Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[N:7]2.N[CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.C[N:40](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:40][CH:36]3[CH2:37][CH2:32][CH2:33][CH2:34][N:35]3[CH3:38])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[N:7]2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(Br)ccc(OC3CCNCC3)c2n1
Reactant: CN1CCC(N)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)NC2CCCCN2C)ccc1Nc1ncc2c(Br)ccc(OC3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A mixture of 4-(5-bromo-8-(piperidine-4-yloxy)quinazolin-2-ylamino)-3-methoxybenzoic acid (1 eq), 4-amino-N-methylpiperidine (2 eq), HATU (1.5 eq) and DIEA (3 eq) in NMP was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 45% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:17]=1>>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyridin-3-yl-benzaldehyde, of Preparation 23, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.55 (m, 1H), 7.81 (d, 1H), 7.53 (d, 2H), 7.46 (d, 2H), 7.32 (m, 1H), 7.22 (m, 3H), 7.09 (d, 1H), 3.84 (s, 2H), 3.80 (s, 2H), 3.63 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[CH2:4][CH2:5][CH3:6].O.[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[CH:10]=[C:11]([CH3:13])[CH3:12]>CN(C)P(=O)(N(C)C)N(C)C.C(O)C>[CH2:9]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:24])[C:21]([O:23][CH2:3][CH2:4][CH2:5][CH3:6])=[O:22])=[CH:18][CH:19]=1)[CH:10]=[C:11]([CH3:13])[CH3:12]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
Six grams of powdered potassium hydroxide was dissolved in a mixture of 21.8 g of 2-(p-prenylphenyl)propionic acid in 125 ml of hexamethylphosphoric triamide and 125 ml of ethyl alcohol with stirring at room temperature. To the solution was added 27.4 g of n-butyl bromide and the mixture was stirred at room temperature for 24 hours. The mixture was poured into 500 ml of water and extracted with n-hexane. The extract was washed with 2 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 17.3 g of n-butyl 2-(p-prenylphenyl)propionate. b.p. 131°-133° C./0.15 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[Li+].[CH3:10][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.Cl.CCOC(C)=O>[CH3:10][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCOCC1
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-carbonitrile (2 g, 18.00 mmol) in THF (10 mL) at 0-5° C. was slowly added LHMDS (21.59 mL, 21.59 mmol). The mixture was stirred for 1.5 hr 0° C. Iodomethane (3.37 mL, 54.0 mmol) was added slowly and stirring was continued for 30 min at ˜0° C. and ˜2 hr at ambient temperature. The mixture was cooled to 0° C. and carefully diluted with 1N aqueous HCl (30 mL) and EtOAc (5 mL) and concentrated. The resulting residue was taken up in diethylether and the separated organic layer was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo providing crude 4-methyltetrahydro-2H-pyran-4-carbonitrile as an orange oil, which was directly used in the next reaction without further purification. Yield: 1.8 g. LCMS (m/z): 126.1 [M+H]+; Retention time=0.44 min.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH:14]=[CH2:15])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24]=[C:25]1CC[CH2:26]1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCCl.CCOC(C)=O>[Si:1]([O:8][C@@H:9]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH:14]=[C:15]1[CH2:26][CH2:25][CH2:24]1)[CH2:10][OH:11])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C1CCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC=C1CCC1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A solution of tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-1-hydroxyhex-5-en-3-ylcarbamate (1.0 g, 2.9 mmol) and Grubbs Catalyst 2nd generation (0.12 g, 0.14 mmol) in DCE (6 mL) was treated with methylenecyclobutane (0.79 g, 12 mmol) and heated to 80° C. in a sealed vial overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, and brine. The organics were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography gave tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-5-cyclobutylidene-1-hydroxypentan-3-ylcarbamate (0.900 g, 81% yield) as a 2:1 mixture with starting alkene.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[CH2:1]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCCBr
Product: BrCCCCCCOCc1ccccc1
Yield: 36 %

