Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:24][C:25](=[O:26])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CCN(CC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.8 mmol) was dissolved in DMF (2 mL), and sodium hydride (1.98 mmol) was added. The mixture was stirred for about 10 minutes and 2-chloro-N,N-diethyl-acetamide (269 mg, 1.8 mmol) was added. The mixture was heated to 80° C. for about 2 hours. The mixture was concentrated and deprotected, which was then chromatographed to give about 395 mg of the final compound as a clear oil (75%). MS found 292.2
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)([O:6]CC)=[O:5])C.Br.O>C(O)(=O)C>[O:27]=[C:16]1[NH:15][C:14]2[C:28]3[CH:29]=[CH:30][CH:31]=[C:10]([CH2:9][P:4]([OH:6])([OH:5])=[O:3])[C:11]=3[CH2:12][C:13]=2[N:18]2[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:17]12
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CP(=O)(OCC)OCC)c1C3
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CP(=O)(O)O)c1C3
Yield: 61.6 %

Procedure:
A mixture of 0.6 g of ethyl 9-(diethoxyphosphorylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate, 30 ml of hydrobromic acid at 30% in acetic acid and 10 ml of distilled water is heated at reflux for 2 hours. The reaction mixture is filtered and the solid is washed with 3×20 ml of distilled water, and then with 2×10 ml of acetone and finally dried under vacuum (1 mm Hg, 0.13 kPa) at close to 40° C. 0.3 g of 4-oxo-9-phosphonomethyl-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is obtained in the form of a beige solid melting above 260° C. [Analysis: C15H12N3O6P, 0.09 HBr, 0.38 HCl, 1.54 H2O, % calculated C: 49.87, H: 3.3, N: 11.63, O: 26.57, P: 8.57, % found C: 49.8, H: 3.4, N: 11.1].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([CH2:26][NH2:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:27][CH2:26][C:23]1[CH:22]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:25][N:24]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCc1cc(-c2ccccc2)on1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A suspension of 4-chloro-3-nitroquinoline (2.29 g, 11.0 mmol) and (5-phenylisoxazol-3-yl)methylamine (1.92 g, 11.0 mmol) in dichloromethane (200 mL) was cooled to 0° C., and triethylamine (2.30 mL, 16.5 mmol) was added. The resultant solution was allowed to warm to room temperature slowly and stirred overnight. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 2.90 g of 3-nitro-N-[(5-phenylisoxazol-3-yl)methyl]quinolin-4-amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]=1.CN(C)C=O.[H-].[Na+].Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:5]([C:9]([CH3:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:19]=[C:20]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: CCCCCCCCBr
Reactant: CC(C)(c1ccccc1)c1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.5 %

Procedure:
To a 500 mL three-necked, round-bottomed flask equipped with a condenser, magnetic stirrer, thermometer, and a nitrogen atmosphere axe charged 4.00 g (8.71 mmol) of the product of Example 9, 50 mL of N,N-dimethylformamide and 0.40 g (10 mmol) of sodium hydride (60% in mineral oil). The mixture is heated to an external temperature of 50° C. and 1.68 g (8.70 mmol) of 1-bromooctane are added. The mixture is stirred at this temperature for six hours and is allowed to cool to room temperature. The mixture is poured into a beaker of water which is extracted four times with chloroform. The combined chloroform layers are washed four times with water and dried over anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure to afford a yellow oil. The crude product is purified with medium pressure chromatography with 10:1 heptane:ethyl acetate followed by recrystallization from acetone/water to yield 1.12 g of the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([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)[CH:6]=1.C([Mg]Br)C.[C:30]1([C:40](=[O:42])[CH3:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1>ClCCl>[C:30]1([C:40]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)([OH:42])[CH3:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CC(=O)c1nccc2ccccc12
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1nccc2ccccc12
Reaction time: 16 h

