Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:19][O-:20].[Na+].O>CO>[Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCN(C(=O)C(C)(C)C)c1nc(OC)ccc1Br
Yield: 89.3 %

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethyl-N-2-propen-1-ylpropanamide (12.388 g, 37.370 mmol) in methanol (100 ml) at rt under argon was treated with sodium methoxide solution (25% w/v in methanol, 17.76 g, 82.212 mmol) and then heated at reflux for 42 h. The reaction was then cooled, treated with water (500 ml), and extracted with diethyl ether (3×200 ml). The organic extracts were dried (MgSO4), and evaporated to give the product (10.918 g, 89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[CH3:31][NH2:32]>CO>[OH:10][CH2:11]/[C:7](/[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[C:8](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)\[C:9]([NH:32][CH3:31])=[O:12]
Reactant: CN
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CO
Product: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 86 %

Procedure:
A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH2 in MeOH (25 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo to afford (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (920 mg, 86%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1c(Cl)cccc1CO
Reactant: BrCc1ccccc1
Product: Nc1c(Cl)cccc1COCc1ccccc1

Procedure:
This material was prepared from 2-amino-3-chlorobenzyl alcohol and benzyl bromide by the general procedure outlined in Example 82. The product was purified by Kugelrohr distillation to yield an oil, bp 118°-125° C. (0.1 mm). The product was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][N:12]([C:16](=[O:26])[CH2:17][O:18]CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][N:12]([C:16](=[O:26])[CH2:17][OH:18])[CH2:13]2)[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)COCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)CO)C[C@H]4C3)c(F)c2)C(=O)O1

Procedure:
The (S)-N-[[3-[3-fluoro-4-[cis-3-(benzyloxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (110 mg, 0.22 mmol), methanol (25 mL) and 10% palladium on carbon (100 mg) are combined and placed under 40 p.s.i. of hydrogen and shaken for 5 days. The reaction is filtered through celite, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.20, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 167-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[CH:20]=[N:1]2
Reactant: COC(OC)OC
Reactant: Nc1cccc(Cl)c1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(n2cnc3cccc(Cl)c3c2=O)C(=O)N1
Reaction time: 0.08 h
Yield: 48 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-chloro-benzamide (0.8 g, 2.8 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (280 mg) was heated to 150° C. via a microwave oven for 30 minutes. To the mixture, was added methanol (15 mL), and the mixture was stirred for 5 minutes. The suspension was filtered and washed with methanol to give 3-(5-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (400 mg, 48% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.35 min (99.2%); mp: 308-310° C.; 1H NMR (DMSO-d6) δ 2.13-2.19 (m, 1H, CHH), 2.57-2.72 (m, 2H, 2CHH), 2.83-2.89 (m, 1H, CHH), 5.43 (br, 1H, NCH), 7.60 (dd, J=1, 8 Hz, 1H, Ar), 7.66 (dd, J=1, 8 Hz, 1H, Ar), 7.79 (t, J=8 Hz, 1H, Ar), 8.39 (s, 1H, CH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.18, 30.84, 56.16, 118.35, 126.81, 129.74, 132.45, 134.54, 148.18, 149.98, 157.62, 169.68, 172.39; LCMS: MH=292, 294; Anal Calcd for C13H10N3O3Cl+0.15H2O: C, 53.04; H, 3.53; N, 14.27. Found: C, 52.68; H, 3.14; N, 14.17.
Reaction SMILES: Cl[C:2]1[C:3]([F:20])=[N:4][C:5]([F:19])=[C:6]([F:18])[C:7]=1[CH2:8][O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:19][C:5]1[C:6]([F:18])=[C:7]([CH2:8][O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[C:3]([F:20])[N:4]=1
Reactant: O=C(OCc1c(F)c(F)nc(F)c1Cl)c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(OCc1cc(F)nc(F)c1F)c1ccccc1
Yield: 85.6 %

Procedure:
Benzoic acid 3-chloro-2,5,6-trifluoro-pyridin-4-ylmethyl ester (4.52 g, 15 mmol), anhydrous ethanol (50 ml), 10% palladium on carbon (500 mg), and triethylamine (2.5 ml, 18 mmol) were placed into a 500 ml bottle. The mixture was hydrogenated under hydrogen atmosphere (50 psi) for 1.5 hr. The reaction mixture was filtered through celite pad and the pad was washed with ethanol. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:15)) to afford 3.43 g (85%) of benzoic acid 2,3,6-trifluoro-pyridin-4-ylmethyl ester as a white solid. m.p. 73-76° C.; 1H NMR (200 MHz, CDCl3) δ 5.52 (2H, s), 6.95 (1H, m), 7.30-7.70 (3H, m), 8.09-8.15 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH2:7][N:8]([C:27](=[O:28])[CH:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[CH:9]1[CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a chilled (0.5° C.) methylene chloride solution of N-cyclobutyl-glycine t-butyl ester (63.2 g, 0.34 mol) and triethylamine (26 g, 0.4 mol) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (61.4 g, 0.34 mol). After stirring overnight the reaction mixture was filtered and the filtrate was concentrated. The residue was redissolved in ethyl acetate, washed with 5% HCl (3×500 ml), brine (500 ml) and saturated aqueous sodium bicarbonate (6×600 ml), dried over MgSO4, filtered, and concentrated yielding 80.6 g (72%) of the product as a brown oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].C(=O)([O-])[O-].[K+:37].[K+]>CO.O>[K+:37].[C:23]([NH:22][C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)NC(C)(C)C)c(OC)c1

