Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Br)[C:15]([F:22])=[CH:14][N:13]=1>C1COCC1>[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)[C:15]([F:22])=[CH:14][N:13]=1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1c(Br)ncc(F)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2c(F)cnc(Br)c2[N+](=O)[O-])CC1
Reaction time: 0.25 h

Procedure:
NaH (86.67 mg, 2.167 mmol) was added portionwise to a solution of 1-methylpiperidin-4-ol (192.0 mg, 1.667 mmol) in THF (5.000 mL) at 0° C. and the resulting solution stirred for 15 min and then 2,4-dibromo-5-fluoro-3-nitro-pyridine (500 mg, 1.667 mmol) in THF (5.000 mL) was added and the reaction mixture stirred at RT overnight. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). Combined organic extracts was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatograph on silica eluting with ethyl acetate/petroleum ether (24 g column, 0-100% EtOAc) using the ISCO column companion system. Product fractions were combined and concentrated in vacuo to leave the product as a yellow oil that solidified on standing. (125 mg). MS (ES+) 334.0 336.0.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)C=CC=CC=1>C(#N)C>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:32]([N:14]2[CH2:15][CH2:16][CH:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:17])[O:3][C:4]=4[CH:10]=3)[CH2:13]2)=[O:31])[CH:35]=1
Reactant: FC1(F)Oc2ccc(CC3CCNC3)cc2O1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 38.8 %

Procedure:
To a solution consisting of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-pyrrolidine (111 mg, 0.399 mmol), triethylamine (0.1 mL, 0.72 mmol) and acetonitrile (2 mL) was added pyridin-3-yl-carbamic acid phenyl ester (90.1 mg, 0.421 mmol). The mixture was heated at 35° C. for 18 h, cooled to rt and then concentrated. The crude residue was purified (FCC) to give the title compound (56 mg, 39%). MS (ESI): mass calcd. For C18H17F2N3O3, 361.12. m/z found, 362.2 [M+H]+. 1H NMR (CD3OD): 8.63-8.59 (m, 1H), 8.16-8.13 (m, 1H), 7.97-7.92 (m, 1H), 7.35-7.30 (m, 1H), 7.16-7.09 (m, 2H), 7.06-7.02 (m, 1H), 3.66-3.53 (m, 2H), 3.48-3.38 (m, 1H), 3.19-3.11 (m, 1H), 2.85-2.72 (m, 2H), 2.62-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.78-1.66 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=[N:31][C:23]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:32]([C:29]3[CH:30]=[N:31][C:23]4[N:22]([CH3:21])[CH2:27][CH2:26][O:25][C:24]=4[CH:28]=3)=[O:33])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Product: CN1CCOc2cc(C(=O)Nc3cnc(OCC(F)(F)F)c(-c4ccc(Cl)cc4)c3)cnc21

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 479.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH2:5]2.[CH3:13]O>[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH:5]2[CH3:13]
Reactant: CO
Reactant: O=C1Cc2cc(F)c(F)cc2N1
Agent: [Ni]
Product: CC1C(=O)Nc2cc(F)c(F)cc21

Procedure:
1.5 g (9.0 mmol) 5,6-difluoro-1,3-dihydro-indol-2-one were stirred with 1.0 g Raney nickel in 50 mL methanol 3 h at 200° C. in an autoclave. The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)s1
Yield: 81.2 %

Procedure:
A mixture of the title compound of Example 2 (200 mg, 1.37 mmol), thionyl chloride (500 μl, 6.85 mmol) and DMF (20 μl) in dry methylene chloride was refluxed for 2 hours. The solvents were evaporated and the residue dried in vacuo to give 183 mg (81%) of the title product as a brown solid, mp 123-5 C. 1H-NMR (CDCl3): δ 7.74 (m, 1H), 6.64 (m, 1H),). GC-MS (m/e, %) 166/164 (M+, 11), 129(100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[Si:26]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CCCO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (1 g, 14.1 mmol), dimethylaminopyridine (0.34 g, 2.8 mmol), and triethylamine (2.9 ml, 21 mmol) in tetrahydrofuran (38 ml) was added tert-butyl(chloro)diphenylsilane (4.3 ml, 16.9 mmol). The mixture was stirred at room temperature overnight. The resulting white slurry was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-17% ethyl acetate in hexane) to afford the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.65 (dd, 4H), 7.43 (dt, 2H), 7.40 (d, 4H), 3.82 (t, 2H), 2.52 (t, 2H), 1.10 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])O)[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH2:19]1[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>>[CH2:19]1[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([BH:15][OH:17])[CH:10]=4)[C:5]([F:18])=[CH:4][N:3]=3)=[CH:22][C:21]=2[O:20]1
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1ccc2c(c1)OCCO2
Product: OBc1cccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.46 (bs, 1H), 9.11 (bs, 1H), 8.05 (d, 1H, J=4.2 Hz), 7.95 (bs, 1H), 7.88 (s, 1H), 7.78 (d, 1H, J=7.5 Hz), 7.52 (d, 1H, J=7.5 Hz), 7.29 (t, 1H, J=7.5 Hz), 7.16 (s, 1H), 7.02 (d, 1H, J=8.7 Hz), 6.65 (d, 1H, J=8.7 Hz), 3.40 (s, 4H); LCMS: purity: 98%; MS (m/e): 383 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]=3[O:20][C:21](=[O:23])[CH3:22])[O:11][C:10]=2[CH3:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:49]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]=3[O:20][C:21](=[O:23])[CH3:22])[O:11][C:10]=2[CH2:28][Br:49])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2c(C)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Yield: 72.1 %

