Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.C(O)(C)(C)C.[Br:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]([CH:73]([F:75])[F:74])=[CH2:72])=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+].[OH2:82]>C(OCC)(=O)C>[Br:64][C:65]1[CH:66]=[CH:67][C:68]([C@@:71]([OH:22])([CH:73]([F:74])[F:75])[CH2:72][OH:82])=[CH:69][CH:70]=1
Reactant: C=C(c1ccc(Br)cc1)C(F)F
Reactant: O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: OC[C@@](O)(c1ccc(Br)cc1)C(F)F
Temperature: 25 °C

Procedure:
To a 250 mL flask charged with commercial AD-mix-alpha (7 g) were added tert-butyl alcohol (25 mL) and H2O (25 mL). The mixture was stirred at room temperature to give 2 clear phases and the low phases appeared yellow orange. After cooling to 0° C., 1-bromo-4-[1-(difluoromethyl)vinyl]benzene (1.1 g, 4.7 mmol) was added at once and the mixture was stirred at approximately 4° C. overnight. A bright yellow mixture resulted. The mixture was kept at 0° C. and solid sodium sulfite (8 g, 64 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. Ethyl acetate (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with Ethyl acetate (2×10 mL). Combined Ethyl acetate extracts were dried (Na2SO4) and concentrated. Purification by combi-flash (40 g column; eluted with hexanes—Ethyl acetate (20% -60%) in 25 min.; flow rate: 35 mL/min and collected 18 mL/fraction) yielded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]3[CH2:21][CH:12]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([I:20])=[CH:15][C:14]=4[C:8]=2[N:7]=[C:6]1[C:22]([O:24]CC)=O)[CH2:11]3.[NH3:31]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]3[CH2:21][CH:12]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([I:20])=[CH:15][C:14]=4[C:8]=2[N:7]=[C:6]1[C:22]([NH2:31])=[O:24])[CH2:11]3
Reactant: N
Reactant: CCOC(=O)c1nc2c(n1Cc1ccccc1Cl)C1CC(C1)c1cc(F)c(I)cc1-2
Product: NC(=O)c1nc2c(n1Cc1ccccc1Cl)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 100 %

Procedure:
A pressure tube containing a solution of ethyl 3-(2-chlorobenzyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (89 mg, 0.17 mmol) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 36 hr. Evaporation of the reaction mixture furnished the title compound (86 mg, 0.17 mmol, 100%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.63 (d, J=11.35 Hz, 1H), 2.81 (dd, J=7.72, 3.00 Hz, 2H), 3.14-3.23 (m, 1H), 3.54 (td, J=8.43, 4.26 Hz, 1H), 5.39 (br. s, 1H), 5.92 (s, 1H), 6.42 (d, J=7.57 Hz, 1H), 6.82 (d, J=8.83 Hz, 1H), 7.09-7.15 (m, 1H), 7.17-7.23 (m, 1H), 7.41 (d, J=0.95 Hz, 1H), 7.44-7.66 (m, 1H), 8.83 (d, J=6.94 Hz, 1H); M+1=530/532.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:22])[C:20]=1[OH:21])[CH:16]=O>>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:16][C:15]2[CH:18]=[C:19]([CH3:22])[C:20]([OH:21])=[C:13]([CH3:12])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: CSc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4-methylthioacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11](COCC[Si](C)(C)C)[CH:12]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.250 g, 0.715 mmol) in 3.5 mL of DCM was added 2,2,2,-trifluoroacetic acid (2.2 mL, 28.6 mmol) and allowed to stir at ambient temperature for 1 hour before the reaction mixture was diluted with 5 mL of toluene and then concentrated under reduced pressure. The resulting residue was dissolved in 2 mL of 7M ammonia in methanol and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with a gradient of 2-5% methanol in DCM with 1% ammonium hydroxide to afford 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.468 mmol, 65.5% yield). MS (apci) m/z=220.1 (M+H).
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[NH4+].O>C(OCC)(=O)C>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (50 ml), 1-(4-methoxycarbonyl-phenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (10.0 g) and ammonium acetate (9.9 g) were charged in 500-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 90 to 100 ° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, water (250 ml) and ethyl acetate (250 ml) were added, the mixture was stirred, and an ethyl acetate layer was separated. The ethyl acetate layer was further washed with water (250 ml) and a saturated saline solution (100 ml). The ethyl acetate layer was concentrated in vacuo to make 50 ml, and n-heptane (250 ml) was added to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The crystals were filtered at room temperature and washed with a solution (50 ml) consisting of n-heptane and ethyl acetate (5:1). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (100 ml) to give 1-amino-1-(4-methoxycarbonyl-phenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (6.56 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.O>CN1CCCC1=O>[CH:37]1([S:40]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NS(=O)(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were added triethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204 mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and recrystallized from hexane/ethyl acetate to give the title compound (74 mg, 16%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:11]#[N:12])=[C:6]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(Oc2ccccc2)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1Oc1ccccc1
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a stirred suspension of 270 mg (0.98 mmol) 2-amino-4-methanesulfinyl-6-phenoxy-pyrimidine-5-carbonitrile in 10 ml DME were added 0.33 ml (3.45 mmol) 2-(hydroxymethyl) pyridine and 0.22 ml (1.48 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 40 mg (13%) 2-amino-4-phenoxy-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[C:35]2[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=2[CH:33]=[CH:32]1)C1C=CC=CC=1.C(O)(=O)C.COC(O)C.[H][H]>[Pd].O>[C@@H:10]1([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[CH:33]=[CH:32]2)[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 80 %

