Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:14][C:10]=2[N:11]=[CH:12][N:13]=1>CN(C=O)C.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:9]3[C:8]([O:5][CH2:4][CH2:3][OH:6])=[N:13][CH:12]=[N:11][C:10]=3[O:14][C:15]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1
Reactant: OCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCO)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Add, at 0° C., 59 mg (1.5 mmol) of 60% sodium hydride to a solution of 461 mg (7.4 mmol) ethylene glycol in 10 ml DMF. After warming to room temperature, continue stirring for 1 h. Then add 0.50 g (1.5 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir the mixture for 3 h at room temperature. Next, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. The raw product thus obtained is purified by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). In this way, 412 mg (77% of theor.) 2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}ethanol is obtained.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:15]I.Cl>CN(C=O)C.O>[I:15][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc2occc2[nH]1
Reactant: II
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1[nH]c2ccoc2c1I
Temperature: -10 °C
Reaction time: 12 h
Yield: 45.9 %

Procedure:
A mixture of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (5.00 g, 30.3 mmol) and KOH (3.40 g, 60.6 mmol) in DMF (100 mL) was cooled to −10° C. Iodine (7.31 g, 28.8 mmol) in DMF (40 mL) was charged via an addition funnel over 30 min. The resulting mixture was warmed to rt and stirred for additional 12 h. The reaction mixture was poured into water, adjusted with HCl (2 N) to pH 6-7, and extracted with EtOAc. The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give a light tan solid methyl 6-iodo-4H-furo[3,2-b]pyrrole-5-carboxylate (3.85 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.98 (br, s, 1H); 7.55 (d, J=2 Hz, 1H); 6.52 (d, J=2 Hz, 1H); 3.91 (s, 3H). MS (m/z 291).
Reaction SMILES: [I-:1].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18]Cl)=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4].O>CC(C)=O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18][I:1])=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4]
Reactant: [I-]
Reactant: C=C(CCl)COc1ccc(C(C)=O)cc1C=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(CI)COc1ccc(C(C)=O)cc1C=O
Reaction time: 5 h
Yield: 100.1 %

Procedure:
531 mg (3.54 mmol) of sodium iodide are added to 894 mg (3.54 mmol) of 5-acetyl-2-{[2-(chloromethyl)-2-propenyl]oxy}benzaldehyde in solution in 10 ml of distilled acetone. The medium is brought to reflux and is stirred for 5 hours. Water is added and then the solution is concentrated. After the addition of water and dichloromethane, the phases are separated by settling and then the aqueous phase is extracted with dichloromethane. The combined organic phases are washed, dried and then concentrated under vacuum to give 1.22 g (100%) of 5-acetyl-2-{[2-(iodomethyl)-2-propenyl]oxy}benzaldehyde in the form of a white solid which turns yellow in air; 1H NMR (300 MHz, CDCl3): 10.46 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.15 (dd, J=2.4 Hz and 8.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 5.52 and 5.32 (2s, 2H), 4.86 (s, 2H), 4.01 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:14]([Cl:28])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH:25]=2)=[C:14]([Cl:28])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Temperature: 60 °C
Yield: 36 %

Procedure:
A mixture of {[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (7.25 g, 0.016 mol) and 4-chlorobenzoic acid (5.13 g, 0.03 mol) in Eaton's reagent (25 mL) was heated at 60° C. for 16 h. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethylacetate 90:10) to afford pure ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl-amino)-acetic acid ethyl ester. (3.36 g, 36% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[S:15])[NH2:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O>C(O)(C)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:14]=[C:13]([C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)[S:15][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(N)=S)cc1
Solvent: CC(C)O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Yield: 41.6 %

