered, concentrated and cooled. A crystalline solid forms and this is separated by filtration and dissolved in distilled water at room temperature and the solution is filtered and concentrated. A precipitate forms and is separated by filtration to give 1-[2-hydroxy-3-(4-ethyl-1-piperazinyl)-4-oxo-2-cyclobuten-1-ylidene]-4-ethylpiperazinium hydroxide inner salt melting at about 179.5°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:16]2[N:15]=[C:14]([N:26]2[CH2:31][CH2:30][N:29]3[CH2:32][CH:33]([CH2:36][O:37]S(C)(=O)=O)[CH2:34][CH2:35][CH:28]3[CH2:27]2)[N:13]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[O:37][CH2:36][CH:33]1[CH2:32][N:29]2[CH2:30][CH2:31][N:26]([C:14]3[N:13]=[C:12]([NH2:11])[N:17]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:16]4[N:15]=3)[CH2:27][CH:28]2[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)OCC1CCC2CN(c3nc(N)n4nc(-c5ccco5)nc4n3)CCN2C1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN3CC(COc4ccccc4F)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 100 °C

Procedure:
A solution containing 3-fluorophenol (1.5 eq.) in DMF was treated with sodium hydride (60% oil dispersion, 4 eq.) for 2 hours at around 50° C. A solution containing containing methanesulfonic acid 2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1 eq., see subpart (a) above) in DMF was added. The resulting mixture was then heated at around 100° C. for 24 hours. The solvent was removed, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford the desired product as a white powder: 1H NMR (400 Hz, DMSO-d6) δ 7.96 (d, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.15 (d, J=3.0 Hz, 1H), 6.92-6.83 (m, 3H), 6.75 (dd, J=3.0, 2.0 Hz, 1H), 4.84 (m, 2H), 4.08 (dd, J=10.0, 5.0 Hz, 1H), 3.74 (dd, J=10.0, 7.0 Hz, 1H), 3.65 (m, 2H), 3.33 (m, 3H), 3.10 (m, 1H), 2.97 (m, 1H), 2.39 (m, 1H), 1.99 (m, 2H), 1.67 (m, 1H), 1.48 (m, 1H). MS m/z: 465 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][S:38]([C:35]3[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=3)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-(trifluoromethyl)benzenesulfonyl chloride following the procedure of Example 61 as an off-white solid: MS (EI) m/z 601.1 (M+H)+; 1H NMR (DMSO-d6): δ 7.00-7.10 (m, 3H), 7.24 (d, J=8.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 2H), 7.50-7.60 (m, 3H), 7.70 (d, J=8.5 Hz, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.87 (d, J=7.4 Hz, 2H), 7.96 (d, J=7.4 Hz, 2H), 8.34 (d, J=6.2 Hz, 1H), 9.11 (s, 1H), 10.65 (s, 1H).