Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH:14]=[CH:13][C:11]([NH2:12])=[N:10][C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].Cl.C1(C2(C=CC(C3N=CC=CN=3)(N)CC2=O)S(N)(=O)=O)CCCCC1>O.N1C=CC=CC=1>[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23]([NH:12][C:11]2[CH:13]=[CH:14][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8](=[O:9])[N:10]=2)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccn(C2CCCCC2)c(=O)n1
Agent: Cl
Agent: NC1(c2ncccn2)C=CC(C2CCCCC2)(S(N)(=O)=O)C(=O)C1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(C3CCCCC3)c(=O)n2)cc1

Procedure:
A mixture of 29.0 g. of 1-cyclohexylcytosine, 90 ml. of pyridine and 35.1 g. of N-acetylsulfanilyl chloride was stirred overnight, poured into 900 ml. of water, and acidified by addition of 80 ml. of concentrated hydrochloric acid. After several hours of vigorous stirring, the precipitated product solidified to yield 33.3 g. of N4 -acetyl-N1 -(1-cyclohexyl-1,2-dihydro-2-oxo-4-pyrimidinyl-sulfanilamide, m.p. 219°-234°. A sample purified by two recrystallizations from ethanol melted at 247°-250°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Li+].C(O)C>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Yield: 96.5 %

Procedure:
To a solution (20 mL) of methyl 4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoate (1.86 g) synthesized above in tetrahydrofuran was added 2N lithium hydroxide aqueous solution (10.2 mL), and the mixture was stirred with heating under reflux for 2 hr. A 4N aqueous lithium hydroxide solution (5.10 mL) was additionally added, and the mixture was stirred with heating under reflux for 4 hr. A 4N aqueous lithium hydroxide solution (5.10 mL) and ethanol (20 mL) were further added, and the mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (61.2 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.74 g, 96%) as a pale-brown solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[O:15][CH2:16][CH2:17]Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].O>CN(C)C=O>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[O:15][CH2:16][CH2:17][N:23]2[C:22](=[O:24])[C:21]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]4[C:19]2=[O:29])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCOc1c2ccccc2cc2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOc1c2ccccc2cc2ccccc12

Procedure:
2-(9-Anthryloxy)ethyl chloride (7.0 g) and potassium phthalimide (2.8 g) were heated to 130° C. in dimethylformamide (70 ml) for 7 hours. The cooled solution was added to water and extracted with ethyl acetate. The extract was dried and evaporated to yield N-[2-(9-anthryloxy)ethyl]phthalimide.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=O>O1CCCC1>[CH2:2]([O:3][C:4]([C:6]([CH3:7])=[CH:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)=[O:5])[CH3:1]
Reactant: O=Cc1ccc(-c2cccc3cncn23)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(-c2cccc3cncn23)cc1
Reaction time: 0.17 h

Procedure:
Triethyl 2-phosphonopropionate (0.61 g) is added to a solution of lithium diisopropylamide (from 0.32 g of diisopropylamine and 1.7 ml of 1.64M n-butyllithium) in 20 ml of tetrahydrofuran at 0° under nitrogen. After stirring for 10 minutes, 5-(p-formylphenyl)-imidazo[1,5-a]pyridine (0.50 g) is added dropwise in a solution of 5 ml of tetrahydrofuran. The reaction mixture is stirred for two hours at 0° and quenched with 25 ml of water. The layers are separated and aqueous phase is extracted with ethyl acetate (2×10 ml). The organic phases are combined, dried over sodium sulfate, filtered and evaporated to yield an oil which is chromatographed on silica gel with ethyl acetate as eluent to yield 5-[p-(2-ethoxycarbonylprop-1-enyl)phenyl]imidazo[1,5-a]pyridine; IR (CH2Cl2) 1700 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: CCC(Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N)C1CC1
Reactant: COC(=O)C(C)=O
Solvent: CCO
Product: CCC(C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-chloro-4-difluoromethoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.088 g, 0.24 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated as in Part F of Example 113 with the exception that ethanol was used as the solvent, gave 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115a): 1H NMR (300 MHz, CDCl3) δ 8.48–8.46 (2d, 1H, J=4.7 Hz), 7.37–7.33 (m, 2H), 7.19–7.14 (m, 2H), 6.86–6.37 (t,1H, J=73.3 Hz), 5.16–4.92, 4.90–4.41 (2m, 1H), 2.57 (s, 3H), 2.49–2.38 (m, 1H), 2.29–2.19 (m, 1H), 2.10–1.93 (m, 1H), 0.90–0.85 (t, 3H, J=7.3), 0.80–0.71 (m, 1H), 0.59–0.50 (m, 1H), 0.49–0.48 (m, 1H), 0.23–0.18 (m, 1H). MS (AP) m/z 420.1 [(M+H)+, 100].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:14]([CH:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4])[C:12]([O:18][CH2:19][CH3:20])=[O:17])(=[O:15])[CH3:16]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CC(=O)c1ccc(Br)cc1)C(C)=O