Procedure:
6-Benzyloxyhexyl bromide was prepared from benzyl alcohol (4.75 g, 44 mmol) and 1,6-dibromohexane (9.76 g, 40 mmol) using the general procedure given above. Yield: 36%, bp 100-105° C./torr: 1H-NMR: 1.2-1.9 (m, 8 H), 3.37 (t, 4 H), 4.46 (s, 2 H), 7.28 (m, 5 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26](=[O:28])[CH3:27].O1C2C=CC=CC=2C=C1>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:1]([O:8][C:9]1[C:10]2[CH:11]=[C:25]([C:26](=[O:28])[CH3:27])[O:17][C:13]=2[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=Cc1c(O)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc2occc2c1
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(OCc3ccccc3)cccc2o1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
A solution of 2-(benzyloxy)-6-hydroxybenzaldehyde (Example 38B, 11.10 g, 48.63 mmole) in N,N-dimethylformamide (120 mL) was treated with powdered anhydrous cesium carbonate (15.8 g, 48.63 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with chloroacetone (4.65 mL, 58.4 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting aldehyde left by tlc and formation of the intermediate alkylated aldehyde). The reaction mixture was then maintained under vacuum (10 mbar) for 15 min to remove any un-reacted chloroacetone and then flushed with nitrogen. Then anhydrous cesium carbonate (1.0 g, 3.1 mmol) was added and the mixture was heated at 55° C. and stirred for 40 h (more cesium carbonate, 1 g, was added after 24 h and 32 h) till complete conversion of the intermediate alkylated aldehyde into the benzofuran as monitored by TLC. The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (400 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4.5×12 cm, elution toluene-ethyl acetate 2-4%) gave 11.67 g (90% yield) of the title benzofuran as a light yellow solid. Recrystallization from a mixture of ethyl acetate (40 mL) and hexane (40 mL) gave colorless prisms (10.50 g). LC (Method A): 2.162 min. HRMS (ESI) calcd for C17H15O3 [M+H]+ m/z 267.1016. found 267.1022. 1H NMR (CDCl3, 600 MHz) δ ppm: 2.56 (s, 3H), 5.20 (s, 2H), 6.73 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.3-7.5 (m, 6H), 7.63 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]1([P:23]([C:30]2C=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:36](OCC)C>ClCCl>[Br-:1].[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[P+:23]([CH3:36])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3ccccc3[P+](C)(c3ccccc3)c3ccccc3)ccc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
In a 250 mL round bottom flask was charged 6-(bromomethyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 8 (2.00 g, 7.11 mmol) in solution in 11 mL of dichloromethane. Triphenylphosphine (2.15 g, 8.18 mmol) was added via spatula at room temperature. The reaction mixture was stirred overnight at RT (16 h). Diethyl ether (200 mL) was added and the white precipitate formed was filtered and washed copiously with diethyl ether and dried in vacuo over P2O5. (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtalenyl)-methyl-triphenylphosphonium bromide 9 (3.40 g, 88% yield) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13](Cl)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1.C(Cl)Cl.[CH2:27]([O:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:37][CH2:36][CH2:35][O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)Cl)cc1Cl
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)OCCOCc2ccccc2)cc1Cl

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-chloroformyl-6-chloro-2-methylthiopyrimidine (prepared in the above (1)), methylene chloride 15 ml and 2-benzyloxyethanol 224 mg is refluxed for 30 minutes. After cooling the reaction mixture is diluted with water and neutralized with an aqueous saturated sodium hydrogen carbonate solution. The solution is washed with ethyl acetate. The methylene chloride layer is diluted with ethyl acetate, washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; hexane:ethyl acetate=5:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-chloro-2-methylthiopyrimidine as a colorless oil 655 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl-].[Cl:12][C:13]1[CH:38]=[CH:37][C:16](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1.[C:39](=O)([O-])[O-].[K+].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]([C:16]2[CH:37]=[CH:38][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH2:39])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: C=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1O
Yield: 8.4 %

Procedure:
5-Chlorosalicylaldehyde (313 mg, 2 mmol) and 4-chlorobenzyltriphenyl-phosphonium chloride (847 mg, 2 mmol) were dissolved in N,N-dimethylfomamide (20 mL). Potassium carbonate (1.382 g, 10 mmol) dissolved in water (10 mL) was added, and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (44.6 mg, 8.4%) as a light gray solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[CH2:36][C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[C:36](=[CH:15][C:12]4[NH:11][C:8]5[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=5[C:13]=4[CH3:14])[C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 102 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (prepared according to Bioorganic&Medicinal Chemistry Letters, 12 (16), 2153˜2157, 2002) as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (240 mg, 61.5%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>CS(C)=O.C(Cl)Cl>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N[C@H](C(=O)O)C(C)C)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of L-valine (36.6 mg, 0.312 mmol) and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temp for 30 min. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was stirred at 120° C. under nitrogen for 48 hr. The cooled reaction mixture was loaded onto an SCX column. The column was flushed with acetonitrile and then the desired product was eluted with 20% ammonia in acetonitrile. The solvent was removed in vacuo from the appropriate fractions to give an orange solid which was dissolved in DCM and washed with water. The organics were passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (22 mg). MS (ES) C25H2535ClN4O4 requires 480. found 481 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][Cl:27].C(N(CC)CC)C>C1COCC1>[ClH:27].[OH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]1[CH2:5][CH2:4][N:3]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:2][CH2:1]1
Reactant: COc1cccc(CCl)c1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)c1
Product: Cl
Temperature: 20 °C
Yield: 102.2 %