Procedure:
A mixture of 2.5 g of 7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5 ml of acetic acid, 500 mg of 20% palladium on charcoal, and 95 ml of methoxyethanol is hydrogenated at 50°-55° C. and approximately 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, and coevaporated with xylenes to provide a red syrup which is dissolved in water and treated with Amberlite ion exchange resin (20 ml of wet IR-45). The resin is filtered and washed several times with boiling water. The combined filtrates are evaporated in vacuo to provide 992 mg of crude 7-β-D-arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. Recrystallization of this material from water provides 800 mg of product, m.p. 117°-120° C. (after drying at 100° C. for one hour); [α]D25 =+16.2 (1.02% in H2O).
Reaction SMILES: C1(C)C=CC=CC=1[C:7]1[CH:8]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3C=CC=CC=3C)[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.O(C1C=C(C=CC=1)C[Cl:39])C1C=CC=CC=1.[CH2:43]([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[CH3:44]>C1C=CC=CC=1>[Cl-:39].[O:13]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][N+:45]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:43][CH3:44])[C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: Cc1ccccc1-c1cccc(Oc2cccc(-c3ccccc3C)c2)c1
Solvent: c1ccccc1
Product: CC[N+](CC)(CC)Cc1cccc(Oc2ccccc2)c1
Product: [Cl-]

Procedure:
18.2 g of the chlorinated product of m-tolylphenyl ether containing 13.2 g of 3-phenoxybenzyl chloride was treated with a solution of 9.1 g of triethylamine in 60 ml of benzene in the same manner as described in Example 1. Thus, 17.8 g of colorless, needle-like 3-phenoxybenzyl triethyl ammonium chloride was obtained (hygroscopic, no clear m.p.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:9][N:8]=1)[CH3:2]>CO.C1COCC1.C(O)(C(F)(F)F)=O.[Pd]>[CH3:30][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])=[N:8][CH:9]=2)[CH:18]=[C:17]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd/C (10.0 mg, 9.40 mol) was added to a solution of ethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]prop-2-enoate (96.0 mg, 0.224 mmol) in MeOH (2.00 mL) and THF (1.00 mL). One drop of TFA was added to the reaction mixture and was purged and flushed with argon (3×). The reaction mixture was stirred for 4 hours at room temperature under an atmosphere of hydrogen. The mixture was filtered through CELITE and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:7 ethyl acetate in hexanes) to afford ethyl 3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. C22H22F3N4O2 [M+H]431. found 431.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:5]=1[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12])([O-])=O>C(O)C.[Pt].[H][H]>[NH2:1][C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: [H][H]
Reactant: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1N

