Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19][CH3:20])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19][CH3:20])[C:8]2=[S:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 156.3 %

Procedure:
Reaction of 151a (0.295 g, 1.04 mmol) and Lawesson's reagent (0.252 g, 0.624 mmol) in toluene (15 mL) within 12 h as described for the synthesis of 147a gave compound 153a (0.291 g, 94%) as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 3.90 (3H, s), 6.04 (2H, s), 6.62-6.68 (2H, m), 7.38-7.42 (1H, m), 7.48 (2H, t, J=7.2), 7.68 (2H, d, J=8.0), 7.82 (1H, d, J=4.8), 8.53 (1H, s); 13C NMR (CDCl3, 100 MHz) δ 50.9, 56.4, 110.0, 112.0, 120.2, 122.4, 128.5, 129.3, 132.2, 136.4, 141.9, 158.7, 171.5 HRMS (EI) calcd for C15H14N4O2 [M]+ 282.1117. found 282.1115. HRMS (EI) calcd for C15H14N4OS [M]+ 298.0888. found 298.0888.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH2:11][CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>O1CCCC1>[NH2:7][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:11]([CH3:12])[C:10]#[N:13]
Reactant: CCC#N
Reactant: N#Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C#N)=C(N)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 49.5 %

Procedure:
In a 2 L round bottom flask (fitted with rubber septum, nitrogen blanket and stir bar) combine 4-chlorobenzonitrile (60.0 g, 1.00 equiv, 432 mmol), propionitrile (61.2 mL, 2.00 equiv, 864 mmol), tetrahydrofuran (43.2 mL) and 1.0 M potassium t-butoxide in t-butanol (tert-butyl alcohol, potassium derivative, 475 mL, 1.10 equiv; 475 mmol); and stir for 24 h. Quench with aqueous NaHCO3 and extract with ethyl acetate. Wash the organic phase 2 times with brine, dry (K2CO3), filter, and concentrate to dryness. Purify by flash chromatography on silica, eluting with 15:85 to 50:50 ethyl acetate/hexane, to afford 3-amino-3-(4-chlorophenyl)-2-methylacrylonitrile (as an uncharacterized E-/Z-mixture). Yield: 49.5%. LCMS: 193.0 (m+1).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].C([O:14][C:15](=[O:20])[C:16]([CH2:18][OH:19])=[CH2:17])C.Cl>O>[C:15]([CH:16]([CH2:18][OH:19])[CH2:17][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([OH:20])=[O:14]
Reactant: C=C(CO)C(=O)OCC
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(CC(=O)O)CC(CO)C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
(0.05 mole) of iminodiacetic acid were suspended in 25 ml of water and neutralized with sodium hydroxide to pH=10-12. 6.5 g. (0.05 mole) of ethyl--2--hydroxymethylacrylate was added dropwise to the solution and the temperature of the resulting mixture increased to 80°C. The pH was maintained at 10-12 by further addition of sodium hydroxide. The reaction mixture was stirred at 80°C for 20 hours and then cooled to room temperature and acidified to pH=1.5 with concentrated hydrochloric acid. The solvent was distilled under reduced pressure to half the weight of the solution and the product was allowed to crystallize. The white precipitate was filtered, washed with water and methanol and then dried in a vacuum to 5.3 g. of white powder. The yield was 45% of theoretical and the product had a melting point of 195 °C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([N:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH3:15])[CH2:13][C:12]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[O:16])=[CH:5][CH:4]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(CC(=O)N1CCOC1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 4-trifluoromethylaniline (193 mg, 1.2 mmol) and 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol) and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated off and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(4-trifluoromethylanilino)butyryl-1,3-oxazolidin-2-one (238 mg, 75% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 83% e.e.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C.O>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:35]([NH:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=4)=[O:36])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Reactant: O=C=Nc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Temperature: 70 °C

Procedure:
To 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 150.0 mg, 0.41 mmol, prepared as described in Example 68, Scheme 185) in acetonitrile (12.5 mL) were added 3-fluoro-isocyanato-benzene (604, 61.6 mg, 0.45 mmol), 4-dimethylaminopyridine (10.0 mg, 0.082 mmol) and triethylamine (0.25 mL, 0.0018 mol). The reaction mixture was heated at 70° C. overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (605, 0.100 g, 48.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:31]4[C:30]([F:29])=[CH:35][C:34]([F:36])=[CH:33][N:32]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Nc1ncc(F)cc1F
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(F)cc(F)cn4c3-c3ccccc3)cc2)CCC1
Yield: 10.3 %

