Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[CH3:22][NH2:23]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(C2CCc3c(Cl)nc(Cl)nc32)cn1
Reactant: CN
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of 2,4-dichloro-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (33 mg, 0.099 mmol) in NMP (Volume: 5 mL) was added methanamine (0.247 mL, 0.494 mmol). The reaction mixture was stirred at room temperature for 2 h. The product was partitioned between ethyl acetate & water. The organic layers were combined and dried in vacuum to afford 2-chloro-N-methyl-7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (8 mg, 0.024 mmol, 24.64% yield). LC-MS (M+H)+=329.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:34][CH2:35][CH3:36])[C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.O>[CH2:34]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[CH:12][NH:11][C:9]=2[N:10]=1)[CH2:35][CH3:36]
Reactant: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2Cc2ccc(OC)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O
Product: CCCN(CCC)c1nc2[nH]cc(-c3c(C)cc(C)cc3C)c2c(=O)n1C
Yield: 15.6 %

Procedure:
A Solution of 2-(dipropylamino)-5-mesityl-7-(4-methoxybenzyl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.21 mmol) in trifluoroacetic acid (3 ml) and anisole (0.1 ml) was refluxed for 3 days. The mixture was diluted with water (20 ml), neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (20 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 12 mg (15%) of the title compound.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])=[CH:4][CH:3]=1)#[N:17]
Reactant: COc1ccccc1C(=O)C=CN(C)C
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A stirred mixture of 3-dimethylamino-1-(2-methoxyphenyl)-2-propene-1-one (5.74 g), cyanoacetamide (2.48 g) and sodium methoxide (from sodium hydride (50%, 4.32 g) and methanol (3.5 ml)) in dry dimethylformamide was heated under reflux for 10 hours. The reaction mixture was poured into water, acidified to pH4 with glacial acetic acid and extracted with ethyl acetate. The ethyl acetate extract was evaporated under reduced pressure to low volume and water was added to cause precipitation of a crude product (3.67 g) which was collected and recrystallised twice from dimethylformamide to yield the title compound, 1.68 g, m.p. 236°-238° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C(Cl)Cl.CCOCC>[F:1][C:2]1[C:3]([C:33]([F:35])([F:34])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (61, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2.0 N solution in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL), washed with saturated NaHCO3 solution, and the concentrated under reduced pressure to yield (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone (62) as a white solid (80 mg, 97%): 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.487-7.336 (m, 2H), 5.193-5.008 (m, 1H), 4.76-4.58 (br s, 1H), 3.75 (s, 2H), 3.25-3.04 (m, 2H), 2.94-2.84 (m, 1H), 2.84-2.71 (br s, 1H), 2.60-2.53 (m, 2H), 1.89-1.58 (m, 4H); ESI MS m/z 415.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:34][C:35]([CH2:38][CH3:39])=[N:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[O:34][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:37][N:36]=1)[CH3:39]
Reactant: CCc1nnc(CCl)o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 2-(chloromethyl)-5-ethyl-1,3,4-oxadiazole (257 mg; compound D4) in the presence of potassium carbonate (242 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(OCC)(=O)C.CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(C(F)(F)F)c1
Yield: 82.6 %

Procedure:
A solution of 173 mg (0.394 mmol) of [[2-(methylthio)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of ethyl acetate and 1 mL of methanol was heated to reflux and treated with 1.05 g of Raney Ni in portions over 3 hours. The reaction was diluted with 2 mL of methylene chloride and the solids were removed by filtration through a filter aid. The reaction mixture was dried with sodium sulfate and concentrated to provide 128 mg (83%) of [[6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.4 Hz, 3H), 2.63 (q, J=7.4 Hz, 2H), 3.80 (s, 3H), 5.10 (s, 2H), 5.51 (s, 2H), 6.43 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.38 (m, 1H), 7.44 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 8.38 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[OH:11].[C:12]1(C)[C:13]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:25]N(C=O)C>>[F:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:18]([C:13]3[CH:12]=[CH:17][C:16]([CH3:25])=[CH:15][CH:14]=3)(=[O:19])=[O:20])[CH:9]=[CH:10][C:4]=2[C:3]=1[OH:11]
Reactant: Oc1c(F)cnc2[nH]ccc12
Reactant: CN(C)C=O
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(O)c(F)cnc32)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-ol (1.2 g, 7.9 mmol) in 80 mL DMF at 0° C. was added toluenesulfonyl chloride (1.8 g, 9.5 mmol) followed by NaH (0.8 g, 19.7 mmol, 60% w/w). The reaction was slowly warmed to 45° C. after 3 hours and stirred for an additional 3 hours. The mixture was then concentrated in vacuo. The crude oil was dissolved in 100 mL EtOAc and washed with water (2×50 mL) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 1.5 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:7](=[C:9]([C:15]([OH:17])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:8]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]([C:4]1[O:5][C:6]2[C:7](=[C:9]([C:15]([Cl:21])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)c2cc(C(C)=O)oc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c2cc(C(C)=O)oc12