Procedure:
(4S,5R)-N-(t-Butylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (PREPARATION 2—less polar isomer, 6.27 g, 14.2 mM) is stirred at 20-25° under nitrogen in methanol (50 mL). To this mixture is added a solution of potassium carbonate (2.50 g, 18.1 mM) in water (6 mL). After 6 hr the reaction is concentrated under reduced pressure to remove the methanol and the residue freeze dried to give the title compound (admixed with potassium carbonate salts as a powder), NMR (DMSO-d6, TMS) 1.10, 3.77, 4.17, 4.70, 5.16, 6.50, 6.60 and 7.14-7.42 δ.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)(=O)/C=C\C(O)=O>C(O)C>[C:2]1([CH:8]2[C:17]3[C:12](=[C:13]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CC(=O)NC1c2c(Cl)cccc2C(c2ccccc2)CN1C
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(=O)NC1c2c(cccc2N2CCCC2)C(c2ccccc2)CN1C

Procedure:
A mixture of 7.0 g (0.02 mole) of 4-phenyl-8-chloro-acetylamino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 70 ml of ethanol and 20 ml (17.0 g, 0.24 mole) of pyrrolidine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in a mixture of 100 ml of water and 100 ml of ether and the mixture is made alkaline by adding 30 ml of a 30% aqueous sodium hydroxide solution under cooling and stirring. The layers are separated, the aqueous phase is extracted five times with 100 ml of ether each, the organic phase is dried over anhydrous sodium sulfate, clarified with activated charcoal and evaporated. The residue is dissolved in 100 ml of warm ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 40 ml of ethanol is added. The product is precipitated by adding 1000 ml of ether. The sticky solid dimaleate salt is dissolved in 100 ml of water and the solution is made alkaline by adding 60 ml of a 30% aqueous sodium hydroxide solution under cooling and stirring. The aqueous layer is extracted once with 200 ml and four times with 100 ml of ether each. The ether phases are united, dried over anhydrous sodium sulfate and clarified with activated charcoal. The ether is evaporated and the residue is washed with a mixture of ether and petrolether. Thus 5.4 g of 4-phenyl-2-methyl-8-pyrrolidino-acetylamino-1,2,3,4-tetrahydro-isoquinoline are obtained in the form of white crystals (0.0154 mole). Mp.: 130° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[O:13])[CH:27]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)ncn1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)ncn1
Yield: 12.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-amino-6-chloropyrimidine (1.51 g, 11.7 mmol) in 12 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized from acetonitrile-DMF to yield 0.38 g of the title compound, mp 254°-256° C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:53](=[O:56])([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:56][CH2:53][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:8])=[CH:7][CH:6]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of octal bromide (35.8 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. and the mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture is extracted with ethyl acetate (3×40 mL). The combined organic fraction is dried (Na2SO4) and the solvent evaporated. The residue is purified by chromatography on a column (300 g) of silica gel. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.). The third fraction (di-substituted compound, trans-isomer) is eluted with toluene:ethylacetate (15:1 by vol.). The fourth fraction (di-substituted compound, cis-isomer) is eluted with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethylacetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried under high vacuum to give the product as a violet solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].CS(O[CH2:27][CH2:28][O:29][CH3:30])(=O)=O>CN(C=O)C>[CH3:30][O:29][CH2:28][CH2:27][N:4]1[C:5]2=[N:10][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][C:7](=[O:17])[N:6]2[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]1
Reactant: COCCOS(C)(=O)=O
Reactant: CC1(C)CNc2nc(N3CCOCC3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1CC(C)(C)Cn2c1nc(N1CCOCC1)cc2=O
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
0.22 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.7 g of 60% NaH are added and stirred for 30 mins. 0.24 g of 2-methoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured into a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.1 g (yield=39%) of 9-(2-methoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6](OC)=O)#[N:4].[Br:10][C:11]1[CH:18]=C[C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.Cl>CS(C)=O.O>[Br:10][C:11]1[CH:18]=[CH:6][C:5]([C:3]#[N:4])=[C:13]([CH2:14][C:15]#[N:16])[CH:12]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0° C. in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4-Bromo-2-fluorobenzonitrile (118 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 90° C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104° C. over 3 hours. 2.3 L of water was added and the mixture was heated at reflux 16 hours. The mixture was cooled to 5° C. and 700 mL of 0.2N HCl was added. The mixture was allowed to stir at 5° C. for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78%). LCMS (API-ES) m/z: 223, 221 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:17])=[C:14]([OH:16])[CH:15]=2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:17])=[C:14]([O:16][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(O)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cnc(N)c(OS(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol) in CH2Cl2 (180 mL) was added N,N-diisopropylethylamine (3.2 mL, 0.019 mol), 4-methyl-benzenesulfonyl chloride (2.66 g, 0.014 mol), and PS-DMAP (catalytic amount). The reaction was stirred at ambient temperature for 6 hr then filtered to remove the resin. The resin was washed with CH2Cl2 (3×20 mL), and the combined fractions were washed with 10% citric acid (100 mL), saturated NaCl (100 mL), dried (Na2SO4) and filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel, 100% CH2Cl2 to 95:5 CH2Cl2:MeOH) and the fractions containing the desired product were combined and concentrated in vacuo to yield 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acid methyl ester (3.3 g, 8.2 mmol, 88%). 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H), 3.93 (s, 3H), 4.81-4.88 (brs, 2H), 7.36-7.44 (m, 5H), 7.81 (d, 2H, J, 8.3 Hz), 8.05 (d, 2H, J, 8.4 Hz), 8.19-8.27 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:30][CH:27]2[CH2:28][CH2:29][N:25]([CH3:24])[CH2:26]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CN1CCC(N)C1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of Example A3 (500 mg, 1.42 mmol), 1-methyl-pyrrolidin-3-ylamine (170 mg, 1.7 mmol) and DBU (383 mg, 2.84 mmol) in NMP (5 mL) was heated with a microwave at 160° C. for 2 h. After cooling to RT, the mixture was purified by silica gel chromatography to yield 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one (500 mg, 85% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][O:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[N+:11]([C:5]1[C:6]2[O:10][N:9]=[CH:8][C:7]=2[C:2]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c2cnoc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCCCNc1ncc([N+](=O)[O-])c2oncc12
Reaction time: 8 h

