Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CC(=O)OC
Product: COC(=O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 210 °C

Procedure:
Anthracene (89.0 gm) was combined with methyl acrylate (51.5 gm) and xylenes (500 ml) in a Parr bomb and heated to 210° C. for 12 hours. The solvent was removed on a rotary evaporator and the residue was recrystallized from methanol to provide the product as a white solid (mp=113°-114° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:9])[CH3:8].ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:15]#[N:14])[CH:4]=1)(=[O:9])[CH3:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)c1cccn1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C#N)cn1C
Temperature: 25 °C
Yield: 33.9 %

Procedure:
1-(1-Methyl-1H-pyrrol-2-yl)-ethanone (4.00 g, 32.48 mmol) in dry methylene chloride (30 mL) was cooled to −78° C. under nitrogen. Chlorosulfonyl isocyanate (2.8 mL, 32.5 mmol) was added dropwise, and the mixture allowed to warm to room temperature over 1 h. The reaction was cooled down to −78° C. and dimethylformamide (8 mL) was added. The reaction was allowed to warm up to room temperature (2 h) and was then poured into a 1 N sodium carbonate solution, which was extracted with methylene chloride. The organic layers were washed with water, dried (anhydrous MgSO4) and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate:hexanes 1:5 to 1:3) to afford 5-acetyl-1-methyl-1H-pyrrole-3-carbonitrile (1.63 g, 34%), which was used without further characterization.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH:7]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:15][CH2:14]/[CH:13]=[CH:12]/[C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C/c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC/C=C/c1cccnc1
Reaction time: 0.5 h

Procedure:
Methane sulfonyl chloride (0.22 ml) was added to a mixture of (E)-3-(3-pyridyl)-2-propen-1-ol (0.36 g) and triethylamine (0.74 ml) in dichloromethane (5 ml) under −10° C. After being stirred at the same temperature for 0.5 hour, the reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-1-yl methanesulfonate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2=[C:10]3[N:15]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]2[C:7](=[O:27])[N:6]([CH3:28])[C:5]1=[O:29])[C@H:14]([C:23]([OH:25])=[O:24])[CH2:13][CH2:12][C:11]3=[O:26].[CH3:30]O>>[OH:26][CH:11]1[C:10]2[N:15]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]3[C:7](=[O:27])[N:6]([CH3:28])[C:5](=[O:29])[N:4]([CH3:3])[C:9]3=2)[C@H:14]([C:23]([O:25][CH3:30])=[O:24])[CH2:13][CH2:12]1
Reactant: CO
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC[C@H]3C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCC(O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.179 g, 4.72 mmol) was added slowly to a suspension of (S)-1,3-dimethyl-2,4,10-trioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylic acid (1.8 g, 4.72 mmol) in methanol (40 mL). The mixture was stirred at room temperature for 30 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:4]2[C:5]3[CH:14]=[C:13]4[O:15][CH2:16][O:17][C:12]4=[CH:11][C:6]=3[S:7][C:8]=2[CH:9]=[O:10])=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1sc2cc3c(cc2c1Cl)OCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3