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (15.5 g, 35.4 mmol) in dichloromethane (80 mL) at 20° C. was treated with ethyl magnesium bromide (12.0 mL, 36 mmol, 3M in ether) and allowed to react for 1 h. A solution of 1-isoquinolin-1-yl-ethanone (Intermediate H2) (3.65 g, 21.3 mmol) in dichloromethane (20 mL) was added via addition funnel at 20° C. and stirred for 16 h. The mixture was quenched with sat. ammonium chloride (100 mL) and diluted with dichloromethane. The residue was isolated in an aqueous workup. The product was extracted with CH2Cl2 and purified by chromatography on silica gel with 5% NH3-MeOH: CH2Cl2 to give 1-isoquinolin-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H3) as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[C:8]([CH3:16])[CH:9]=1)(=[O:15])[CH3:14]
Reactant: CS(N)(=O)=O
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A test tube for microwave was charged with tris(dibenzylidenacetone)dipalladium (0) chloroform adduct (205 mg, 0.20 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine] (345 mg, 0.60 mmol), 4-acetyl-2-methylphenyl trifluoromethanesulfonate (1.41 g, 5.0 mmol), methanesulfonamide (570 mg, 6.0 mmol), cesium carbonate (1.63 g, 7.0 mmol) and 1,4-dioxane (5 ml). The mixture was subjected to microwave irradiation at 120° C. with stirring for 10 minutes. Then, it was filterd off and the filtrate was concentrated under reduced pressure to furnish the crude residue which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane:ethyl acetate (2/1) to give 390 mg (34% yield) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38](O)[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1>ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Trifluoromethanesulfonic anhydride (22.9 μL, 0.14 mmol) and triethylamine (23.7 μL, 0.17) were added under argon to a vial containing 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol) in dichloromethane (1 mL). The vial was then sealed and the reaction was left stirring overnight at ambient temperature. The reaction mixture was placed directly onto a flash column and purified by eluting with hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 to afford 11 mg (25%) of 3-(2-pyridyl)-5-(3-cyano-5-(trifluoromethylsulfonyloxy)phenyl) -1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.88 (d, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.24 (d, 1H), 7.93 (t, 1H), 7.83 (s, 1H), 7.52 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.CC([O-])=O.[K+].[N:26](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:13][C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:26]=[CH:12]2
Reactant: CC(C)CCON=O
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Methyl 2-amino-5-chloro-3-methylbenzoate (6.6 g, 33.1 mmol) was dissolved in CHCl3 (90 mL) then cooled in an icebath while acetic anhydride (7.2 mL, 76.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for ca. 1 h, then KOAc (650 mg, 6.6 mmol) was added, followed by isoamyl nitrite (9.7 mL, 72.8 mmol). The reaction mixture was heated under reflux until the reaction was complete by TLC (overnight). While cooling to room temperature, precipitation was observed. The precipitate was collected and dried to afford methyl 5-chloro-1H-indazole-7-carboxylate as a yellow solid (4.83 g, 69%): 1H NMR (300 MHz, CDCl3) δ 11.25 (s, 1H), 8.10 (s, 1H), 8.05 (s, 3H), 7.97 (s, 1H), 4.09 (s, 1H); MS (ESI+) m/z 211 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:4]=1)=[O:2].C1(C2N(CCCCCCC(O)=O)C3=NC(C4C=CC(C)=CC=4)=C(C4C=CC(C)=CC=4)N=C3C=2)CC1>>[CH:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1)=[O:2]
Reactant: CCOC(=O)CCCCCCn1cc(C=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cc1ccc(-c2nc3cc(C4CC4)n(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc3c(C=O)cn(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1

Procedure:
The titled compound was prepared from ethyl 7-(7-formyl-2,3di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Intermediate C) analgously to 7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid (Example 1 step 7);
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][OH:5].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:9]([Si:6]([O:5][CH2:4][CH2:3][C:2]#[CH:1])([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, 0° C. solution of homopropargyl alcohol (10 g, 0.14 mol) and tert-butyldimethylsilyl chloride (21.5 g, 0.14 mol) in dichloromethane (50 mL) was treated with triethylamine (22.8 mL, 0.168 mol). The mixture was then stirred overnight at room temperature. The mixture was washed with water and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (95:5 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.08 (s, 6H), 0.90 (s, 9H), 1.96 (t, J=3 Hz, 1H), 2.41 (dt, J=6 Hz, J=3 Hz, 2H), 3.75 (d, J=6 Hz, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Br)[CH3:2].[NH2:11][C:12]([NH2:14])=[S:13].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH2:1]([S:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]([NH2:14])[S:13][CH:7]=1)[CH3:2]
Reactant: NC(N)=S
Reactant: CCSC(=O)CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCSC(=O)Cc1csc(N)n1
Yield: 65.3 %