Procedure:
A mixture of 2,4′-dibromoacetophenone (3.0 g, 10.8 mmol), ethyl acetoacetate (1.48 mL, 10.8 mmol) and potassium carbonate (4.5 g, 32.4 mmol) were heated in 2-butanone (50 mL) at reflux for 24 hours. Upon cooling, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by chromatography with DCM to provide the title compound as an oil. 1H NMR (CDCl3) δ ppm 1.30 (3H), 2.10 (3H), 3.19 (2H), 3.75 (1H), 4.15 (2H), 7.50 (2H), 7.81 (2H); MS (ESI) m/z 326/328.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]([CH2:11][CH3:12])([CH2:13][CH3:14])[C:6]([OH:8])=[O:7])=[O:15])[CH3:2]
Reactant: CCOC(=O)C(CC)(CC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC)(CC)C(=O)O
Yield: 72.7 %

Procedure:
A solution of diethyl-malonic acid diethyl ester (3.0 g, 13.89 mmol) and potassium hydroxide (0.778 g, 13.89 mmol) in ethanol (50 ml) was stirred at room temperature for 18 hrs. The solvent was evaporated off and the residue was dissolved in water (20 ml) and extracted with dichloromethane (20 ml). This organic layer was discarded. The aqueous layer was then acidified with concentrated HCl and extracted with dichloromethane (3×20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to give a colorless oil (1.9 g, 72%). 1H NMR (300 MHz, methanol-d4) δ 4.17 (m, 2H), 1.89 (m, 4H), 1.25 (m, 3H), 0.83 (m, 6H). ES-LCMS m/z 188 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-chloro-6-methylbenzoic acid (4.0 g, 23.4 mmol) in methanol (50 mL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated, and the residue was dissolved in ethyl acetate (50 mL). The solution was extracted with saturated NaHCO3 (3×50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-6-methylbenzoate (3.07 g, 71% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Yield: 99 %

