Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C([Li])CCC.C(O[K:21])(C)(C)C>C(OCC)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][K:21]
Reactant: CC(C)(C)O[K]
Reactant: Cc1ccccc1N(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1ccccc1C[K]
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
13.4 g of ortho-dimethylaminotoluene (or N,N-dimethyl-o-toluidine) (M=135 g.mol−1; 99 mmol) are diluted in a mixture of 40 ml of hexanes and 20 ml of diethyl ether. At ambient temperature, under nitrogen and with stirring, 40 ml of a solution of butyllithium (2.5M in hexane) are added. After 3 h, 1 equivalent of tBuOK is added in fractions, under argon. The solution is heated and a yellow precipitate appears. The stirring is maintained overnight. The solution is filtered and the yellow precipitate is washed three times with a mixture of hexanes (3×40 ml). After drying under vacuum, the solid is milled and dried again under vacuum overnight. 14.9 g of yellow powder of ortho-dimethylaminobenzyl potassium are obtained (yield=80%). 1H NMR (THF-d8, 22° C.): δ=2.03 and 2.57 (2×1H, s, KCH2—), 2.67 (s, 6H, —NMe2), 5.11 (t, 1H, JH-H=7 Hz, aromatic CH), 6.04 (d, 1H, JH-H=7 Hz, aromatic CH), 6.16 (t, 1H, JH-H=7 Hz, aromatic CH), 6.26 (t, 1H, JH-H=7 Hz, aromatic CH).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-chlorophenyl)acetate dihydrochloride (I112) (0.12 g, 0.32 mmol) in DCM (5 ml), were added triethylamine (0.13 ml, 0.95 mmol) and benzoyl chloride (44.0 μl, 0.38 mmol), and the reaction was stirred at RT for 3 hours. Then the solvent was evaporated, and the residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-chlorophenyl)acetate (0.126 g; quantitative yield).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[NH2:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:26][CH:25]=1)(=[O:23])[NH2:22]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(C(N)=O)cc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.49 mmol) in dioxane (5 mL) was added 4-carbamoylphenylboronic acid (169 mg, 1.02 mmol), K3PO4 (217 mg, 1.02 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (9% ethyl acetate in petroleum ether) to afford methyl 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (103 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:20](Cl)[Cl:21]>O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:20][Cl:21])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1.07 g, 5.29 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.78 g, 21.2 mmol), TBAHSO4 (0.18 g, 0.53 mmol) and a solution of chloromethyl sulfochloridate (638 μL, 6.35 mmol) in DCM (5 mL). The title compound was obtained as a white solid (1.16 g, 87.7%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:37])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:37])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ((R)-1-{2-[4-(biphenyl-2-ylcarbamoyloxy)-piperidin-1-yl]-acetyl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Intermediate Z2) (1.17 g, 2.24 mmol) in DCM (10 ml) is treated with TFA (5 ml) and stirred at room temperature for 2 hours. The solution is basified by addition of saturated sodium bicarbonate solution and then extracted with DCM. The combined organic portions are washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield the title product. [MH+ 423.20].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99 %

Procedure:
A mixture of trans 3-bromocinnamic acid (m.p. 177°-179° C.; 11.4 g), thionyl chloride (11.9 g) and dry benzene (150 ml) was heated at reflux for 2 hours. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3-bromocinnamoyl chloride (12.2 g), b.p. 100°-100.5° C./0.2 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Yield: 95.7 %

