Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#N.F[B-](F)(F)F.[SiH](CC)(CC)CC.[OH2:26]>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])=[O:26]
Reactant: O
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Agent: CC[SiH](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C=O)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
A solution of 305 mg (1.74 mmol) of methyl 3-cyano-4-methylbenzoate and excess Et3O+BF4− in 7 mL of CH2Cl2 was stirred at 45° C. After 13 h and about 24 h more Et3O+BF4− was added and after a further 20 min. the temperature was increased to 50° C. After 37 h, the temperature was increased to 55° C. and heating was continued for 1.5 h. After this time, the crude solution was added with 3 mL of CH2Cl2 to 0.16 mL of Et3SiH in 5 mL of CH2Cl2. After the solution was stirred at 55° C. for 2 h, 10 mL of H2O was added, and the mixture was stirred at 120° C. for 15 min. and the temperature was decreased to 115° C. for 1 h, stopped for 2 h, and then resumed for 17 h. EtOAc was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (7.5% EtOAc/hexanes) provided 25 mg of methyl 3-formyl-4-methylbenzoate as colorless oil with some impurity. 5-(methoxycarbonyl)-2-methylbenzoic acid was synthesized from the aldehyde following the general procedure as described above for the methyl substituted benzoic acid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1c(F)cc(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)cc(F)c2OC)c(N)n1

Procedure:
The same procedure as described in Example 376 was used, starting with 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 2-bromo-4,6-difluoroanisole (Metrix) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(3,5-difluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 326.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH3:45])=[C:6]([CH:43]=1)[CH2:7][C@@H:8]1[CH2:14][NH:13][C:12](=[N:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][N:10]([C:23]([NH:25][C@@H:26]([C:29]2[O:30][CH:31]=[C:32]([C:34]([O:36]CC(Cl)(Cl)Cl)=[O:35])[N:33]=2)[CH2:27][CH3:28])=[O:24])[C:9]1=[O:42]>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH3:45])=[C:6]([CH:43]=1)[CH2:7][C@H:8]1[C:9](=[O:42])[N:10]([C:23]([NH:25][C@@H:26]([C:29]2[O:30][CH:31]=[C:32]([C:34]([OH:36])=[O:35])[N:33]=2)[CH2:27][CH3:28])=[O:24])[CH2:11][C:12](=[N:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][CH2:14]1
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1nc(C(=O)OCC(Cl)(Cl)Cl)co1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To the compound 61a obtained in Step (1) (90 mg) was dissolved in acetic acid (2 ml), zinc powder (180 mg) was added, and the mixture was stirred at room temperature for 3 hours. The insolubles were filtered out, then the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (silica gel, chloroform/methanol/acetic acid=8/1/0.25) to obtain the title compound (17.4 mg).
Reaction SMILES: [CH3:1][C@H:2]([CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:3][CH2:4][O:5][C@H:6]([CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:7]O.[CH2:47]([N:49]([CH2:52]C)[CH2:50]C)C.Cl[P:55]1(=[O:60])[O:59][CH2:58][CH2:57][O:56]1>C1(C)C=CC=CC=1>[OH-:5].[CH3:1][C@H:2]([CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[CH2:3][CH2:4][O:5][C@@H:6]([CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:7][P:55]([OH:56])([O:59][CH2:58][CH2:57][N+:49]([CH3:52])([CH3:50])[CH3:47])=[O:60]
Reactant: O=P1(Cl)OCCO1
Reactant: CCN(CC)CC
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@H](C)CCOC[C@H](CO)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@H](C)CCOC[C@@H](CP(=O)(O)OCC[N+](C)(C)C)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: [OH-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
1 mmol of (s)-2,3-bis[[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyl]oxy]propanol was dissolved in 7.5 ml of toluene and the solution was treated with 1.5 mmol of triethylamine and at 0° C. in the course of 30 minutes with 1.5 mmol of 2-chloro-1,3,2-dioxaphospholan-2-oxide in 2 ml of toluene. The reaction mixture was stirred at room temperature for a further 5 hours, the precipitated hydrochloride was filtered off with the exclusion of moisture and the filtrate was evaporated under reduced pressure. The residue was treated with 7.5 ml of a solution of 4 g of trimethylamine in 100 ml of acetonitrile and reacted at 70° C. overnight in a pressure flask, whereby the product precipitated partially. The solvent was removed under reduced pressure, the residue was dissolved in methanol and passed several times over 20 g of ion exchanger Amberlite MB-3. The solvent was removed and the crude product was chromatographed on silica gel with chloroform/methanol water (60:35:5). There was obtained O-[[(S)-2,3-bis[[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyl]oxy]propyl]hydroxyphosphinyl]choline hydroxide (internal salt) in a yield of 76.