Procedure:
A solution of 4',5,7-triacetoxy-2-methylisoflavone (5 g), benzoyl peroxide (0.3 g) and N-bromosuccinimide (3.9 g) in 300 ml carbon tetrachloride was heated under reflux for 12 hours, the solvent was distilled off under reduced pressure, water was added to the solid residue, the mixture was stirred well, and the crude product collected by filtration was recrystallized from a methanol/chloroform mixed solvent, affording 4.3 g of 4',5,7-triacetoxy-2-bromomethylisoflavone.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([NH:19][CH3:20])=[C:10]2[S:15](O)(=[O:17])=[O:16])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:22].O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([NH:19][CH3:20])=[C:10]2[S:15]([Cl:22])(=[O:17])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCc1cccc2c(S(=O)(=O)O)c(NC)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1cccc2c(S(=O)(=O)Cl)c(NC)ccc12
Temperature: 60 °C
Yield: 82.4 %

Procedure:
2 (23.9 g, 0.081 mol) was cooled with ice under nitrogen and mixed with phosphorus pentachloride (18.7 g, 0.0896 mol). The mixture was heated on a water bath at 60° C. for 2 hours and poured into a mixture of ice (164 g) and water (341 g). Ethyl acetate (400 mL) and sodium hydrogen carbonate (50 g, 0.60 mol) were added. The phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed, dried (sodium sulphate), and treated with activated carbon (1.1 g). Evaporation of the solvent gave 20.8 g of 3 as an oil. The product can be purified by chromatography.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Yield: 67.3 %

Procedure:
A mixture of 29 g. (0.0915 mole) of methyl 5-cyano-5-(3,4-dimethoxyphenyl)-2-oxocyclohexanecarboxylate (prepared in Example 10) in 600 ml. of acetic acid and 300 ml. of 10% sulfuric acid is stirred mechanically on a steam bath for about 24 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is successively washed with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from a mixture of ethyl acetate and cyclohexanone to give 15.96 g. (67.3% yield) of 4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone, having a melting point of 112.5° to 114.5°C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])(=O)=O.[C:33]1([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][C:23]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:30])[C:19]2[CH:18]=[C:17]([CH2:16][O:15][C:8]3[C:9]([CH:10]=[O:11])=[CH:12][CH:13]=[CH:14][C:7]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(COc3c(C=O)cccc3OS(=O)(=O)C(F)(F)F)ccc21
Product: CC1(C)CCC(C)(C)c2cc(COc3c(C=O)cccc3-c3ccccc3)ccc21
Yield: 53.6 %