Procedure:
Hydrogenate 3.0 g of 2-(2,4-dinitrobenzylidene)-1-methylpyrrolidine in 50 ml of ethanol with platinum/hydrogen. Filter the catalyst from the hydrogenated product and concentrate the filtrate to obtain the title compound as a yellowish viscous oil which decomposes rapidly in contact with air and under light.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:6]=[C:5]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(Br)cc1Br
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Yield: 68.18 %

Procedure:
To a solution of ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in J. Chem. Soc. Perkin Trans-1: Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 2.0 g (6.36 mmol) in a mixture of toluene:water (35:2 ml) was added (4-chlorophenyl)boronic acid [0.99 g, 6.36 mmol] and potassium carbonate (1.76 g, 12.73 mmol) at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite and the celite cake was washed with ethyl acetate (50 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using and 6% ethyl acetate in hexanes as an eluent to obtain the title compound (1.5 g, 68.18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[C:25]1[C:26]2[N:27]([CH:32]=[CH:33][N:34]=2)[N:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:31][C:29]1[CH:30]=[C:25]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:26]2[N:27]([CH:32]=[CH:33][N:34]=2)[N:28]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: COc1ccc(CNc2ccc(C)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a flask was added N-(4-methoxybenzyl)-5-methylpyridin-2-amine (147 g, 645 mmol) in THF (5 mL) at 25° C. The solution was stirred at 25° C. and potassium t-butoxide (1936 mL, 1936 mmol) was added. The reaction solution was stirred at 25° C. for 30 minutes. Next, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (150 g, 645 mmol, Example 1 from WO 2007/038314) was added and the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched with ethyl acetate and the solvent was removed in vacuo. The residue was redissolved in ethyl acetate, washed with sat NaHCO3, and sat. NaCl and dried (Na2SO4), filt and concentrated in vacuo to give the crude product. The residue was purified via ISCO (5% EtOAC/DCM; 12 g column) to give pure product 6-chloro-N-(4-methoxybenzyl)-N-(5-methylpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.1367 g, 0.360 mmol, 0.056% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][C:37](=[O:39])[CH3:38])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 94.5 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added acetyl chloride (0.0141 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (82.2 mg, 0.156 mmol, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]1.[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([NH:25][CH:26]([CH2:30][CH2:31][CH3:32])[C:27](O)=[O:28])=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:27](=[O:28])[CH:26]([NH:25][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[C:19]([F:21])[CH:20]=[C:15]([F:14])[CH:16]=2)[CH2:30][CH2:31][CH3:32])[N:7]=[CH:6]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)Cn1cnc([N+](=O)[O-])c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC(=O)OC)cn1

Procedure:
(4-Nitro-imidazol-1-yl)-acetic acid methyl ester was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 409.1 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(-c2ccc(N)cc2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)nc1C
Yield: 79 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (50 mg, 0.29 mmol), thionyl chloride (3 mL), pyridine (5 mL) and ethyl 2-(4-aminophenyl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (94b) (113 mg, 0.43 mmol), to obtain 96 mg of the title compound as a pale yellow solid (80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:32]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)=[O:32])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOCCOc1cc2c(C=O)cnc(Cc3cccc(OCC)c3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OCC)c3)c2cc1OC
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (61 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (60 mg, 95% yield).
Reaction SMILES: C(OCC)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.C1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.Cl>O1CCCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
100 ml (0.11 mol) of a diethyl ether solution of 1 M 4-methoxyphenylmagnesium bromide was dropwise added to a tetrahydrofuran solution (200 ml) of 14.81 g (0.10 mol) of phthalic anhydride at −78° C., and stirred overnight at room temperature. Aqueous 1 N hydrochloric acid solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, then the reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 25.63 g (yield: 100%) of 2-(4-methoxyphenyl)-benzoic acid as a yellow oily substance.