Procedure:
A mixture of 5,6-dichloronicotinic acid (5.2 g, 27 mmol) in thionyl chloride (50 mL) containing dimethylformamide (2 drops) was heated under reflux conditions for two hours; cooled and concentrated under reduced pressure to afford 5,6-dichloronicotinoyl chloride (5.6 g, 99%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:34])([F:33])[CH:5]([CH3:32])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:24](=[O:25])[CH2:23][O:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:20]2)=[CH:14][CH:13]=1)[C:7]([O:9]CC)=[O:8]>O1CCOCC1>[F:34][C:4]([F:3])([F:33])[CH:5]([CH3:32])[CH:6]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:24](=[O:25])[CH2:23][O:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:20]2)=[CH:16][CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(C(=O)O)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
11.4 ml (11.4 mmol) of 1 N aqueous sodium hydroxide solution were added to a solution of 1283 mg (2.86 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoate in 10 ml of dioxane, and the mixture was stirred at 80° C. overnight. After the reaction had gone to completion, the dioxane was removed under reduced pressure and the solution that remained was diluted with water and then adjusted to pH 2 using 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 1058 mg (2.52 mmol, 88% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[S:3]([O:6][C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32]C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:5])=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]([F:1])([F:45])[S:3]([O:6][C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:4])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.2 g, 0.304 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The mixture was stirred at rt for 1.5 h then was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (20 mL) and was extracted with dichloromethane (3×20 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated and adsorbed to silica gel then was purified by flash chromatography using a 12-100% ethyl acetate in hexanes gradient and a 12 g Thomson silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.109 g, 0.195 mmol, 64.3% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ=5.57 (dd, J=6.8, 1.9 Hz, 1H), 4.73 (d, J=1.6 Hz, 1H), 4.63-4.60 (m, 1H), 2.54 (td, J=10.9, 5.3 Hz, 1H), 2.17 (dd, J=17.1, 6.9 Hz, 1H), 2.08-1.99 (m, 1H), 1.70 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 1.82-0.91 (m, 20H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)[OH:44])C>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]([NH2:36])=[O:44])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH3:13])=[N:7]2
Reactant: CCN(O)CC
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Solvent: ClCCl
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C(N)=O)c3)c(=O)c12
Temperature: 50 °C
Yield: 97 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen and charged with compound 141 (219 mg, 0.40 mmol) and anhydrous methylene chloride (15 mL). N,N-Diethylhydroxylamine (146 mg, 1.64 mmol) was added to the resulting solution, and the reaction mixture was heated for 16 h at 50° C., cooled to ambient temperature, and then evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography to give a 97% yield of compound 143 as a white solid. m.p. 195-197° C.; 1H NMR (CDCl3) δ (ppm) 8.34 (d, 1H, J=10.9 Hz), 7.59-8.06 (m, 7H), 7.28 (m, 1H), 6.95 (bs, 1H), 6.00 (bs, 2H), 5.60 (s, 2H), 5.28 (bs, 1H), 3.62 (t, 2H, J=8.4 Hz), 2.85 (s, 3H), 1.53 (dd, 3H, J=6.7, 10.8 Hz), 0.96 (t, 2H, J=8.3 Hz), 0.01 (s, 9H); m/z=571 (M+H).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Br:6][C:7]1[CH:16]=[C:15]([C:17](OC)=[O:18])[CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10].Cl>C(O)C>[Br:6][C:7]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:8]=1[CH2:9][OH:10]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: OCc1ccc(CO)c(Br)c1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
Crushed calcium chloride (14.55 g, 131.1 mmol) was added over a period of 20 minutes to a solution of sodium borohydride (6.61 g, 174.8 mmol) in ethanol (150 ml) with stirring at 0° C., and then a solution of dimethyl 2-bromoterephthalate (described in J. Med. Chem., 13, 1235 (1970); 11.94 g, 43.7 mmol) in ethanol (20 ml) was added thereto. After the mixture was stirred at the same temperature for 30 minutes, sodium borohydride (5.3 g, 140 mmol) and calcium chloride (1 g, 9.0 mmol) were further added thereto. The resulting mixture was stirred for 40 minutes, and a 2N aqueous solution of hydrochloric acid (250 ml) was added thereto. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride. The extract was concentrated under reduced pressure, and a solid residue was obtained. The residue was washed with a small amount of ethyl acetate to afford the title compound (7.98 g, 84% yield) as a colorless solid (mp. title compound (7.98 g, 84% yield) as a colorless solid (mp. 104° C.)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:21]=1.[OH-].[Na+].C(OC(C)C)(C)C>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(C)Oc1ccc(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cn1
Temperature: 40 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
To a solution of 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.0 g of 5-chloromethyl-2-i-propyloxypyridine in 50 ml of toluene were added 8.8 g of a 5% aqueous solution of sodium hydroxide and 0.2 g of tetra-n-butylammonium bromide, and the mixture was stirred at 40° C. for 5 hours. After termination of the reaction, water was added thereto to remove the aqueous layer. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent of distillation under reduced pressure to give 3.7 g of a crude product. The crude product was added with i-propyl ether and recrystallized therefrom to obtain 3.0 g of 2-t-butyl-4-chloro-5-{(6-i-propyloxy-3-pyridyl)-methylthio}-3(2H)-pyridazinone, m.p. 111.2°~113.3° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=1)C1C=CC=CC=1.O.C(O)C1C=CC=CC=1>C(OCC)C>[CH2:24]([O:23][C:18]1[CH:17]=[C:16]([CH2:15][OH:14])[CH:21]=[CH:20][C:19]=1[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: OCc1ccccc1
Product: Cc1ccc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of lithium aluminum hydride in diethyl ether (50 mL) was added dropwise a solution of 3-Benzyloxy-4-methyl-benzoic acid benzyl ester (7.5 g) in diethyl ether (11 mL) under argon atmosphere at 0° C., and this mixture was stirred at room temperature for 6 hours. To this reaction mixture was added dropwise water (3.2 mL), and then Celite was added to this mixture and filtered. This filtrate was concentrated to give title compounds as a mixture of benzyl alcohol (7.0 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][O:17][CH3:18])[CH:10]=O.O.[CH3:20]N(C=O)C>C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br-]>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][O:17][CH3:18])[CH:10]=[CH2:20]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(C=O)cc1OCOC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=Cc1ccc(OCOC)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A solution of CH3PPh3Br (10.72 g, 30 mmol) in anhydrous DMF (50 mL) under argon atmosphere was cooled to 0-5° C. Sodium hydride (2.0 g, 60% suspension in mineral oil, 50 mmol, 1.66 eq.) was added in portions. The mixture was stirred at room temperature for 1 hour and then 3,4-di-(methoxymethoxy)-benzaldehyde (6 g, 26.52 mmol) was added in portions. The resulting mixture was stirred at room temperature until completion of the reaction (about 2 hours). The mixture was cooled again to 0-5° C. and water (5 mL) was slowly injected to decompose the excess NaH. After an additional 10 min, the mixture was mixed with water (200 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was mixed with hexanes and loaded to a silica gel column that was eluted with a mixed solvent of hexane and EtOAc to afford, after evaporation, 3.974 g of 3,4-di(methoxymethoxy)styrene as a yellowish oil (17.72 mmol, yield 66.8%). MS (ESI) m/z: 225 (M+1)+ and 247 (M+23)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].O>C(#N)C.O.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>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)c2)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: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2ccnc(-c3ccc(C(C)C)cc3)c2)c1
Yield: 70 %