Procedure:
2-Acetyl-7-methoxybenzofuran-4-carboxylic acid (0.12 g) was suspended in anhydrous dichloromethane (4 ml) at room temperature under nitrogen and oxalyl chloride (0.1 ml) added followed by 3 drops of N,N-dimethylformamide. Evaporation in vacuo after 2 h afforded the title compound as a yellow solid (~0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1.O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][CH:40]([SH:42])[CH3:41]>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([S:42][CH:40]([CH3:41])[CH3:39])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)S
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)SC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 6 h
Yield: 41.2 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid was dissolved in 30 ml of dichloromethane, and the resulting solution was cooled to below 10° C. on the water bath. Then, 2.1 g of N,N'-dicyclohexylcarbodiimide (DCC) was added, followed by addition of 0.8 g of 2-propanethiol. The reaction was allowed to proceed at room temperature for about 6 hours. After completion of the reaction, the formed solid substance was filtered off, and the filtrate was subjected to evaporation-removal of the solvent under reduced pressure to obtain a crude product. The thus obtained crude product was subjected to purification by the silica gel column chromatography (elution was performed by using a mixed solvent of toluene and n-hexane). As a result, there was obtained 1.6 g of S-1-methylethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-phenylthioacetate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (80 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (83.0 mg), tetrakis(triphenylphosphine)palladium(0) (22.6 mg) and potassium carbonate (54.0 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (46.2 mg).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)N>C(O)CCC>[NH2:4][C:3]1[NH:5][C:9](=[O:17])[C:10]2[C:16](=[CH:15][CH:14]=[CH:13][CH:11]=2)[N:2]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1ccccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc2ccccc2c(=O)[nH]1
Yield: 18.6 %

Procedure:
Guanidine hydrochloride (47.77 g, 0.5 mol) was added portionwise to a stirred suspension of sodium methoxide (32.42 g, 0.60 mol) in n-butanol (450 ml) at ambient temperature over 0.5 hour. After a further 0.5 hour a solution of methyl anthranilate (15 g, 0.10 mol) in n-butanol (150 ml) was added dropwise and then slowly brought to reflux. After distilling off ca. 100 ml of solvent the reaction mixture was heated under reflux at 116° for 117 hours. The cooled suspension was filtered, excess solvent removed and the residue dissolved in water, acidified to pH 5 and extracted with diethyl ether. The aqueous suspension was reacidified to pH 5, filtered off, washed with water and dried. The solid was then triturated in methanol, filtered, washed with ether and dried to give 2-amino-4-(3H)-quinazolone (3.0 g, 19%) m.p. >300°.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C=O)C>O>[CH2:35]([O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), potassium carbonate (95 mg), benzylbromide (81 μl) and DMF (5 ml) was stirred at room temperature for 3 hrs. After diluting with water, the mixture was extracted with ether. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate and n-hexane was added to the residue. The mixture was crystallized to give the title compound (152 mg, 84%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:20])[C:12]3[N:13]([CH2:16][CH2:17][CH2:18][N:19]=3)[C:14]=2[CH:15]=1>>[Cl:6][C:7]1[C:8]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][C:10]2[C:11](=[O:20])[C:12]3[N:13]([CH2:16][CH2:17][CH2:18][N:19]=3)[C:14]=2[CH:15]=1
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Reactant: O=S(=O)(O)Cl
Product: O=C1C2=NCCCN2c2cc(Cl)c(S(=O)(=O)Cl)cc21
Temperature: 71.5 °C
Yield: 6 %

