Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(CC=O)=CC=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][OH:17].C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[OH:11][C:12]1[CH:13]=[C:14]([CH2:15][CH:16]=[O:17])[CH:18]=[CH:19][CH:20]=1
Reactant: OCCc1cccc(O)c1
Agent: O=CCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=CCc1cccc(O)c1
Yield: 22 %

Procedure:
3-hydroxyphenylacetaldehyde was prepared by a synthesis analogous to that of 4-hydroxyphenylacetaldehyde (Heterocycles, 2000, 53, 777-784). 3-Hydroxyphenethyl alcohol (1.0 g, 7.5 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). TEA (2.0 mL, 14 mmol, Aldrich) was added slowly with stirring. Pyridine-sulfur trioxide (SO3.py) complex (2.4 g, 15 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (8 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was quenched with ice-cold water, then extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (3:1, then 1:1) yielded 225 mg (22%) of 3-hydroxyphenylacetaldehyde.
Reaction SMILES: [C@@H]1([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)O[C@H](CO)[C@@H](O)[C@H]1O.P(Cl)(Cl)(Cl)=O>COP(OC)(OC)=O>[N:14]1[C:15]2[N:16]([NH2:21])[CH2:17][N:18]=[CH:19][C:20]=2[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: NN1CN=Cc2c(N[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)ncnc21
Solvent: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnc2c1C=NCN2N

Procedure:
The method of this invention comprises the steps of a) reacting 6-cyanopurine with bis(trimethylsilyl)trifluoroacetamide in acetonitrile under reflux and thereafter with tetra-O-acetyl-β-D-ribofuranose in the presence of trimethylsilyltrifluoromethanesulfonate to stereospecifically produce 9-(tri-O-acetyl-β-D-ribofuranosyl)-6-cyanopurine in high yield; b) reacting said 9-(tri-O-acetyl-β-D-ribofuranosyl)-6-cyanopurine with methanolic ammonia in a sealed pressure vessel at ambient temperature to produce N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine; c) reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with phosphoryl chloride in trimethylphosphate at a temperature below about 10° C. to produce N4 -5-O-phosphono-β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine or, alternatively reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with acetic anhydride in the presence of an acid scavenger to produce N4 -(2,3,5-tri-O-acetyl-β-D-ribofuranoxyl)pyrimido[4,5-d]pyrimidine-4,8-diamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[C:16]([O:20][C:21](=[O:30])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][C:21](=[O:30])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:24][CH2:25]1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (480 mg, 2.0 mmol) was reacted with tert-butyl(trans-4-aminocyclohexyl)carbamate (430 mg, 2.0 mmol) to afford the desired product (600 mg, 71%) as a light orange solid: 1H NMR (500 MHz, CDCl3) δ 10.91 (br s, 1H), 8.96 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 5.10-4.99 (m, 1H), 4.48 (br s, 1H), 3.55 (br s, 1H), 2.69 (s, 3H), 2.34-2.25 (m, 2H), 2.19-2.10 (m, 2H), 1.56-1.45 (m, 2H), 1.47 (s, 9H), 1.44-1.33 (m, 2H);
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26](=[O:43])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]5[N:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=5)=[O:35])[CH:28]=4)=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:44])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([C:27]4[CH:28]=[C:29]([NH:33][C:34]([C:36]5[N:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=5)=[O:35])[CH:30]=[CH:31][CH:32]=4)=[O:43])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:44])=[CH:13][CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)n(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN)cc3)c2)n(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A dry 100 mL round bottom flask equipped with an Ar(g) inlet was charged with {4-[(6-{3-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-benzoyl}-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzyl}-carbamic acid tert-butyl ester (as prepared in Example 203, 0.113 g, 0.186 mmol) and CH2Cl2 (0.622 mL). The resulting solution was cooled to 0° C. in an ice bath. TFA (0.015 mL) was then added and the reaction mixture was allowed to stir at 0° C. for 30 minutes after which the bath was removed and the reaction was allowed to stir at room temperature for an additional 1 h. Subsequently the reaction mixture was neutralized with saturated NaHCO3(aq) and then washed with EtOAc (3×20 mL). The combined organic layer was then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was chromatographed over silica (5% MeOH/95% CHCl3) to afford pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[(4-aminomethyl-phenylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide in 61% yield (0.057 g, 0.113 mmol).