Procedure:
1 g (2.25 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 292.8 mg (2.25 mmol) 3,5-difluoro-pyridin-2-yl-amine and 900 mg molecular sieves (3A, dried over night at 120° C. in a drying oven) in 20 mL ethanol were heated at reflux in a pressure pipe for 20 hours. The reaction mixture was sucked off via a glass fibre filter and evaporated to dryness. The residue was redissolved in dichloromethane, washed with hydrochloric acid (1 M), saturated sodium bicarbonate and brine and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 109.9 mg (9.8%) of the pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21].[Li]CCCC.[C:27]([O:31][C:32](=O)[O:33]C(C)(C)C)([CH3:30])([CH3:29])[CH3:28].O>C(Cl)Cl.CCCCCC>[C:27]([O:31][C:32]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:18][CH:17]=2)[C:12]([CH3:21])=[CH:13][C:14]1([CH3:20])[CH3:19])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A mixture of 2.4 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (see Example 1) in 35 mL of CH2Cl2 was cooled down to −78° C. To this mixture, 13.1 mL of 1.6 M n-BuLi in hexane was added dropwise. The mixture was warmed to 0° C. and 2.9 g of (di-tert-butyl)carbonate was added. The mixture was allowed to stir at 0° C. for 1 hour. The reaction was then worked up by adding water and extracting with EtOAc three times. The organic layers were combined, washed sequentially with 1 N HCl, water, saturated aqueous sodium bicarbonate solution, water, saturated aqueous NaCl solution, dried over magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 1.4 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:9]1([S:8][S:7][CH2:6][C@H:2]2[C:3](=[O:5])[O:4][C:16](=[O:18])[NH:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CSSc1ccccc1)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1N[C@@H](CSSc2ccccc2)C(=O)O1
Temperature: 47.5 °C
Yield: 85 %

Procedure:
To a rapidly stirred (over-head stirrer) suspension of S-thiol-phenyl-L-cysteine (1b) (57.5 g, 0.25 mol) in THF (250 mL) was added solid triphosgene (26 g, 88 mmol) in one portion at 45-50° C. (before addition, remove the heating mantle). When the temperature drops to 45° C., put the heating mantle back on and maintain the inside temperature around 45-50° C. until the solution becomes homogeneous. After the removal of the heating mantle, the solution was purged with argon overnight into a NaOH bubbler to remove any residual phosgene. The solvent was evaporated in vacuo and this provided anhydride 2b (55 g) in 85% yield. 2b: m.p. 217° C. (decomp); 1H NMR (300 MHz, CDCl3) δ 2.90-2.98 (m, 1H), 3.30 (d, 1H, J=12 Hz), 4.68 (d, 1H, J=9 Hz), 6.01 (s, 1H), 7.34-7.58 (m, 5H); 13C NMR (75.5 MHz, CD3Cl3): δ 39.4, 56.5, 128.3, 128.9, 129.5, 135.2, 150.8, 167.7. Due to the unstable nature of this anhydride, it was stored in the refrigerator overnight under an atmosphere of argon and used immediately the next day without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][C:4]=2[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 55.6 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (5.0 g, 21.9 mmole), from Preparation 4, ethyl acrylate (3.3 g, 32.9 mmole), Pd(OAc)2 (1.1 g, 0.74 mmole), tri-ortho-tolylphosphine (1.3 g, 4.4 mmole), and diisopropylethylamine (11.4 mL, 65.7 mmole) in propionitrile (200 mL) and DMF (25 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (3.0 g, 59%) as a light yellow solid: MS (ES) m/e 233 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[C:1]1([CH:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)CCC(C(=O)O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(O)CCC(C(=O)O)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 2.34 g of 2-phenyl-5-oxooctanoic acid, 0.3 g of NaBH4, 0.5 g of NaOH and 25 ml of methanol is boiled for 5 hours and worked up as usual. 2-Phenyl-5-hydroxyoctanoic acid is formed as an intermediate but is not isolated. 2-Oxo-3-phenyl-6-propyltetrahydropyran is obtained.
Reaction SMILES: [OH2:1].[C:2]([F:5])([F:4])=[CH2:3].[C:6]([O:13][CH3:14])(=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=[O:10]>C(OCC)(=O)C>[C:6]([O:12][O:13][C:6]([O:12][CH:2]([CH3:3])[CH3:3])=[O:1])([O:13][CH:14]([CH3:2])[CH3:14])=[O:1].[C:2]([F:5])([F:4])=[CH2:3].[C:6]([O:13][CH3:14])(=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=[O:10]
Reactant: O
Agent: C=C(F)F
Agent: COC(=O)/C=C\C(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)OOC(=O)OC(C)C