Procedure:
A mixture of 22.52 g (47.05 mmol) (S)-3-(2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester, 1 g 20% Pd on charcoal, 250 mL tetrahydrofuran and 250 mL ethanol was shaken under a 50 psig. hydrogen atmosphere for 26 h. The mixture was filtered through a pad of celite and concentrated. The residue was passed through a 100 g plug of silica eluting with 6:4 ethyl acetate:hexanes to give 17.5 g (45.05 mmol, 95.7%) of (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a thick colorless oil. MS (APCI) m/z 387.0 (M−1).
Reaction SMILES: CO[C:3]([C:5]1[C:14](=[O:15])[N:13]([CH3:16])[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[O:17]C(=O)C(C)C)=[O:4].O[NH:24][C:25](=[NH:27])[CH3:26]>C1(C)C=CC=CC=1>[OH:17][C:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:13]([CH3:16])[C:14](=[O:15])[C:5]=1[C:3]1[O:4][N:27]=[C:25]([CH3:26])[N:24]=1
Reactant: CC(=N)NO
Reactant: COC(=O)c1c(OC(=O)C(C)C)c2nccnc2n(C)c1=O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2c(O)c3nccnc3n(C)c2=O)n1
Temperature: 25 °C

Procedure:
To a solution of 8-isobutyryloxy-5-methyl-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (Example 7.3) (0.10 g) in toluene (4 ml) was added N-hydroxy-acetamidine (0.025 g). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and the solid was isolated by filtration and dried to give Compound No. B5 of Table 5 (0.050 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46](B4OC(C)(C)C(C)(C)O4)[CH:47]=3)[CH:42]=[N:41]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:46]1[CH:47]=[C:48]2[C:43]([CH:42]=[N:41][N:40]2[S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[CH:44][CH:45]=1
Reactant: COc1ccc(S(=O)(=O)n2ncc3ccc(B4OC(C)(C)C(C)(C)O4)cc32)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)n2ncc3ccc(-c4c(N)ncnc4N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)cc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added 1-((4-methoxyphenyl)sulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (201 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50% to 75%, hexane-ethyl acetate) to obtain 97 mg (66% yield) of the title compound as a white solid. Purity 100%. LRMS (m/z): 648 (M−1)−.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:12][CH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31].O>CS(C)=O>[NH2:12][C:13]1([CH2:3][CH2:2][C:1]#[N:4])[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31]
Reactant: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2N
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2(N)CCC#N
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Under argon atmosphere, 1.2 ml of acrylonitrile and 4.48 g of potassium carbonate were added to a stirred suspension of 5.00 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride in dimethyl sulfoxide (30 ml), and the mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed, dried and then filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1:1)] to afford 3.48 g of 3-[3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]propanonitrile as a pale yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:8])[CH3:7].Cl[O-:10].[Na+].ClCl>O1CCCC1.O>[CH3:7][C:6]1[O:8][CH:5]=[CH:4][C:3](=[O:10])[C:2]=1[OH:1]
Reactant: CC(O)c1ccco1
Reactant: [O-]Cl
Agent: ClCl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1occc(=O)c1O