Reaction SMILES: [CH2:1]([CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1O.O=P(Cl)(Cl)Cl>>[CH2:1]([CH:8]([C:9]([O:11][C:17]1[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=1[Cl:23])=[O:10])[C:12]([O:14][C:21]1[C:16]([Cl:15])=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=1[Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1c(Cl)cc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzylmalonic acid (10.0 g, 51.5 mmol), 2,4,6-trichlorophenol (20.3 g, 103 mmol), and POCl3 (12.0 mL, 129 mmol) was stirred under air at 105° C. for 2 hours. The reaction was then cooled to room temperature, poured on 150 mL ice, and extracted with 4:1 ether/DCM (3×150 mL). The combined organic layers were washed with water (1×400 mL) and 4 M aqueous NaCl (1×100 mL), and the yellow organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation at <40° C. to provide the title compound as a tan thick oil that became a beige solid upon standing.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])C)=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16].C[O-].[Na+].BrN1C(=O)CCC1=O.[OH2:30].[CH3:31]O>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:31])=[O:30])=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: COCOc1ccc(C(C)=O)cc1OC(F)(F)F
Reactant: O
Reactant: CO
Agent: C[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Product: COCOc1ccc(C(=O)OC)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-methoxymethoxy-3-trifluoromethoxyphenyl)ethanone (540 mg) was dissolved in methanol (30 mL), and sodium methoxide (1.10 g) and N-bromosuccinimide (1.09 g) were added to the solution, and then the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (590 mg) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:9]=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([NH:14][C:12]1[N:13]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[N:9]=[C:10]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:11]=1)=[O:5]
Reactant: COCC(=O)Cl
Reactant: Nc1nc(N)nc(NC2CC2)n1
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc(NC(=O)COC)nc(NC2CC2)n1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
7.2 g of methoxyacetyl chloride are slowly added dropwise to a suspension of 5.0 g of 2,4-diamino-6-cyclopropylamino-1,3,5-triazine in 50 ml of pyridine. The reaction mixture is subsequently stirred for 1 hour at 55° C. and then for 16 hours at room temperature. After filtration of the reaction mixture, washing of the filter residue with water and finally drying, the product is obtained as white crystalline powder having a melting point of 175°-180° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.O[Li].O>CO.O>[O:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Oc1ccc(CN2CCOCC2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Oc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(morpholinomethyl)phenyl acetate (1.9 g, 8.1 mmol) in 1:1 methanol/water (40 mL) at 0° C. was added LiOH.H2O (339 mg, 8.1 mmol). The reaction was stirred at RT for 2 h. The mixture was concentrated to remove methanol, and the aqueous layer acidified with 3 N HCl. The aqueous layer was extracted with ethyl acetate (4×30 mL) and the organics dried and concentrated to give 454 mg recovered starting material. The aqueous layer was then made basic again (to pH 9) with 1 N NaOH and extracted with ethyl acetate (7×20 mL). These combined organics were washed with brine, dried with Na2SO4, and concentrated to give a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)([O-:19])=[O:18]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:27][C:22]4[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=[CH:24][C:23]=4[N:26]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc([N+](=O)[O-])cc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-5-nitrobenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4-nitro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:9](Cl)(=O)C=C.[C:14]([O:18]CC)(=[O:17])[CH:15]=[CH2:16].C(Cl)(=O)C(C)=C>>[C:14]([O:18][C:2]1([CH3:4])[CH2:3][C:7]([CH3:9])([CH3:8])[O:6][C:1]1=[O:5])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)OCC
Reactant: C=C(C)C(=O)OCC
Reactant: C=CC(=O)Cl
Agent: C=C(C)C(=O)Cl
Product: C=CC(=O)OC1(C)CC(C)(C)OC1=O

