Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].[C:12]1(=[O:17])[O:16][CH:14]([CH3:15])[CH2:13]1.Cl>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16]
Reactant: CC1CC(=O)O1
Reactant: Oc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc(F)c(Cl)c1
Temperature: 23 °C
Yield: 10.2 %

Procedure:
To a solution of 27.2 g (0.68 mol) sodium hydroxide in 272 ml water was added 100 g (0.68 mol) 3-chloro-4-fluorophenol. The solution was warmed to reflux and 55.4 ml (0.68 mol) of beta-butyrolactone was added dropwise over a 1 hour period. The reaction was cooled to 23° C. and the pH brought to 7 with concentrated hydrochloric acid. The neutral solution was washed with 3×150 ml diethyl ether to remove unreacted phenol and then acidified to pH 2 with concentrated hydrochloric acid, extracted with 150 ml 1,2-dichloroethane, dried over magnesium sulfate and concentrated in vacuo to 4.3 g of an oil which by nuclear magnetic resonance examination was composed of 44 mol percent product and 56% 3-hydroxybutyric acid. The original diethyl ether washes were extracted with 3×150 ml saturated sodium bicarbonate. The combined bicarbonate solutions were extracted with 150 ml diethyl ether and then the pH was brought to 2 with concentrated hydrochloric acid. Extraction with diethyl ether, washing with brine and drying over magnesium sulfate and concentration in vacuo gave 16.2 g (10.2%) of title product as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N+:5]([O-])[CH:6]=[C:7]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=2)[N:3]=1.NC(N)=N.C[OH:25]>>[NH2:1][C:2]1[NH:11][C:10](=[O:25])[C:9]2[NH:8][CH:7]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: CO
Reactant: CCCCOCc1c[n+]([O-])c2nc(N)nc(N)c2n1
Agent: N=C(N)N
Product: CCCCOCC1CNc2nc(N)[nH]c(=O)c2N1

Procedure:
2,4-Diamino-6-n-butoxymethylpteridine-8-oxide. The product of Example 4A was reacted with guanidine in methanol according to the procedure described in Example 2 to give the title compound; mp >250°. UV: (0.1N HCl) λmax 252.5 (30,900), 282 (10,700), 343.5 (sh) (6,200), 356.5 (8,500), 369.5 (7,800) nm. NMR: δ (d6 -DMSO) 0.88 (t, 3H); 1.0-1.8 (m, 4H); 3.51 (t, 2H); 4.49 (s, 2H); 7.01 (br s, 2H); 7.75 (br s, 2H); 8.37 (s, 1H). IR: (KBr) 3700-2800, 1632, 1546, 1461, 1356, 1331, 1163, 1053, 978 cm-1. Anal. calcd. for C11H16N6O2 : C, 49.99; H, 6.10; N, 31.80. Found: C, 49.79; H, 6.11; N, 31.67.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]([F:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]>[Pd].CO>[NH2:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([O:8][CH2:9][O:10][CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: COCOc1c(F)cc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: COCOc1c(F)cc(N)cc1F
Reaction time: 2 h

Procedure:
A suspension of 3,5-difluoro-4-(methoxymethyl)oxynitrobenzene (35.0 g) and palladium catalyst (10% on charcoal, 3.00 g) in methanol (250 mL) ) was hydrogenated at 1 atm for 2 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 4-amino-2,6-difluoro-1-(methoxymethyl)oxybenzene. This was used in the next step without further purification. To a solution of crude 4-amino-2,6-difluoro-1-(methoxymethyl)oxybenzene thus obtained in tetrahydrofuran (500 mL) was successively added sodium hydrogencarbonate (17.4 g), water (100 mL) and benzyl chloroformate (30.0 g) at 0° C., and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=6:1) of the residue gave Reference Example 8 (49.10 g).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28].Cl>ClCCl>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)=[O:41])([CH3:28])[CH3:29]
Reactant: c1ccc(CN[C@H]2CC[C@@H](c3ccccc3)CC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 400 mg of cis-N-benzyl-N-(4-phenylcyclohexyl)amine in 20 ml of dichloromethane were added 2 ml of pyridine and then a solution of 310 mg of 2,6-diisopropylphenylisocyanate in 5 ml of dichloromethane dropwise. The mixture was stirred at room temperature, poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 460 mg of cis-N-(2,6-diisopropylphenyl)-N'-benzyl-N'-(4-phenylcyclohexyl)urea, melting at 153°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O>[C:11]([NH:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(N)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cnc(Cl)c(C#N)c1
Yield: 76 %