Procedure:
1 equivalent of sodium hydride and then 0.094 mol of the product obtained in Step D are added at ambient temperature and under an inert atmosphere to a solution of 0.10 mol of 4-chlorophenol in 250 ml of dimethylformamide. After 12 hours' reaction at 80° C., the reaction mixture is concentrated under reduced pressure. The residue is then diluted with ethyl acetate, washed with water and then with an aqueous solution of NaOH and then of NaCl, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 98/2) allows the expected product to be isolated.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].[BrH:11].Br.[NH+]1C=CC=CC=1.[Br-]>C(O)(=O)C>[Br:11][CH2:8][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: CC(=O)c1ccccc1C
Reactant: Br
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 60 mL of Acetic acid. To the stirred solvent was added 1-o-tolyl-ethanone (3.0 g, 22.35 mmol) RM cooled to 0° C. was added 47% hydrobromic acid (9.7 mL, 178.63 mmol), pyridinium hydro bromide per bromide (8.6 g, 26.89 mmol) slowly. The resulting mixture was stirred at RT for 3 h. The RM was then quenched with 10% sodium bicarbonate solution in water (150 mL) at 0° C. and extracted with ethyl acetate (75 mL×2). The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2SO4 and evaporated to dryness. The crude compound thus obtained was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate (ratio) as eluent to give the product (2.50 g, yield: 52.5%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10]Br)[CH:6]=[CH:7][CH:8]=1.[Mg].[CH3:13][C:14]1([CH3:31])[CH2:18][O:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2OC)=[N:15]1.O>O1CCCC1>[CH3:28][O:27][C:21]1[C:20]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:19]([C:16]2[O:17][CH2:18][C:14]([CH3:13])([CH3:31])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Reactant: COc1cccc(CCBr)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCc2c(C3=NC(C)(C)CO3)ccc(OC)c2OC)c1
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)ethylbromide (12.2 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of magnesium (1.46 g) in dry tetrahydrofuran (20 ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution of 4,5-dihydro-4,4-dimethyl-2-(2,3,4-trimethoxyphenyl)oxazole (7.95 g) in dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 16 hours. Water (400 ml) was added and the aqueous phase thoroughly extracted with ethyl acetate (2×250 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90% petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200°/1 mm Hg) 9.7 g of the title compound were obtained. MS m/e 369.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][CH:6]1[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][CH:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC1CCC(O)C(C(C)(C)C)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCC(C)CC1C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 680 g (4 moles) of 2-tert-butyl-4-methylcyclohexanol and 612 g (6 moles) of acetic anhydride was heated to 145°-160° C. and the resulting acetic acid was distilled off slowly in the course of 3 hours. When the reaction was complete, the mixture was cooled, the excess acetic anhydride was distilled off under 20 mbar, the residue was cooled and then taken up in 500 ml of diethyl ether, the ether solution was washed acid-free with aqueous sodium bicarbonate solution, the solvent was removed and the residue was then fractionated. After a small initial fraction (13 g of boiling point 30°-45° C./0.005 mbar), 806 g of 2-tert-butyl-4-methylcyclohexyl acetate distilled over at 54°-56° C./0.005 mbar. The refractive index nD25 was 1.4505 and the yield was 95% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 115 °C
Yield: 52.3 %

Procedure:
2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at room temperature under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115° C. for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL×3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) δ 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(N)c1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NS(C)(=O)=O)c1ccc(Br)cc1F
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To 1-(4-bromo-2-fluoro-phenyl)-1-methyl-ethylamine (1.2 g, 5.4 mmol) and triethylamine (900 μL, 6.5 mmol) in dichloromethane (10 mL) at room temperature was added methanesulfonyl chloride (500 μL, 6.5 mmol). The solution was stirred 16 h, diluted in 1N HCl(aq) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid. Flash chromatography (SiO2, 40% ethyl acetate/hexane) gave a white solid (950 mg, 57%). 1H NMR (300 MHz, CDCl3): δ ppm 1.76 (s, 6 H) 2.74 (s, 3 H) 4.88 (s, 1 H) 7.24 (d, J=1.51 Hz, 1 H) 7.27-7.30 (m, 2 H)
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:24](O)(=[O:27])[CH2:25][CH3:26].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CCC(=O)O
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred brown solution of (rac)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-2) (92.2 mg, 0.30 mmol) and propionic acid (24.4 mg, 0.33 mmol) in CH2Cl2 (1.5 mL) at 0° C. under Argon was added EDCI (63.3 mg, 0.33 mmol). Stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured into aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution; the combined organic phases were dried over Na2SO4, filtered and evaporated to afford the title compound (111 mg, quantitative) as light yellow foam. MS: 364.2 (M+H+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2[nH]ccc12
Product: Clc1ncnc2[nH]ccc12
Yield: 70 %

Procedure:
3,7-Dihydro-pyrrolo[2,3-d]pyrimidin-4-one (60 mg, 0.45 mmol) was reacted with 3.0 mL of phosphorus oxychloride to give 49 mg (70%) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.57 (s, br, 1H, NH), 8.58 (s, 1H), 7.68 (dd, J=2.53, 3.36 Hz, 1H), and 6.59 (dd, J=1.86, 3.36 Hz, 1H). MS m/e 153 [M-1]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N>C(O)C>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 5 °C