Procedure:
The title compound was prepared in the same manner as in Production Example 10, except that ethyl methacrylate and acrylic chloride were used instead of ethyl acrylate and methacrylic chloride, respectively.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.O>C(Cl)Cl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: c1ccc2cc(Cn3ccnc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of imidazole (15.4 g, 0.226 mol) and 2-bromomethylnaphthalene (22 g, 0.0995 mol) in 200 ml of methylene chloride was stirred at room temperature overnight. The mixture was stirred with 200 ml of water, the organic layer was washed with water (2×200 ml), and stirred with 30 ml of conc. HCl and 200 ml of water. After filtration for the removal of the solid, the methylene chloride layer was discarded, and the aqueous layer was extracted with 200 ml of ether. The above aqueous layer was basified with 3N NaOH solution, extracted with methylene chloride, and the organic layer was dried over magnesium sulfate. The above organic solution was concentrated in vacuo to afford 13.65 g of 1-(2-naphthylmethyl)imidazole, m.p. 87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(OCC)(O[CH2:21][CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(Cl)c1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Into a 500 ml four-neck flask were charged 26.5 g (0.11 mol) of (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoic acid obtained in Step 1, 260 ml of dimethylformamide (DMF), 24.7 g (0.16 mol) of diethyl sulfate, and 30.4 g (0.22 mol) of potassium carbonate under a nitrogen atmosphere, followed by 2 hours of reaction at 35 to 45° C. After completion of the reaction was confirmed by HPLC analysis, a mixed solution of 3.6 g (0.06 mol) of acetic acid/3.6 g of DMF was added dropwise and the whole was stirred at 30 to 35° C. for 1 hour to decompose excess diethyl sulfate. Thereafter, extraction with a mixed solution of 400 ml of ethyl acetate/400 ml of water/23.4 g of hydrochloric acid was conducted and the organic layer was washed twice with 400 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 9 ml of ethanol, and 19 ml of water to obtain 25.4 g (yield 86.0%) of the aimed compound as light yellow crystals. The total yield from 1-chloro-2-methoxybenzene was 52.0% and the purity was found to be 99.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=O)[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:24][OH:25])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn3ccccc3c2C(=O)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
To a solution of 4.4 (14.9 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 4.15 g of hydroxylamine hydrochloride, followed by a solution of 13.73 g (14.9 mmol) of NaOH in 10 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent under vacuum, 5 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 2.33 g (50.5%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1022.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][N:9]([C:15]1[O:16][CH:17]=[C:18]([CH3:20])[N:19]=1)[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])([O:3]CC)=[O:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:6][CH2:7][CH2:8][N:9]([C:15]1[O:16][CH:17]=[C:18]([CH3:20])[N:19]=1)[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCN(C(=O)C(C)C)c1nc(C)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1coc(N(CCCC(=O)O)C(=O)C(C)C)n1
Yield: 57.3 %

Procedure:
A solution of 2[ N-(3-carbethoxypropyl)-isobutyramido]-4-methyloxazole (9.9 g., 0.035 mol.) prepared in a manner similar to that described in Example 44 was dissolved in ethanol (100 ml.) and N NaOH solution (35 ml.) and the solution was stirred for 20 hours at ambient temperature. The solution was evaporated and the residue was dissolved in water, washed with ether, acidified and extracted with ether. The extract was dried and evaporated and the residue was recrystallised from benzene-petrol to give the product 5.1 g., m.p. 81°-82° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1I)[C:6]#[N:7])#[N:2].C[S-:13].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:13])[C:6]#[N:7])#[N:2]
Reactant: C[S-]