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:19])[F:20])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(-c2ccc(F)cc2C(F)(F)F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of methyl 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylate (0.23 g, 0.77 mmol) in methanol (4.0 ml) was added 5N NaOH (3.0 ml) and the mixture was stirred at 80° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (8.0 ml). The mixture was diluted with ethyl acetate and washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (1:1 to 1:9 hexane:ethyl acetate) to give the title compound (211 mg, 96%) as a white solid.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1.C([O-])([O-])=O.[K+].[K+]>C(O)(C(F)(F)F)=O>[C:22]1([C:7]2[S:6](=[O:29])(=[O:28])[N:5]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][O:33]3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: BrCC1CCCO1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1CC1CCCO1
Temperature: 120 °C
Yield: 34.3 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.364 mmol) was dissolved in TFA (3 mL) and heated in a microwave reactor at 120° C. for 20 mins. TFA was removed in vacuo and coevaporated with DCM two times. The residue was dissolved in MeCN (3 mL) and mixed with 2-(bromomethyl)tetrahydrofuran (0.312 g, 1.892 mmol), TEA (0.148 g, 1.454 mmol) and K2CO3 (0.251 g, 1.818 mmol) and heated in a microwave reactor at 140° C. for 15 mins and at 160° C. for 80 mins. The residue was purified by column chromatography (Horizons Biotage) using a 75:25 mixture of hexane and EtOAc as eluant, to give the title compound (0.055 g, 36%); 1H NMR (500 Mz, CDCl3): δ 7.53-7.49 (m, 2H), 7.46-7.41 (m, 3H), 7.31-7.25 (m 2H), 7.22-7.18 (m, 1H), 7.10-7.06 (m, 2H), 5.30-5.24 (br m, 1H), 4.42-4.36 (m, 1H), 4.00-3.95 (m 1H), 3.86-3.79 (m 2H), 3.72-3.65 (dd 1H), 2.91-2.83 (m 2H), 2.49-2.43 (m 2H), 2.14-2.06 (m 1H), 2.06-1.89 (dm 2H), 1.77-1.68 (m 1H), 1.44-1.36 (m 4H); 13C NMR (125 MHz, CDCl3): δ 159.7, 141.7, 135.6, 131.9, 129.9, 128.8, 128.6, 128.5, 126.2, 125.1, 107.0, 68.5, 44.2, 35.4, 29.6, 29.2, 28.3, 25.7; Mass Spectrum: M−H+ 425.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[N:4]=1>O1CCCC1.[Pd]>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:12])[N:4]=1
Reactant: Cc1nc(N(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nc(N(C)C)ccc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of N,N,6-trimethyl-5-nitropyridin-2-amine (2.73 g, 15.1 mmol) in tetrahydrofuran (50 mL) was added 10% palladium on carbon (50% wet, 273 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 14 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a brown solid (2.30 g, 15.1 mmol).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.CN1CCOCC1>CN1CCCC1=O>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cc3)CC4)nc(N)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (17 mg, 0.039 mmol), 4-fluorobenzonitrile (7.1 mg, 0.058 mmol) and 4-methylmorpholine (13 μL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL) was heated at 180° C. overnight. After cooling, the mixture was filtered, diluted with methanol, and purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=426.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].[CH3:36][NH2:37].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:37][CH3:36])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Yield: 75 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (436 mg, 0.866 mmol) and 2.00N methylamine in THF (1.93 mL, 3.85 mmol) were combined to provide 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (141 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6): δ 2.89 (s, 3 H), 3.53-3.61 (m, 3 H), 7.24-7.31 (m, 3 H), 7.49-7.51 (m, 2 H), 7.65-7.75 (br. m, 1 H), 7.79 (m, 1 H), 8.03 (s, 1 H), 8.37-8.39 (m, 1 H), 8.65-8.73 (m, 2 H), 9.40 (s, 1H); MS (ESI) m/z: 487.0 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([N:16]([C:18]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[C:25]([O:32][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2)[CH3:17])(=[O:15])=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([N:16]([C:18]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[C:25]([O:32][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:34])=[O:35])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2)[CH3:17])(=[O:15])=[O:14]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCN)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 5-(4-(tert-butoxycarbonylamino)-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.1; 5.52 mmol) in dichloro methane (5 mL) was added trifluoro acetic acid (5 mL) at 0° C. After addition the reaction was warmed to room temperature. The solvent was evaporated and the residue was co-evaporated with toluene (3×). The resulting residue was dried under vacuum and used in the next step (Example 3.3) without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([OH:17])=O)=[CH:8]2.[NH:18]1[CH2:27][CH2:26][CH2:25][C@H:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:15]([N:18]1[CH2:27][CH2:26][CH2:25][C@H:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:8]2