Procedure:
A solution of 5-amino-2-chloronicotinonitrile (2.6 g, 0.017 m) and acetic anhydride (50 ml) was heated at reflux for 30 minutes. After cooling to 25°, the reaction mixture was poured into water, neutralized with saturated Na2CO3 solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was recrystallized from benzene/hexane to yield 2.5 g (76% yield) of 5-acetamido 2-chloronicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CO.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:1].[C:24]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cc(Nc2cccc(N3CCCCC3)n2)c2nccn2n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(-c2cc(Nc3cccc(N4CCCCC4)n3)c3nccn3n2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A mixture of 6-chloro-N-(6-(piperidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (130 mg, 0.4 mmol), phenylboronic acid (74 mg, 0.6 mmol), Pd2(dba)3 (24 mg, 0.04 mmol), X-phos (76 mg, 0.16 mmol) and K2CO3 (166 mg, 1.2 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a white solid. This was dissolved in methanol and three drops of concentrated HCl was added. After 5 minutes, the mixture was concentrated in vacuo to give the final product (135 mg, 58.3%) as an HCl salt. 1H NMR (300 MHz, CDCl3): δ 9.07 (s, 1H), 8.50 (d, 1H, J=2.1 Hz), 8.25 (d, 1H, J=2.1 Hz), 8.14-8.10 (m, 2H), 7.97-7.94 (m, 1H), 7.65-7.61 (m, 3H), 7.29 (d, 1H, J=8.1 Hz), 7.20 (d, 1H, J=8.1 Hz), 3.78-3.74 (m, 4 h), 2.02-3.00 (m, 4 h), 1.85-1.83 (m, 2H). LC-MS: 371, [M+H]+, tR=2.016 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=7.5 min.
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[C:12]1[CH3:13]>CC(C)=O>[C:1]1([CH2:9][NH:10][C:15](=[O:16])/[CH:14]=[C:12](/[CH3:13])\[C:11]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:15](=[O:16])/[CH:14]=[C:12](/[CH3:13])\[C:11]([OH:17])=[O:18])[CH:2]=1
Reactant: NCc1cccc(CN)c1
Reactant: CC1=CC(=O)OC1=O
Solvent: CC(C)=O
Product: C/C(=C/C(=O)NCc1cccc(CNC(=O)/C=C(/C)C(=O)O)c1)C(=O)O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A 2.5-liter glass resin kettle was charged with 136.2 g (1.0 mole) of m-xylylenediamine and 2000 ml of reagent acetone and flushed with nitrogen. The kettle was fitted with a dropping funnel, reflux condenser, mechanical stirrer and thermocouple. The addition funnel was charged with 246 g (2.2 moles) of citraconic anhydride which was slowly added over a 21/2-hour period, with stirring and refluxing the acetone. The reaction mixture was allowed to cool to room temperature with stirring. Suction filtering and acetone wash of the solid product (air-drying) gives a 246 g of a tan powder, melting at 148°-150° C. The structure was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.C(O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:34]1[CH2:33][CH2:32][N:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:36][CH2:35]1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: COc1ccc(N2CCNCC2)cc1OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(C=C3C(=O)Nc4cc(OC)c(OC)cc43)CC2)cc1OC

Procedure:
3.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.3 g. acetic acid and 4.1 g. N-(3,4-dimethoxyphenyl)piperazine [J. Med. Chem. 10 (5) 812 (1967)] in 40 ml. benzene were reacted as described in Example 5 to give 4.67 g. product, m.p. 193°-195° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([OH:15])(=O)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([Cl:18])(=[O:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reaction time: 48 h