Procedure:
4-Chloro-7-nitro-[1,2,5]benzoxadiazole (100 mg, 0.501 mmol) was dissolved in methanol (5 ml). N-Boc-1,3-propanediamine (44 mg, 0.25 mmol) was then added and the reaction mixture stirred overnight. The solvent was evaporated and the residue was purified using silica gel chromatography with ethyl acetate:hexane (1:1) to afford dark brown solid. This material was then treated with a solution of 4.0 M HCl in dioxane (excess) overnight to remove the Boc group. The solution was evaporated to afford N1-(7-nitro-[1,2,5]benzoxadiazol-4-yl)propane-1,3-diamine as the hydrochloride salt, which was used without further purification. Yield: 60 mg (51%). MS (m/z): (M+H)=237.22.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].C(N(CC)CC)C.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26].[OH-].[Na+]>ClCCl>[F:10][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:26])=[CH:4][C:3]=1[CH2:2][OH:1]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccc(F)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c(CO)c1)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
3-Hydroxymethyl-4-fluoroaniline (34.2 g, 243 mmol) was dissolved in dichloromethane (600 mL) under anhydrous conditions and cooled to 0° C. Triethylamine (120 mL, 0.861 mol) was added, followed by a solution of picolinic acid chloride hydrochloride (86.0 g, 0.483 mol) in methylene chloride (300 mL). The reaction mixture was stirred at 0° C. for 0.5 hours and at room temperature for 1 hour, and poured into ice water (2 L). The resulting mixture was basified with 1N sodium hydroxide solution, extracted with methylene chloride (3×800 mL), washed with brine, and dried over magnesium sulfate to give a brown oil, which was purified by flash chromatography (6 in diameter column, elution with 25% ethyl acetate in petroleum ether) to give the title compound (10.0 g, 18%, mp 99°-122° C.) as the first compound of the column, followed by 2-pyridinecarboxylic acid [[2-fluoro-4-[[(2-pyridinyl)oxomethyl]-amino]phenyl]methyl] ester (46.5 g, 52%, mp 116°-118° C.). Additional title compound can be obtained by treating the ester (25.0 g, 71 mmol) with potassium carbonate (19.8 g, 143 mmol) in water (20 mL), methanol (200 mL), and tetrahydrofuran (200 mL). The mixture was left for 2 days and then concentrated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (500 ml) and the aqueous layer was extracted again with ethyl acetate (2×200 mL). The organic layer was washed with 2.5N sodium hydroxide solution (500 mL) and brine (500 mL), dried, and concentrated to afford more N-(4-fluoro-3-hydroxymethylphenyl)-2-pyridinecarboxamide (15 g, 90%).