Procedure:
A mixture of 8.0 g (30 mmol) of α,α-diphenyl-4-piperidinomethanol, 2.35 g (15 mmol) of 3-methoxybenzyl chloride, 0.5 g of triethylamine and 30 ml of THF is stirred under reflux for 1 hour, during which a colorless precipitate separates out. After cooling to 20° C., the precipitate is filtered off, and the filtrate is concentrated. For working up, the residue is taken up in 5 ml of methylene chloride, and ethereal HCl solution is added until no further precipitation occurs. The mixture is diluted with 30 ml of methylene chloride, the precipitate is filtered, and the filtrate is concentrated. Drying of the oily residue at 40° C. in vacuo results in 6.5 g of final product. Decomposition point about 80° C. Characteristic IR bands: 3360, 1590, 1480, 1438, 1256, 690 cm.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)C1C=CC=CC=1)C>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([CH3:1])=[N:3]2)=[C:8]([Cl:15])[N:7]=1
Reactant: Cc1nc2nc(N)[nH]c(=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nc(N)nc(Cl)c2[nH]1

Procedure:
A suspension of 8-methylguanine (Daves et al., J. Am. Chem. Soc., 82, 2633-2640 (1960)) (1.0 g, 6.1 mmol) in phosphorous oxychloride (30 mL) and N,N-diethylaniline (1 mL) was refluxed for 3 h. The excess phosphorous oxychloride was evaporated under reduced pressure. The resulting brown oil was dissolved in ice-water and was neutralized with a concentrated aqueous NaOH solution. After evaporation of the solvent, the solid residue was suspended in 70 mL of H2O. Undissolved solid was filtered off, and the filtrate was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. Evaporation of pooled fractions 50-60 produced 2-amino-6-chloro-8-methylpurine as a crude solid. Crystallization from ethanol/water with charcoal treatment afforded 2-amino-6-chloro-8-methylpurine as a white solid: yield, 0.57 g (51%); mp >265° C. dec.; 1H NMR δ 2.39 (s, 3H, CH3), 6.62 (s, 2H, NH2, exchange with D2O), 12.56 (s, 1H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H6N535Cl 183.0312, found 183.0309; calcd. m/z for C6H6N537Cl 185.0283, found 185.0286.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([N:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:16]2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.O[Li].O>C1COCC1.O>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([C:15]2[C@@H:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@@H:17]3[C@H:10]([OH:9])[CH2:11][CH2:12][N:13]3[N:14]=2)[CH:30]=[CH:29][C:28]=1[C:31]#[N:32]
Reactant: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2=NN3CC[C@@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of (3S,3aS,4R)-2-(3-chloro-4-cyano-2-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-4-yl benzoate (100 mg, 0.208 mmol) in THF (2 mL) at 0° C. was added a solution of LiOH.H2O (25 mg, 0.586 mmol) in water (1 mL) and the reaction mixture was stirred at room temperature for overnight. Once the starting material had disappeared (monitored by TLC), reaction mixture was extracted with ethyl acetate. Organic layer was washed with water and brine then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without further purification.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[C:11]1[CH:18]=[CH:17][C:14](C=O)=[CH:13][CH:12]=1.C[Si](C)(C)C1C=CC(Cl)=CC=1>>[C:1]([C:11]1[CH:18]=[CH:17][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: C[Si](C)(C)c1ccc(Cl)cc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Various benzophenone derivatives were prepared in accordance with the same procedure as in Example 1 excepting that 0.2 mole of a benzaldehyde derivative was used instead of 4-dimethylaminobenzaldehyde and 0.2 mole of a halobenzene derivative was used instead of 4-trimethylsilylchlorobenzene. The particulars are set out as follows.