Procedure:
To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17 mmol) in isopropanol (20 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (1.44 g, 5.17 mmol). The precipitate was collected by filtration and washed with EtOH (2×5 mL). The filter cake was slurried with NaHCO3 (2×20 mL), water (2×20 mL) then EtOH (2×5 mL) and dried to afford 926 mg (41%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellow powder. LCMS-ESI (m/z) calculated for C22H24BrNOS: 429.1. found 430.0 [M+H]+, tR=3.41 min. (Method 4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[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>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:19]=[N:18]1
Reactant: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Product: Cn1cc(-c2cc(Oc3cnc(N)nc3)ccn2)cn1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine (676 mg, 3.04 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (758 mg, 3.64 mmol), potassium carbonate (1.259 g, 9.11 mmol) and Pd(PPh3)4 (175 mg, 0.152 mmol) were combined in dioxane (12 mL) and water (3 mL). The mixture was degassed with argon, and warmed to 85° C. overnight. The mixture was diluted with EtOAc (75 mL) and water (40 mL) and was filtered to collect an off-white solid. The organic phase was separated, washed with brine (40 mL) and evaporated at reduced pressure to give additional off-white solid. The two crops of solids were combined and triturated with EtOAc (15 mL) with sonication. The solid was collected by filtration, washed with EtOAc (2×5 mL) and dried under vacuum to provide 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-amine (455 mg, 55%). 1H NMR (DMSO-d6): δ 8.34 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 2H), 7.96 (s, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.77 (s, 2H), 6.67 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[CH:11](O)=[O:12]>C1(C)C=CC=CC=1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][CH:11]=[O:12])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC=O)n[nH]1
Yield: 52.6 %

Procedure:
To 14 g (0.1 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 were added 16.3 g (0.3 mole) of 85% formic acid and 30 ml of toluene, followed by heating under reflux conditions while separating water by distillation. When a calculated amount of water and an excessive amount of formic acid distilled out, the heating was stopped. The reaction mixture was diluted with water and then concentrated as whole, whereby crystals were precipitated. The crystals were collected by filtration, washed with a sodium carbonate aqueous solution and water, and then dried to obtain 8.8 g of 5-t-butyl-3-formylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 204° to 206° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1=CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(C(=O)OCc2ccccc2)C1
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Arecoline (39.5 g, 0.25 mol) was dissolved in dry toluene (20 ml). 1-Chloroethyl chloroformate (30.5 ml) was added slowly at 0-5° C. The mixture was heated at 80° C. for 2 h, cooled to room temperature, filtered and evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (400 ml) and extracted with 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to give methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (Yield: 30.5 g, 85%). Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (1.1 g, 7.8 mmol) was dissolved in methylene chloride (20 ml) and cooled to -15° C. Triethyl amine (2.2 ml, 15,8 mmol) and a solution of benzyl chloroformate (1.2 ml, 8,4 mmol) in methylene chloride (10 ml) were added. Stirring at room temperature for 1.5 h followed by evaporation to dryness. The residue was dissolved in methylene chloride and extracted with water two times. The organic layer separated, dried and evaporated to dryness in vacuo to give methyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate as an oil (Yield: 2.0 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N:38]=[C:39]=[O:40])[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[N:50]([CH2:53][C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=O)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:39]3[O:40][C:54]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:53][N:50]=3)[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl] carbamic acid tert-butyl ester (30 mg in 0.50 mL dry methylene chloride) was added 9 mg of 2-azido-1-phenyl-ethanone followed by 14 mg triphenylphosphine and the mixture stirred at room temperature. After 4 hours, the mixture was applied to a silica gel column for purification by flash chromatography (hexane:ethyl acetate, 3:2; then 1:1; then 2:3; then 1:3) to give the title compound (13 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[S:3][C:4]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:23])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1Sc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)sc1S(=O)c1ccccn1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 52.1 %