Procedure:
A mixture of 4.475 g (15 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-methoxy-benzylamino)-pyrazole, 2.83 g (17.25 mmol) of 3-chloro-aniline hydrochloride and 80 ml of ethanol is heated under reflux for 16 hours. Cooling to approx. 5° C., filtering and washing the filter residue with diethyl ether yield the title compound; m.p. 222-223° C.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Si:17]([O:16][C@@H:14]1[CH2:15][C@H:10]([OH:9])[C@@H:11]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH2:12][CH2:13]1)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19]
Reactant: Cn1nccc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1nccc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Yield: 61.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 162f by using the (1S*,2R*,5S*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (327 mg, 1.09 mmol) prepared in Example 163e, potassium carbonate (301 mg, 2.18 mmol) and methanol (5.0 mL), to yield the title compound (207 mg, 87%) as a colorless oil.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:42]=[CH:41][C:16]([CH2:17][C:18]2[NH:19][C:20](=[O:40])[C:21]3[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]=3[N:23]=2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:42]=[CH:41][C:16]([CH2:17][C:18]3[NH:19][C:20](=[O:40])[C:21]4[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:22]=4[N:23]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(Br)cc3)[nH]c(=O)c12
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(-c4cccc(N)c4)cc3)[nH]c(=O)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
697 mg (4.5 mmol) of 3-aminophenylboronic acid monohydrate and 150 mg of tetrakistriphenylphosphine-palladium are added under argon to a solution of 1.66 g (3.47 mmol) of 6-(4-bromo-benzyl)-1-(1-methyl-4-phenyl-butyl)-3-ethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one in 38 ml of THF, and the mixture is stirred for one hour at 70° C. After 4.9 ml of 1N Na2CO3 solution have been added, the mixture is stirred for a further 4 hours at 70° C., the solvent is removed in vacuo, and the residue is taken up in CH2Cl2. The mixture is extracted with 2N HCl, and the aqueous phase is rendered alkaline with 1N NaOH and extracted twice with CH2Cl2. After the extract has been dried over Na2SO4, the solvent is removed in vacuo. Purification by chromatography (toluene/ethyl acetate=4:1) gives 110 mg (6.4%) of a pale yellow solid.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[C:5]=1[Cl:1]
Reactant: Cc1cc(N)cc(C)n1
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)c(Cl)c(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(EXAMPLE 6B): Chlorine gas (from 6 ml of pre-condensed chlorine) was passed into a solution of 4-amino-2,6-dimethylpyridine (2 g) in a mixture of concentrated sulphuric acid (20 ml) and water (20 ml) and the mixture was stirred for 1 hour. The mixture was then cooled to 0° C., basified with 4M sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, saturated sodium chloride solution and dried. Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (9:1 v/v) to give 4-amino-3-chloro-2,6-dimethylpyridine (1.45 g) as an off white solid, m.p. 86° C.; NMR (CDCl3): 2.37(s,3H), 2.52(s,3H), 4.47(s,2H), 6.37(s,1H); mass spectrum (chemical ionisation, ammonia): 157(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (227 mg, 1.13 mmol) in THF (4.0 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring was continued for 10 min. To this solution was added 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (200 mg, 0.56 mmol) and the resulting mixture was stirred at 50-55° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:28]=[C:29]=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.C(OCC)C>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:29]([NH:28][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCN=C=O
Reactant: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCNC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (i.e. the product of Example 1, Step B) (0.10 g, 0.32 mmol) and pentyl isocyanate (0.036 g, 0.32 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to provide a white solid. The solid was slurried in diethyl ether, filtered and air-dried to provide the title compound, a compound of the present invention, as a white powder (0.081 g), melting at 132-134° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:18][CH:17](OS(C3C=CC(OCCCC)=CC=3)(=O)=O)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([NH:41][CH:17]1[CH2:16][N:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)(=[O:13])=[O:14])[CH2:18]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOc1ccc(S(=O)(=O)OC2CN(S(=O)(=O)c3ccc(OCCCC)cc3)C2)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 120 h
Yield: 53.4 %

Procedure:
To a solution of 4-Butoxy-benzenesulfonic acid 1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl ester (0.99 g, 2 mmol) in tetrahydrofuran (4 ml) was added benzylamine (0.86 g, 8 mmol) and the mixture was stirred at 100° C. for 5 days. It was then washed with hexanes, and the residue was extracted with ether. The ether solution was evaporated, and the residue was chromatographed (silica gel, ethyl acetate-hexanes/1:1)to give 0.40 g of an amber gum; MS (ES) m/z 375.0 (MH+); HRMS (ES) Calcd. for C20H27N2O3S (MH+): 375.1742, Found: 375.1743.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:4]=1[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32].[OH-:34].[K+].Cl>CO>[C:25]([CH2:24][O:23][C:5]1[C:4]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[CH2:11][C:12](=[O:34])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)([OH:27])=[O:26]
Reactant: [OH-]
Reactant: COC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc(CC(=O)Cc2c(OC)cc(OC)c(CC=C(C)C)c2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Then, 1.9 g of 1-[4,6-dimethoxy-2-methoxycarbonylmethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone was dissolved in 20 ml of methanol, and 20 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes to effect a reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and diethyl ether to obtain 1.7 g (yield=92.4%) of 1-[2-carboxymethoxy-4,6-dimethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-propanone in the form of a colorless prism.