Procedure:
To the title A compound, (4-methanesulfonyl-phenyl)-methanesulfonic acid, sodium salt is added PCl5 (10 g) in 200 mL of chloroform and the mixture is stirred for 48 h. The solids are filtered off, the chloroform is removed by evaporation, and the residue is triturated with hexanes, and the solids are collected by filtration to afford (4-methanesulfonyl-phenyl)-methanesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH2:32]([N:39]1[C:43]([CH:44]=O)=[CH:42][N:41]=[CH:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([N:39]1[C:43]([CH2:44][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:42][N:41]=[CH:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCc4cncn4Cc4ccccc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(6-(2-amino-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)-acetamide (0.20 g, 0.45 mmol, prepared as described in WO04014871) and 1-benzyl-1H-imidazole-5-carbaldehyde (0.21 g, 1.1 mmol, Combi-Blocks) in 1,2-dichloroethane (4 mL) was stirred for 24 h at 25° C. Sodium triacetoxy-borohydride (0.24 g, 1.1 mmol) was added and the mixture was stirred for 4 d at 25° C. Additional amounts of 1-benzyl-1H-imidazole-5-carbaldehyde (0.21 g, 1.1 mmol, Combi-Blocks) and sodium triacetoxyborohydride (0.24 g, 1.1 mmol) were added, and the mixture was stirred for 24 h at 25° C. The mixture was partitioned between H2O and EtOAc, the organic phase was separated, washed with H2O and brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [gradient: 0.5-2.2% MeOH (2 M in NH3)/CH2Cl2] to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 616 (M+1). Mp: 264.0-264.1° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[C:22]1([NH:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)Nc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccccc1N1CCNCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a vial containing 4-(2-phenylcarbamoyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.438 g, 1.150 mmol) is added 2 mL of CH2Cl2 and 2 mL of TFA. The mixture stirred for 1 h and then concentrated to dryness to give 0.454 g of 4-(2-phenylcarbamoyl-phenyl)-piperazine trifluroacetate in 100% yield.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:4]=[C:3]1[S:15][CH3:16].[CH3:17]I.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:17][NH:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:4]=[C:3]1[S:15][CH3:16]
Reactant: CSc1nnc(-c2ccccc2)c(=O)n1N
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNn1c(SC)nnc(-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A two-phase mixture of 35.1 g (0.15 mole) of 4-amino-3-methylthio-6-phenyl-4H-1,2,4-triazin-5-one, 24.4 ml (0.375 mole) of methyl iodide, 5 g of tetrabutylammonium bromide, 200 ml of toluene and 60 ml of a 50% solution of sodium hydroxide is efficiently stirred for 2 hours, the temperature rising from 20° to 40° C. The organic phase is separated and filtered over silica gel. Evaporation of the filtrate yields 25.1 g (67.5% of theory) of 4-methylamino-3-methylthio-6-phenyl-4H-1,2,4-triazin-5-one which melts at 119°-120° C.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Yield: 75.5 %