Procedure:
Part C. A solution of ethyl 3-(2-chloro-pyridin-4-yl)-benzoate (81 mg, 0.31 mmol), sodium carbonate (99 mg, 0.93 mmol) and 4-isopropylbenzeneboronic acid (60 mg) in acetonitrile-water (2 mL/0.5 mL) is treated with a catalytic quantity of tetrakis(triphenylphosphine)palladium, and heated to reflux for 24 h. The mixture is poured into water (60 mL), and this mixture is extracted with diethyl ether (3×60 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford ethyl 3-[2-(4-isopropyl-phenyl)-pyridin-4-yl]-benzoate (75 mg, 76%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([O:11][CH2:12]C)=[CH:9][C:8]([CH3:14])=[N:7][C:6]=1[Cl:15])[CH3:2].C[O-].[Na+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH3:14])=[N:7][C:6]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(OC)cc(C)nc1Cl

Procedure:
This compound was prepared using a method analogous to that of 2-chloro-4-ethoxy-6-methylnicotinic acid ethyl ester (A.2.17.1), NaOMe replacing NaOEt;
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(Cl)c1O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])c(O)c(O)c1Cl
Reaction time: 18 h

Procedure:
1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde are dissolved in 80 ml of methylene chloride, treated with 0.82 ml of boron tribromide, stirred at 23° for 18 hours, the reaction mixture is treated with 5 ml of methanol while cooling with ice, evaporated, the residue is dried in a high vacuum, digested in water, filtered and recrystallized from acetonitrile. There is obtained 2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde of m.p. 193°-195°.