Procedure:
Into a 2 liter-autoclave, 1000 g of deionized water, 0.8 g of methylcellulose, 2.5 g of ethyl acetate, 4 g of di-iso-propyl peroxydicarbonate (IPP), 396 g of vinylidene fluoride, and 4 g of monomethyl maleate (giving a vinylidene fluoride/monomethyl maleate (mol ratio)=100/0.50), were charged and subjected to suspension polymerization at 28° C. for 47 hours.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:18][N:19]([CH2:30][C:31]([O:33][CH3:34])=[O:32])S(C1C=CC(C)=CC=1)(=O)=O)C.C[O-].[Na+]>CO>[CH3:34][O:33][C:31]([C:30]1[N:19]=[CH:18][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:32]
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(Oc3ccccc3)cccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a stirred solution of 2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-3-phenoxy-benzoic acid ethyl ester (5.07 g, 0.01 mol) in anhydrous methanol (22 mL) was added dropwise a mixture of sodium methoxide solution (30% wt, 5.6 mL) and anhydrous methanol (4 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for additional 3 h before it was concentrated in vacuo. Water was added and the pH of the slurry was adjusted with aqueous 1 N HCl to pH=10. The precipitate formed was separated by filtration, washed with water, saturated sodium bicarbonate solution, and water before it was dried in vacuo to give the title compound as a white solid (2.21 g): 1H NMR (CDCl3, 200 MHz): δ=11.73 (s, 1H), 9.21 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.40 (m, 2H), 7.13 (m, 4H), 4.10 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:15]([OH:29])[CH:16]=1)([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 42 %

Procedure:
A mixture of 4.2 g. (8.73 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridine, 4.0 g. of 10% palladium-on-carbon and 50 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate, evaporated and the residue again dissolved in ethyl acetate and filtered. The filtrate is evaporated and the residue crystallized in ether to yield 1.1 g. (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)cs1)c1cc(Cl)ccc1O
Yield: 31 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCC(c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1ccc(-c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)n[nH]1
Temperature: 130 °C
Yield: 29.9 %

Procedure:
A mixture of 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (137 mg, 0.37 mmol) and cesium carbonate (232 mg, 0.71 mmol) in dimethyl sulfoxide (5 mL) was heated at 130° C. 45 min. The mixture was cooled to rt and partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (40 g silica gel column) chromatography using 2% to 8% methanol in methylene chloride to 10% methanol containing 0.2% ammonium hydroxide in methylene chloride. The recovered product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The product was crystallized using a mixture of ethanol, ethyl acetate, ether and hexane to give 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-2H-pyridazin-3-one (40 mg, 29%); Mp 195-197° C.; MS m/z 362 (M+H).
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1
Reactant: CCCc1ccc(C=C(Br)Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(C#CBr)cn1
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A mixture of 5-(2,2-dibromovinyl)-2-propylpyridine (0.8 g, 0.0026 mol), potassium tertbutoxide (1.2 g, 0.0105 mol) and toluene (14 mL) were heated at 80° C. for 4 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.55 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.O>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:20]([CH3:19])[CH2:25]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 86.5 %

Procedure:
Heat a mixture of 1-chloro-4-(4-fluorophenyl)phthalazine (5.0 g, 19.3 mmol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (5.03 g, 25.1 mmol) and triethylamine (8.1 mL, 59.0 mmol) in DMSO (97 mL) at 115° C. for 3 d. Pour the reaction mixture into water, rinsing with CH2Cl2. Extract with Et2O. Wash the organic layer with water (2×), then dry over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a pale yellow foam (7.05 g, 84%). ES/MS m/z 423.2 (M+1).
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][CH:20](Br)[C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH:19]=[CH:20][C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCC2Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCC=C2
Temperature: 100 °C

Procedure:
To a solution of methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (obtained following Example 2, Step 1) in anhydrous DMF was added triethylamine (2 eq.). The mixture was stirred and heated to 100° C. for 3 h. After cooling to room temperature the mixture was partitioned between 0.1 M HCl and EtOAc. The aq. phase was again extracted with EtOAc and the combined org. phases were dried over sodium sulfate, filtered, concentrated to dryness under vacuum. The crude product so obtained was used in the subsequent step without further purification. An analytical sample of the title compound was obtained by crystallization from methanol. A pale yellow solid was obtained.