Procedure:
Reflux 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (8 g.) in toluene (450 cc.) containing cycloheanone (120 cc.) and aluminium isopropoxide (5 g.) under nitrogen for 4 hours. Cool, and add water (15 cc.) dropwise, followed by anhydrous sodium sulphate. Filter the mixture, wash the residue with ether and combine the filtrate and washings, dry and evaporate finally at 90°/1.05 mm. to give 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17-one (6.0 g.), m.p. 124°-128°, (from methanol); infrared absorption peaks at 5.80, 6.02 μ.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([N:13]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1)[C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16](Cl)[C:15]=1[CH2:24][C:25]([NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1)=[O:26])=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:6]([O:10][C:11]([N:13]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1)[C:14]1[N:19]2[C:18](=[CH:22][CH:21]=[N:20]2)[N:17]=[C:16]2[C:15]=1[CH2:24][C:25](=[O:26])[N:27]2[C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(=O)N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c(Cl)nc3ccnn23)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of tetrahydrofuran (0.3 mL) and N,N-dimethylformamide (0.1 mL) containing tert-butyl (S)-3-(2-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyrimidin-6-yl}acetylamino)piperidine-1-carboxylate (4.3 mg), sodium hydride (with 40% mineral oil added) (10 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction solution, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[C:10]=1[CH3:33])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:33][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][O:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH2:25][CH2:26]1
Reactant: CCOC(=O)N[C@H]1CC[C@H](OCc2nc3ccccc3c(OCc3ccccc3)c2C)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N[C@H]1CC[C@H](OCc2[nH]c3ccccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)carbamate (153 mg) in ethanol-THF (1:1, 6 mL) was added 5% Pd—BaSO4 (70 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5). The resulting solid was washed with ethyl acetate and dried to obtain ethyl {trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl]methoxy]cyclohexyl}carbamate (88 mg) as a crystal.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[F:20][C:21]([F:29])([F:28])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([C:21]([F:29])([F:28])[F:20])[CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: FC(F)(F)C1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCCC(C(F)(F)F)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (±)-3-trifluoromethylpiperidine hydrochloride by the method described in Example 41. Colorless solid (123 mg, 82%). 1H NMR (CDCl3) 1.53-1.76 (m, br, 2H), 1.84-1.95 (m, br, 1H), 2.10-2.22 (m, br, 1H), 2.31-2.43 (m, br, 4H), 2.92-3.16 (m, br, 2H), 4.28-4.45 (m, br, 1H), 4.54-4.72 (m, br, 1H), 7.34 (d, J=4.0, 1H), 7.47 (d, J=4.0, 1H). 13C NMR 7.7, 23.5, 24.2, 40.5 (q, J=27), 44.0 (br), 46.3 (br), 114.5 (q, J=2), 118.5 (q, J=271), 126.1 (q, J=283), 127.8, 129.1, 131.4, 139.3, 155.0 (q, J=41), 157.6, 162.8. 19F NMR −72.8, −63.2. LC/MS 6.99 min, [M+1]+ 413.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3]N1C(=O)C2C(=CC=CC=2)C1=O.CC(C)([O-])C.[Na+:21].[C:22]([O:29]CC)(=[O:28])[C:23]([O:25]CC)=O>C(O)C>[Na+:21].[O:25]=[C:23]([CH2:3][C:2](=[O:1])[CH3:15])[C:22]([O-:29])=[O:28]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CC(=O)C(=O)[O-]
Yield: 184.1 %

Procedure:
The method of Examples 1-4 Part A was followed to treat 2-(2-oxopropyl)-1H-isoindole-1,3(2H)-dione (10.2 g, 50.0 mmol) with a solution of sodium tert-butoxide (5.77 g, 60.0 mmol) in ethanol (60 mL) and diethyl oxalate (8.77 g, 60.0 mmol). Ethyl 541, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dioxopentanoate sodium salt (14.00 g) was obtained as an orange solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:5]1.[H-].[Na+].CS(Cl)(=O)=O>O1CCCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:6]1[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[C:8]2[CH2:9][O:1][CH2:2][CH2:3][N:4]2[N:5]=1
Reactant: OCCn1nc(-c2ccccn2)c(-c2ccnc3ccccc23)c1CO
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2ccnc4ccccc24)COCC3)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-hydroxyethyl)-3-hydroxymethyl-5-pyridin-2-yl-4-quinoline-4-yl-pyrazole, (0.10 g, 0.29 mmol) in tetrahydrofuran (10 mL) cooled at 0° C. is added NaH (0.04 g, 50% in mineral oil). The mixture is stirred for 2 h at room temperature and methanesulfonyl chloride (0.065 g, 0.57 mmol) is added dropwise over 30 min. The reaction is quenched with water and extracted into ethyl acetate. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (10% methanol/dichloromethane) to yield the title compound, 31 mg (33%), as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:20])[CH3:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.C(OCC)(=O)C>[OH-].[OH-].[Pd+2].CO>[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:20])[CH3:19])[CH2:14][CH2:13]1
Reactant: CC(O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)[C@H]1CC[C@H](CN)CC1
Reaction time: 2 h

Procedure:
A 500 mL Parr bottle was charged with 400 mg Pd(OH)2, 7.0 g (24.1 mol) trans-(−)-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-carbamic acid benzyl ester, 125 mL ethyl acetate and 125 ml MeOH. The bottle was placed under 50 psi H2 and shaken for 2 hours. The suspension was then filtered through Celite and concentrated to give 3.6 g of a white solid.