Procedure:
Chlorosulfonic acid (6 mL, 90.3 mmol, 12.2 eq) was added slowly to solid 7-chloro-3,4-dihydropyrimido(1,2-a)indol-10-(2H)-one (1.64 g, 7.43 mmol) with cooling in an ice bath. The ice bath was removed and the reaction mixture was heated to 65-78° C. for 2 hours. After cooling to room temperature the reaction was added drop-wise via pipette onto ice keeping the temperature cold with an external ice bath. The reaction mixture was extracted with CHCl3 (3×) and CH2Cl2 (2×). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified on Biotage KP silica gel eluting with EtOAc to give the title compound as a bright yellow solid (0.142 g, 6% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [I-:1].[C@@H:2]1([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7]O)[C@@H:4]([OH:5])[CH2:3]1.N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Si:28]([O:5][C@@H:4]1[C@@H:6]([CH2:7][I:1])[O:9][C@@H:2]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:3]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [I-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred solution of the thymidine iodide (8.0 g, 24.7 mmol) prepared according to the method of Example 24 in dry DMF, was added imidazole (4.2 g, 61.7 mmol). After 5 minutes tert-butyldimethyl silyl chloride (4.47 g, 29.64 mmol) was added and the mixture stirred for 4 hours. The reaction mixture was then diluted with ethyl acetate (250 ml), washed with water (2×100 ml) and brine (50 ml) and then dried with sodium sulfate. The title compound was purified by flash chromatography using 60% ethyl acetate in hexane in 92% yield.
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]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([N:33]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]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=416.9 (M+H)+
Reaction SMILES: CO[C:3](OC)=[N:4][NH:5][C:6]([O:8][CH3:9])=[O:7].[CH3:12][NH2:13].[CH3:14][OH:15]>>[CH3:14][O:15][CH2:12][NH:13][CH:3]=[N:4][NH:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)NN=C(OC)OC
Reactant: CN
Reactant: CO
Product: COCNC=NNC(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.77 g (25.0 mmol) of methyl N′-dimethoxymethylenehydrazinecarboxylate (85% pure) were admixed with 15.3 g of a 51% strength solution of methylamine (250 mmol) in methanol, and the mixture was stirred at room temperature for 3 days. The orange-red solution was concentrated under reduced pressure to remove excess methylamine. This gave crude methyl N′-(methoxymethylaminomethylene)hydrazinecarboxylate which was then taken up in methanol (15 ml) and, with 4.95 g (27.5 mmol) of sodium methoxide solution (30% in methanol), heated to 50° C. After 3 h 50 min, the reaction mixture was cooled to room temperature, neutralized using 2N HCl and concentrated under reduced pressure. The residue was taken up in water (6 ml) and stored overnight in a fridge. The colourless crystals were filtered off, washed with cold water and dried under reduced pressure. This gave 1.70 g (52.7%) of 5-methoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a colourless solid. Melting point 146-148° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[N:6][CH3:5])#[N:1]
Reactant: CNC(=S)NCCSCc1c[nH]cn1
Reactant: N#CN
Agent: [Pb]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN=C(NC#N)NCCSCc1c[nH]cn1
Yield: 31.1 %

Procedure:
Lead cyanamide (24.7 g.) was added to a solution of N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) in acetonitrile (250 ml.) containing dimethylformamide. The stirred suspension was heated under reflux for 48 hours. Filtration followed by concentration under reduced pressure and purification of the product on a column of silica gel with ethyl acetate-isopropyl alcohol (2.1) as eluant gave N-cyano-N'-[2-(4imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g.), m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S, 13.5. C9H14N6S requires: C, 45.4; H, 5.9; N, 35.3; S. 13.5).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]([O-])=[O:11].[Na+].[Cl-].[K+]>C(O)(=O)C.O>[OH:11]/[N:10]=[C:2](/[C:3](=[O:4])[CH3:5])\[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\O)C(C)=O
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred and ice-cooled solution of ethyl acetoacetate (292 g) in glacial acetic acid (296 ml) was added a solution of sodium nitrite (180 g) in water (400 ml) at such a rate that the reaction temperature was maintained below 10° C. Stirring and cooling were continued for about 30 min, when a solution of potassium chloride (160 g) in water (800 ml) was added. The resulting mixture was stirred for one hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried, and evaporated. The residual oil, which solidified on standing, was washed with petrol and dried in vacuo over potassium hydroxide, giving ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (309 g).
Reaction SMILES: BrC1C=C2C(=CC=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH2:41](C([Sn])=C(CCCC)CCCC)CCC.[C:56]1([CH3:62])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=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>[CH2:62]([C:56]1[CH:61]=[C:60]2[C:59](=[CH:58][CH:57]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2)[CH3:41]
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccccc1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
A solution of 1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g), tetrakis(triphenylphosphine)palladium (116 mg) and tributylvinyltin (1.40 ml) in toluene (30 ml) was refluxed under argon atmosphere for 80 min. The solvent was distilled off and the residue was purified by column chromatography (eluent, hexane:THF=2:1),then crystallized from isopropyl ether-hexane (1:1) to give the titled compound (1.47 g) as a colorless powder.