Procedure:
3-Trifluoromethylsulphonyloxy-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (46) (0.844 g., 1.79 mmol) is coupled with phenyltributylstannane (0.760 g., 2.06 mmol) via the method of Example 3 to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-[1,1'-biphenyl]-3-carboxaldehyde (47) (0.380 g., 0.96 mmol, 54%): chromatographed on silica gel using CH2Cl2 /hexane to afford an oil; 1H NMR (300 MHz, CDCl3) 10.32 (s, 1H, CHO), 7.81 (dd, J=2, 8 Hz, 1H, ArH), 7.61 (m, 3H, ArH), 7.44 (m, 3H, ArH), 7.28 (dd, J=8, 8 Hz, 1H, ArH), 7.20 (d, J=8 Hz, 1H, ArH), 6.88 (d, J=2 Hz, 1H, ArH), 6.84 (dd, J=2, 8 Hz, 1H, ArH), 4.46 (s, 2H, ArCH2O), 1.67 (s, 4H, CH2CH2), 1.22 (s, 6H, 2×CH3), 1.17 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 190.30 (C=0), 159.90, 145.01, 137.32, 137.23, 136.56, 132.38, 130.29, 129.23, 128.62, 127.86, 127.31, 127.18, 126.83, 126.18, 124.62, 34.96, 34.93, 34.15, 31.78, 31.75; IR (film) 2958, 2926, 1688, 1584, 1458, 1364, 1244, 1210, 764, 700 cm-1 ; MS (DCI) m/e 398 (MH+), 201 (C15H21+).
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16]([OH:18])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.ClC(OCC)=O.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1>[OH:35][CH2:34][CH2:36][NH:37][C:16](=[O:18])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1
Reactant: CCCCCCCCCCCCC(C)C1(C(=O)O)CO1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(C)C1(C(=O)NCCO)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 g of 2-tetradecylglycidic acid (0.0007 mole) in 10 ml of anhydrous THF at 0° C. (ice-water bath) with stirring is added 0.070 g of triethylamine (0.0007 mole) in a small amount of THF. The solution is stirred at 0° for 30 minutes and 76 mg. of ethyl chloroformate (0.0007 mole) in a small amount of THF is added. The mixture is stirred at about 0° C. (ice-water bath) for 3 hours (ppt. of Et3NHCl observed). At the end of 3 hours 0.042 g. (0.0007 mole) of ethanolamine in THF is added. The mixture is stirred at room temperature for 16 hours. The THF solvent is concentrated to about 1/3 its volume, water is added and the mixture extracted with ether. The ether extract is dried over Na2SO4 and the ether solvent removed to give a white solid of N-(2-hydroxyethyl)-2-tetradecylglycidamide which, upon recrystallization from acetone has a m.p. of 80°-82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)N
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Yield: 88.8 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (267 mg, 1.0 mmol) was treated with isopropylamine (1.5 mmol) following general procedure B to afford 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (256 mg). 3-Ethyl-1-isopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (14 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 314 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[CH2:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(CC1COCCN1)C(=O)OCC
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2CC(C(=O)OCC)C(=O)OCC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 30.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with diethyl 2-(morpholin-3-ylmethyl)malonate (0.4 g, 1.53 mmol) according to the procedure as described in Example 24 to give the title compound as a pale yellow solid (0.32 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1=NC(=O)C2=C(CN3CCCCC3)C=NC2=N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.6 %

Procedure:
In 4.5 ml of methanol were dissolved 151 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 138 mg of 1,5-dibromopentane, followed by addition of 2.4 ml of 1 N-sodium hydroxide. The mixture was stirred at room temperature for 4 days. The solvent was then distilled off under pressure and the residue was purified by silica gel column chromatography. The fractions containing the desired compound were pooled and after addition of an excess of hydrogen chloride/ethanol, concentrated to dryness, followed by precipitation with ether to give 45 mg of the desired compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.28 (t, J=1.9 Hz, 1H), 8.17 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.03-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 3.88 (s, 2H), 3.81-3.83 (m, 4H), 3.09-3.11 (m, 4H); MS (ESI−) M/Z 408 (M−H)−.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@@:11]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C@H:13]([CH3:14])[O:12]1.C([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH2:26]1)(=O)C>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@:11]([OH:12])([C@H:13]([S:24][C@@H:25]1[CH2:26][O:27][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][CH2:30]1)[CH3:14])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: CC(=O)S[C@H]1CO[C@H](c2ccccc2)OC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 87 °C
Reaction time: 13 h

Procedure:
0.12 ml (0.59 mmol) of a 4.9 M methanolic solution of sodium methoxide were added to a solution of 0.93 g (4.0 mmol) of (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 43, 441-449 (1995)] and 1.14 g (4.8 mmol) of trans-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 15 ml of ethanol. The resulting mixture was stirred at 87° C. for 13 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The organic solution was washed with saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The resulting oily residue was purified by chromatography on a silica gel (75 g) column using a 3:2 mixture of ethyl acetate and hexane as the eluant to afford 0.68 g (yield 40%) of the title compound as a non-crystalline solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3C)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.CN(C)C=O.[O:44]1[C:48]([C:49](O)=[O:50])=[CH:47][N:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][N:20]([C:49]([C:48]4[O:44][CH:45]=[N:46][CH:47]=4)=[O:50])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1cnco1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnco2)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (71 mg, 0.18 mmol) and N,N-diisopropylethylamine (6.0E1 uL, 0.34 mmol) were dissolved in N,N-Dimethylformamide (1.0 mL, 13 mmol). Oxazole-5-carboxylic acid (30.0 mg, 0.265 mmol) 1-hydroxybenzotriazole (27.8 mg, 0.206 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (49.9 mg, 0.260 mmol) were weighed out into a vial, and the solution of the amines was added, then the reaction stirred overnight. The resultant precipitate was removed by filtration and washed with H2O. The resulting solid was purified by reverse phase HPLC: 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 4.98-4.54 (m, 2H), 4.19-4.07 (m, 1H), 4.00-3.54 (m, 7H), 3.48-3.37 (m, 1H), 3.15-3.08 (m, 2H), 2.92-2.65 (m, 2H), 1.26 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H) LC-MS: m/z=+492.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[Cl:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH2:15][SH:16].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:15]([S:16][CH:15](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=1[Cl:12])[C:14]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=1[Cl:12]
Reactant: C#Cc1ccc(O)c(OC)c1
Reactant: Fc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(F)cc2Cl)c2ccc(F)cc2Cl)ccc1O

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 2-chloro-4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-2-chloro-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.