Reactant: N#Cc1ccc(I)c(C#N)c1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(S)c(C#N)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
Under argon, 3.03 g (12.10-3 mol) of 3-cyano-4-iodobenzonitrile and 3.36 g (48.10-3 mol) of sodium thiomethylate are dissolved in 80 ml of anhydrous hexamethylphosphoramide and the solution obtained is then heated at 80° C. for 45 minutes. The resulting reaction medium is hydrolyzed in an ice/1N HCl mixture and then extracted with methylene chloride. The organic phase is washed with water and then dried over magnesium sulfate and evaporated under reduced pressure to give 1.55 g (yield: 81%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:14](=[O:15])[C:6]3=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)c3cc(Cl)ccc3n2CCN1CCN1CCCC1
Temperature: 35 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of 8-chloro-10-phenyl-1,2,3,4-tetrahydropyrazino-[1,2-a]indole-1-one (6.0 g, 0.0202 mole) in dimethyl formamide (40 ml) is added over a period of 1/2 hour to a suspension of sodium hydride (1.4 g, 0.029 mole of a 50% dispersion in mineral oil) in dimethylformamide (20 ml). The mixture is stirred at about 35° C. for 1 hour. A solution of freshly distilled N-(β-chloroethyl)pyrrolidine (3.88 g, 0.029 mole) in dimethylformamide (10 ml) is added over a period of 1/4 hour. The reaction mixture is stirred at 50° C. for 18 hours, then cooled and poured into water (300 ml), this mixture is extracted with dichloromethane (4 portions, 100 ml each). The extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the filtrate is concentrated. The residue is recrystallized from heptane to give the above titled product, 6.15 g (77.3 % yield), melting at 134°-135.5° C.
Reaction SMILES: [C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].C1(C)C=CC=CC=1.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](OC)=O)[CH2:20][CH2:19]1.Cl.[C:29]1([CH3:37])[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1.Cl>C1COCC1>[O:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:2]=[C:1]([NH2:3])[N:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:37])=[CH:30][CH:31]=3)[N:36]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(NN)cc1
Reactant: COC(=O)C1CCOCC1
Reactant: CC#N
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3CCOCC3)cc2N)cc1
Temperature: 25 °C

Procedure:
To a mixture of acetonitrile (500 μL, 390 mg, 9.60 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 17.0 mL, 29.0 mmol) followed by the dropwise addition of methyl tetrahydro-2H-pyran-4-carboxylate (5.1 mL, 5.5 g, 38 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜20 mL, was diluted with EtOH (20 mL) and treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and was acidified to pH 1 by the addition of conc hydrochloric acid. The resulting heterogeneous mixture was heated to 70° C. for 2 hr, then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The residue was diluted with water (30 mL), adjusted to pH 12 by the addition of 2M aq NaOH and the mixture extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with isohexane to afford the title compound, Intermediate A31, as a pale brown solid (1.94 g, 78%); Rt 1.28 min (Method 2); m/z 258 (M+H)+, (ES+).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:13][C:14]([NH:16]C(=O)C1C=CC=CC=1)=[O:15])#[N:2].[OH-].[Na+].CC(O)=O>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:9]=[C:10]([CH3:12])[CH3:11])[NH:13][C:14](=[O:15])[N:16]=1
Reactant: CC(C)=Cc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)=Cc1cccc2[nH]c(=O)nc(N)c12
Temperature: 90 °C
Yield: 77.1 %

Procedure:
A suspension of N-(2-cyano-3-(2-methylprop-1-enyl)phenyl carbamoyl)benzamide (Example 150a) (0.133 g, 0.416 mmol) in EtOH (3 mL) was treated with a solution of NaOH (2 M, 0.416 mL, 0.832 mmol) at room temperature. The obtained mixture was heated at 90° C. for 30 min, cooled to room temperature and neutralized with 10% AcOH. The precipitated product was collected by filtration to give 69.0 mg (77%) of 4-amino-5-(2-methylprop-1-enyl)quinazolin-2(1H)-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.60 (d, J=1.2 Hz, 3H), 1.93 (d, J=1.2 Hz, 3H), 6.58 (s, 1H), 6.67 (broad s, 1H), 6.73 (m, 1H), 7.05 (m, 1H), 7.48 (m, 1H), 7.93 (broad s, 1H), 10.72 (broad s, 1H). MS 216 (MH+).