Procedure:
A mixture of 2-amino-4-methyl-5-(2-pyridylthio)thiazole (1.7 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (20 ml) and dichloromethane (50 ml) was stirred at 5° C. for 3.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyridylsulfinyl)thiazole (0.95 g, yield: 52.2 %). mp: 190°-193° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168°-170° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1.CCN(CC)CC>C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(NN)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (154 mg, 37%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[CH2:10](I)[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:10]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:9])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CI
Reactant: Cn1c(=O)cc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-Methyluracil (3.0 mg, 23.8 mmol), isobutyl iodide (7 mL, 60 mmol) and cesium carbonate (11.6 g, 35.7 mmol) in DMF (30 mL) is stirred at room temperature over a weekend. Solvent is removed under vacuum. The residue is treated with water, and then extracted with dichloromethane four times. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and then filtered through a short silica gel column. The filtrate is concentrated to dryness to give product as off white solids, which is used for the next reaction without further purification. MS (ESI) m/z 183.1 [M+H]+.
Reaction SMILES: [O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(C(OO)=[O:24])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]2[O:24][CH:15]2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=COc1ccccc1)Cc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C(=COc1ccccc1)CC1=CC2OC2C=C1
Reaction time: 120 h
Yield: 40 %

Procedure:
To 6.3 g of p-phenoxyallylbenzene was added 45 ml of chloroform solution containing perbenzoic acid prepared from 11 g of benzoylperoxide, and the resulting mixture was allowed to stand at about 5° C for 5 days. The thus obtained solution was washed with 10% sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue. This was chromatographed over a silica gel, and eluted with chloroform, and there was obtained 2.7 g (yield 40%) of p-phenoxyallylbenzene oxide as an oily substance.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2]
Reactant: CSC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A suspension of 3-[2-(3-cyano-2-methylisothioureido)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (10 g.) in ethanol (200 ml.) was stirred and cooled to 10° with external ice cooling. Methylamine (166 g.) was passed into the suspension over 2 hours at such a rate that the temperature did not rise above 17° with external ice cooling. After 80 g. had been added, all was in solution. After 4 hours the ice bath was removed and excess methylamine was allowed to evaporate overnight. The final volume was about 120 ml. The product was filtered off, washed with a little ethanol, sucked dry and dried at 60°/0.3 m.m. Recrystallisation from aqueous ethanol (1:3 v/v) gave 3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole, m.p. 198°-199°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:31]([O:33]CC1C=CC=C(F)C=1)=[O:32].[OH-].[Na+].O.[CH3:48][C:49](O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:48][C:49]3[N:10]([C:11]([CH3:12])=[N:15][N:16]=3)[C:9]=2[CH:8]=[C:7]1[C:31]([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(F)c3)n2Cc2cccc(F)c2)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(F)c3)n12

Procedure:
A solution of di-tert-butyl 1-(1-(3-fluorobenzyl)-2-{[(3-fluorobenzyl)oxy]carbonyl}-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (0.33 g, 0.54 mmol, from Step 2) in AcOH (10 mL) was heated in portions, in the microwave, to 180° C. for 10 minutes each. The reactions were pooled and AcOH was removed in vacuo. The residue was dissolved in methanol (2 mL) and 1.0 M NaOH in water (10 mL, 10 mmol) was added. When the hydrolysis reaction was complete, it was filtered, diluted with MeCN and H2O and then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.17 g, 97%). LCMS (M+H)+: 325.3.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=3[CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=1[Cl:47]>O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26]([O:46][C:43]4[CH:44]=[CH:45][C:40]([NH2:39])=[C:41]([Cl:47])[CH:42]=4)[C:21]=3[CH:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reaction time: 0.17 h

Procedure:
After adding 12 ml of dimethylsulfoxide to the 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-4, 141 mg (1.5 equivalents) of sodium hydride (60% dispersion, Aldrich) and 507 mg (1.5 equivalents) of 4-amino-3-chlorophenol were added while stirring, and stirring was then continued at room temperature for 10 minutes and then at 135-140° C. for 4 hours. The mixture was returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 1.20 g of the title compound.