Procedure:
In 7.0 ml of N,N-dimethylacetamide was dissolved 2.25 g of the 4-bromo-3-oxothiobutyric acid-S-ethyl ester obtained in Referential Example 4-(1), and 1.14 g of thiourea was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 1 hour. The reaction mixture was introduced into a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, and the pH was adjusted to 6.0 with sodium hydrogencarbonate. Then, the organic layer was separated, washed with two 50-ml portions of water and with 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure. The residue obtained was recrystallized from 20 ml of ethyl acetate to obtain 1.32 g (yield, 65.5%) of 2-(2-aminothiazol-4-yl)thioacetic acid-S-ethyl ester having a melting point of 76°-77° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH2:18][CH2:19][CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCNC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
Tertiarybutoxycarbonyl-L-norleucine (13.2 g) in CH2Cl2 (200 ml) was treated at 0° with L-alanine N-butylamide (5.25 g), DCC (7.77 g) and 1-hydroxybenzotriazole (5 g). The pH of the reaction mixture was adjusted to 7 with N-methyl morpholine and allowed to warm to room temperature overnight. The precipitated urea was filtered off and the filtrate washed successively with saturated aqueous sodium hydrogen carbonate, water and 1M citric acid. The organic phase was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was chromatographed on silica in a gradient of 30-70% ethyl acetate in dichloromethane. Elution with 50% ethyl acetate in dichloromethane afforded the title compound (7.6 g) which crystallised from ethyl acetate as needles m.p. 108°-112°; (Found: C,60.8; H,9.8; N,11.8. C18H35N3O4 requires C,60.5; H,9.9; N,11.75%); νmax (Nujol) 3280, 3340 1675 and 1640 cms-1 δ (CDCl3) 0.9 and 0.91 (each 3H, each t, each J=5 Hz, 2×CH3); 1.1-1.9 (10H, m, (CH2)3 and (CH2)2); 1.38 (3H, d, J=5 Hz, 6H2CHCH3); 1.44 (9H, s, C(CH3)3); 3.24 (2H, tt, J=5 Hz NHCH2) and 4.1 and 4.48 (each 1H, each m, 2×CH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[N:7]=[CH:8]/[CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1>O(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][CH:15]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][N:1]=2)[N:7]=[CH:8][CH:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(/C=N/c1cccnc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2cccnc2C1O
Temperature: 250 °C

Procedure:
Diethyl [(E)-(pyridin-3-ylimino)methyl]malonate (9 g, 34 mmol) was dissolved in 1,1′-oxydibenzene (150 ml). The mixture was heated at 250° C. for 2 hours, and then cooled to room temperature. The reaction mixture was filtered to give ethyl 4-hydroxy-3,4-dihydro-1,5-naphthyridine-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].C(O)(C)C.CS(O)(=O)=O.[CH3:24][N:25]=[C:26](SC)[S:27][CH3:28]>O>[CH3:24][NH:25][C:26](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:27][CH3:28]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CN=C(SC)SC
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
Ten g. of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole was dissolved in 100 ml. of isopropanol, and 2.8 ml. of methanesulfonic acid was added, followed by 6.5 g. of methylcarbonimidodithioic acid, dimethyl ester. The mixture was stirred under reflux for 16 hours, and was evaporated under vacuum to obtain a residue, which was taken up in 100 ml. of water. The solution was extracted with two 25 ml. portions of dichloromethane, and the aqueous layer was cooled. Fifty ml. of dichloromethane and 15 ml. of 50% aqueous sodium hydroxide were added. The layers were separated, and the solution was extracted again with 50 ml. of dichloromethane. The organic layers were combined, dried over potassium carbonate and evaporated under vacuum to obtain 10.3 g. of product, substantially identical to that of Example 1, which was 96.7% pure by HPLC analysis.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl.O>[N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH:20][C:28](=[O:30])[CH3:29])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 101A (20 mg, 0.070 mmole) was dissolved in anhydrous dichloromethane (1.5 mL). To the solution was added triethylamine (35.6 mg, 49 μL, 0.35 mmole) and acetyl chloride (10 μL, 0.14 mmole). The mixture was stirred at room temperature overnight then diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were concentrated to give the crude product. The crude product was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.39 (d, J=2.14 Hz, 1H) 7.84 (d, J=8.54 Hz, 1H) 7.37 (s, 1H) 7.22 (dd, J=8.85, 2.14 Hz, 1H) 3.48-3.59 (m, 1H) 2.72-2.83 (m, 1H) 2.60-2.70 (m, 2H) 2.24-2.39 (m, 6H) 2.21 (s, 3H) 1.54-1.64 (m, 4H) 1.40-1.51 (m, 2H). MS: (M+H)+=330.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CC(C)(C)CN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NCC(C)(C)C)nc(Cl)nc12
Reaction time: 3 h
Yield: 94 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 179 mg (2.1 mmol) of neopentylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 355 mg (yield: 96.1%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[C@H:17]1[CH3:21])([CH3:15])[CH3:14]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: COc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(C#N)ccc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 4-fluoro-3-methoxybenzonitrile (232 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (390 mg) and lithium carbonate (153 mg), the title compound was obtained as a white solid (yield: 42 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2cccnc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.4 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (1.5 mL). Pyridin-3-ylboronic acid (0.33 g, 2.65 mmol) was added and argon was bubbled in the mixture for 15 minutes. Cesium fluoride (0.8 g, 5.3 mmol) and tetrakistriphenylphosphine palladium (0.14 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 0.45 g (55%) of the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:4])[CH3:5]
Reactant: CC(=O)C(F)(F)F
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(O)(c1ccccc1)C(F)(F)F

Procedure:
1,1,1-Trifluoro-2-phenylpropan-2-ol was prepared from benzene and 1,1,1-trifluoroacetone by an AlCl3 -catalyzed Friedel-Crafts reaction.