Procedure:
To a solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5° C. is added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) is added to the reaction flask via a gas inlet tube maintaining the reaction temperature below 5° C. The reaction mixture is then heated to reflux and the tetrahydrofuran removed by distillation. Heating is continued for an additional hour. The reaction mixture is cooled and maltol is isolated by the procedure described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.Cl.[CH3:10][O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH:12]([O:11][CH3:10])[CH2:13]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC1CN(c2ccc(Br)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5 ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassium carbonate (1.5 g) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:32][O-:33].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:33][CH3:32])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2,4-dichloro-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1 g, 2.085 mmol, Intermediate 38: step a) and solid sodium methoxide (0.56 g, 10.42 mmol) in toluene (10 mL) was heated in a sealed tube at 105° C. for 12 hours, cooled to room temperature, diluted with DCM and the resulting suspension filtered through Celite® rinsing several times with CH2Cl2. The solvents were removed under reduced pressure and the residue chromatographed (Heptane/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[Cl:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To the mixture of 2,6-dichloro-nicotinic acid methyl ester (4.0 g, 19 mmol) synthesized in Example 23 and tetrahydrofuran (39 ml), phenyl boronic acid (2.5 g, 19 mmol), potassium carbonate (8.0 g, 58 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 0.97 mmol) were added, and the obtained reaction mixture was stirred for 16 hours while being heated to reflux. The reaction mixture was cooled to room temperature, and then insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, and then water and ethyl acetate were added to the obtained residue, followed by extraction. The organic layer and the aqueous layer were separated, and the aqueous layer was further extracted using ethyl acetate. The organic layers were mixed, washed with saturated saline, and dried using anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=10:1 to 3:1). The obtained crude compound was recrystallized using the mixed solvent of heptane-diethyl ether, thereby obtaining the entitled compound (2.2 g, 47%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[C:16]1([NH:22][C:23]2[N:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CO>[C:16]1([NH:22][C:23]2[C:24]([CH:25]=[CH:1][C:2]([C:4]3[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=3)=[O:3])=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1cccnc1Nc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)C=Cc2cccnc2Nc2ccccc2)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a stirred solution of 3,4,5-trimethoxyacetophenone (213 mg, 1.01 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 mL) after 5 minutes to the reaction mixture 2-(phenylamino)nicotinaldehyde (200 mg, 1.01 mmol) was added, stirred for 6 h at 30° C. The progress of the reaction was monitored by TLC for completion. After completion of the reaction, the reaction mixture was acidified with 2N HCl, the resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The resulting product was purified by by recrystallization from ethanol to afford compound 6a as a pale yellow solid (365 mg, 92% yield).; mp 125-128° C. 1H NMR (CDCl3): δ 8.26 (d, 1H, J=4.1 Hz), 8.01 (d, 2H, J=8.3 Hz), 7.95 (d, 1H, J=15.8 Hz), 7.81 (d, 1H, J=8.3 Hz), 7.55 (d, 1H, J=16.1 Hz), 7.48 (q, 2H), 7.01-7.09 (m, 3H), 6.83 (q, 1H), 6.62 (s, 1H), 3.91 (s, 3H) 3.84 (s, 6H); ESI MS: 391 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>CN(C=O)C.O>[Cl:1][C:2]1[N:3]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:7]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:8][C:9]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)[nH]c(=O)c21
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 69.7 %

Procedure:
A mixture 2-chloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.27 mmol) and cesium carbonate (0.1 g, 0.30 mmol) was taken in DMF (2 ml) and isobutyl bromide (0.055 g, 0.41 mmol) was added drop wise. The reaction mixture was stirred and heated at 60° C. overnight, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography to provide 2-chloro-8-cyclopentyl-1-isobutyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.08 g, 69%) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1>>[CH2:13]([C:3]([CH2:11][CH3:12])([CH2:4][CH2:5][CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:2][O:1][C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:14]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CCC(CC)(CO)CCCS(N)(=O)=O
Product: CCC(CC)(CCCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 5-hydroxy-4,4-diethyl-1-pentanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 157°-158° C.
Reaction SMILES: [CH:1]1([C:10](O)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1([CH2:10][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 2,3-dihydro-1H-inden-1-carboxylic acid (0.50 g) in tetrahydrofuran (5.0 mL), lithium aluminum hydride (0.18 g) was added under ice-cooling and the resultant reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water was added under ice-cooling and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=85:15 to 75:25) to obtain the subject compound (445 mg) as a colorless oil.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH2:11]([O:15][C:16](=[O:19])C=C)[CH2:12][CH2:13][CH3:14].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:15][C:16]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: C=CC(=O)OCCCC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C12C=CC(CC1)C2
Temperature: 190 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 180 ml, 1.34 mol), butylacrylate (JUNSEI, 500 ml, 3.49 mol), and hydroquinone (2.7 g, 0.025 mol) were put in a 2 L autoclave. After heating to 190° C., reaction was carried out for 5 hours while stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 80° C. to obtain the product (yield: 78%). The mole ratio of exo-isomers to endo-isomers of the product was 56.2:43.8.