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: COc1ccc(OC)c2c1C=C(C(=O)O)CC2
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C1=Cc2c(OC)ccc(OC)c2CC1
Reaction time: 0.08 h

Procedure:
To a DMF solution (40 ml) containing 9b (6.24 g, 26.2 mmole) and (S) (-)-ethyl prolinate (4.20 g, 29.3 mmole), a DMF solution (40 ml) of DEPC (4.70 g, 28.8 mmole) is added, and then a DMF solution (40 ml) of triethylamine (2.65 g, 26.2 mmole) is dropwise added thereto at 0° C. in 5 minutes. The resultant mixture is stirred at 0° C. for 2 hours and then at room temperature for 48 hours in a nitrogen stream. After completion of the reaction, the reaction mixture is diluted with ethyl acetate (1.2 liters), and the ethyl acetate solution is washed with 5% hydrochloric acid (120 ml×2), water (120 ml×2), a saturated aqueous solution of sodium chloride (120 ml×2), a saturated aqueous solution of sodium hydrogen carbonate (120 ml×2), water (120 ml×2) and a saturated aqueous solution of sodium chloride (120 ml×2) in order, dried over anhydrous magnesium sulfate and subjected to filtration and evaporation to afford the crude product 10b as a pale brown caramel (10.3 g, 104%), which is purified by column chromatography (silica gel, 250 g; solvent, ether) to obtain a pure product 10b as a colorless caramel (8.3 g, 83%). [α]D20 -10.3° (c=2.28, ethanol). IRνmaxfilm cm-1 : 1730 (CO2Et), 1635 (C=C), 1603 (CON). NMR (in CDCl3 ): 1.27 (3H, t, J=7.5Hz, CO2CH2CH3), 1.70-3.10 (8H, m, CH2CH2C= and NCH2CH2CH2), 3.50-3.92 (2H, m, N--CH2), 3.78 (6H, s, two OCH3), 4.17 (2H, q, J=7.5Hz, CO2CH2CH3), 4.50 (1H, m, NCHCO), 6.15 (1H, d, J=10.7Hz, one of aromatic protons), 6.29 (1H, d, J=10.7Hz, one of aromatic protons), 7.21 (1H, broad s, CH=).
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[CH:13]=[CH:12][C:11]=2[C:19]([O:21]C)=[O:20])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[CH:13]=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2ccsc2c1C1=NC(C)(C(C)C)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2c(C(=O)O)ccc3ccsc23)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 7-(4-isopropyl-4methyl-5-oxo-2-imidazolin-2-yl)-6-benzo [b]thiophene carboxylate (90% pure, 0.420 g, 1.20 mmol), aqueous sodium hydroxide (1.01 mL, 2.53 mmol) and tetrahydrofuran (15 mL) is stirred overnight at 40°-45° C., cooled to room temperature, concentrated in vacuo, and acidified to pH 1-2 with concentrated sulfuric acid. Extraction with ethyl acetate, drying (MgSO4), concentration and recrystallization from acetonitrile:hexanes (9:1) affords the title product as an off-white solid, 0.22 g, mp 200°-202° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Cc1cc(N)cc(Cl)c1O
Product: Cc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 19.20 min.; purity: 94%; MS (m/e): 360 (M+); 1H NMR (CDCl3): δ 7.93 (1H, d, J=3.1 Hz), 7.54 (1H, d, J=2.6 Hz), 7.30 (1H, t, J=2.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.02 (3H, m), 6.78 (1H, s), 6.61 (1H, dd, J=7.9 Hz, J=2.1 Hz), 2.26 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19]
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(CO)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CCC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To 2,4-dimethoxybenzyl-alcohol (4.3 g, 25.6 mmol) and pyrrolidine-2,5-dione (succinimide, 1.2 g, 12.2 mmol) dissolved in tetrahydrofuran (25 ml) and dichloromethane (25 ml) was added triphenyphosphine (6.4 g, 24.4 mmol). After cooling to 0° C., diethylazidodicarboxylate (DEAD, 4.25 g, 24.4 mmol) was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm to room temperature and kept at room temperature with stirring overnight. Following concentration in vacuo, 100 ml of a (1:1)hexane/ether solution was added and this mixture was stored at 0° C. overnight. The resulting solid precipitate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (3/1—ethyl acetate/hexane) to afford 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol, 46%). 1H NMR (CDCl3) δ 7.07 (d, 1H), 6.38 (m, 2H), 4.60 (s, 2H), 3.76 (s, 3H), 2.62 (s, 4H).
Reaction SMILES: ClC1C=CC=CC=1C[N:5]1[C:14]2[C:9](=CC=CC=2)[N:8]2[CH:15]=N[C:17]([C:18](OCC)=O)=[C:7]2[C:6]1=[O:23].Cl[C:29]1[CH:47]=[CH:46][CH:45]=[CH:44][C:30]=1[CH2:31][N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][C:34](=O)[C:33]1=[O:43].[N+:48](CC(OCC)=O)#[C-]>>[CH2:31]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]2[CH:15]=[N:8][C:9]([C:14]3[N:5]=[C:6]([CH:7]4[CH2:17][CH2:18]4)[O:23][N:48]=3)=[C:34]2[C:33]1=[O:43])[C:30]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:29]=1
Reactant: O=c1[nH]c2ccccc2n(Cc2ccccc2Cl)c1=O
Reactant: CCOC(=O)c1ncn2c1c(=O)n(Cc1ccccc1Cl)c1ccccc12
Reactant: [C-]#[N+]CC(=O)OCC
Product: O=c1c2c(-c3noc(C4CC4)n3)ncn2c2ccccc2n1Cc1ccccc1

Procedure:
Ethyl 5-(2-chlorobenzyl)-4,5-dihydro-4-oxo-imidazo[1,5-a]-quinoxaline-3-carboxylate, m.p. 203°-209° C. by reaction between 4-(2-chlorobenzyl)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 16)
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].Cl.[CH3:13]O>C=O>[ClH:1].[CH2:13]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7][NH:8]1
Reactant: NCCc1cccc(O)c1
Reactant: CO
Agent: C=O
Agent: Cl
Product: Oc1ccc2c(c1)CCNC2
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxyphenethylamine hydrochloride (3.0 g) in methanol (6 mL), formaldehyde (37% aqueous solution, 2.7 mL) and a catalytic amount of concentrated hydrochloric acid were added, followed by stirring at 45° C. for 18 hours. The reaction mixture was concentrated and the obtained solid was washed with a mixed solvent of diisopropyl ether-methanol (1:2) to thereby give the title compound (2.8 g) having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[N:3][CH:2]=1.[SH:9][CH:10]([CH3:14])[CH:11]([OH:13])[CH3:12]>>[OH:13][CH:11]([CH3:12])[CH:10]([S:9][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1)[CH3:14]
Reactant: CC(O)C(C)S
Reactant: BrCc1ccncn1
Product: CC(O)C(C)SCc1ccncn1

Procedure:
By the same method, 4-pyrimidylmethyl bromide is reacted with 3-mercapto-2-butanol to yield 4-(3-hydroxy-2-butylthiomethyl)pyrimidine, with 3-mercapto-1,2-propanediol to yield 4-(2,3-dihydroxy-1-propylthiomethyl)pyrimidine, with 2-mercaptophenol to yield 4-(2-hydroxyphenylthiomethyl)pyrimidine, with ethyl 2-mercaptoacetate to yield ethyl 2-(4-pyrimidylmethylthio)acetate, with ethyl 2-mercaptopropionate to yield ethyl 2-(4-pyrimidylmethylthio)propionate, with ethyl 2-phenyl-2-mercaptoacetate to yield ethyl 2-phenyl-2-(4-pyrimidylmethylthio)acetate (when ethyl esters are prepared, it is preferable to substitute an equivalent of sodium ethoxide for sodium methoxide), with mercaptoacetone to yield 4-pyrimidylmethylthioacetone, with 1-phenyl-1-mercaptoacetone to yield 1-(4-pyrimidylmethylthio)-1-phenylacetone, and with methyl 3-mercaptopropionate to yield methyl 3-(4-pyrimidylmethylthio)propionate (when methyl esters are prepared it is preferable to substitute methanol for ethanol).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.[Pt]=O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2ncccc12
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCc2ncccc21
Reaction time: 8 h

Procedure:
Methyl quinoline-5-carboxylate (3.67 g, 19.61 mmol) was dissolved in TFA (60 mL) and added platinum oxide (0.49 g, 2.16 mmol) then hydrogenated at room temperature overnight. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was chromatographed through a 120 g ISCO Redi-sep column and eluted with 5% of (10% NH4OH in MeOH) in DCM to yield methyl 5,6,7,8-tetrahydroquinoline-5-carboxylate: LC-MS: M+1=192.