Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]CC2C=CC=CC=2)[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21])C1C=CC=CC=1>[C].[Pd].O1CCOCC1>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]
Reactant: O=C1NC(=O)C(c2ccccc2OCc2ccccc2)(c2ccccc2OCc2ccccc2)N1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccccc2O)(c2ccccc2O)N1
Temperature: 80 °C

Procedure:
11.0 Grams of 5,5-bis(2-benzyloxyphenyl)hydantoin (Example 12) were reduced in 150 ml. of dioxane in the presence of 2 g of palladium-carbon catalyst in an autoclave under a hydrogen pressure of 10 Kg/cm2 at room temperature. After completion of the hydrogen absorption, the whole was heated at 80° C. under a hydrogen pressure of 10 Kg/cm2 for about 5 hours. The reaction liquid was subjected to filtration to remove the catalyst and concentrated under reduced pressure and the resulting precipitates were filtered out. The product was recrystallized from a mixture of acetone-chloroform to obtain 3.4 g of 5,5-bis(2-hydroxyphenyl)hydantoin in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH:30]([NH:32][NH2:33])=[O:31].C(Cl)CCl.CC(N(C)C)=O>O.CN(C=O)C>[CH:30]([NH:32][NH:33][C:27]([C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26]1)=[O:28])=[O:31]
Reactant: NNC=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)O)CC3)s2)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)NNC=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
1-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylic acid (TEA salt, 110 mg, 0.206 mmol), formic acid hydrazide (37 mg, 0.617 mmol), HOST (95 mg, 0.617 mmol), and EDC (118 mg, 0.617 mmol) were combined with DMF (5 mL) and DMA (80 mg, 0.617 mmol). The reaction was stirred for 3 h at room temperature. It was subsequently diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether and filtered to provide N′-formyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarbohydrazide (88 mg, 92%) as a colorless solid. MS ESI: [M+H]+ m/z 463.0.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[C:16]([F:30])[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:18]([F:20])[CH:19]=1
Reactant: OC(c1ccc(F)cc1)c1c(F)cc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3c(F)cc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 490 mg (2.76 mmol) of the compound from Example 8A and 753 mg (2.76 mmol) of the compound from Example 178A in analogy to the synthesis of the compound from Example 278. 140 mg (12% of theory) of the target compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[N:11]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Agent: Cl
Product: O=S(=O)(Oc1cccc(OCCN2CCNCC2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[2-[N-(tert-butoxycarbonyl)piperazin-4-yl]ethoxy]phenyl ester (994 mg, 2.0 mmol), as prepared in the preceding step, was treated with 4N HCl (40 mL in 1,4-dioxane) and stirred at room temperature for 2 h. After concentrating in vacuo, the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with NH3) to give the title compound as a white foam (705 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 2.00 (bs, 1H), 2.54 (t, 4H), 2.76 (t, 2H), 2.93 (t, 4H), 4.02 (t, 2H), 6.72 (m, 2H), 6.78 (dd, 1H), 7.16 (t, 1H), 7.37 (dt, 1H), 7.61 (m, 2H), 7.95 (dd, 1H). Mass spectrum MALDI-TOF, sinapinic acid matrix) calcd. for C18H21N2O4SCl: 397.1 (M+H). Found: 397.6.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=1)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:14]N(C)C=O.C(OC(OCC)N(C)C)C>O>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[C:7]2[C:8]([C:9](=[O:13])[CH2:10][CH2:11][CH2:12]2)=[CH:14][NH:6]1
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Reactant: CN(C)C=O
Agent: CCOC(OCC)N(C)C
Solvent: O
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution consisting of 40 parts of α-cyano-3-oxo-1-cyclohexen-1-acetamide in 125 parts by volume of dimethylformamide, in an atmosphere of nitrogen, is added dropwise, over a period of 10-15 minutes, 40 parts of dimethylformamide diethyl acetal. After the reaction mixture is stirred at room temperature for about 18 hours, 10 parts of water is added and the organic solvents are removed by distillation under reduced pressure. The residual oily product is extracted with dilute aqueous sodium hydroxide and the extract is washed several times with chloroform, then filtered to remove the small amount of insoluble material. Neutralization of the alkaline solution by the addition of dilute hydrochloric acid results in precipitation of the product, which is purified by recrystallization from aqueous acetone to afford 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile, melting above 290°. It is further characterized by ultraviolet absorption maxima at about 227, 232, 279 and 324 mμ with molecular extinction coefficients of 17,900, 16,000, 13,000 and 6,800, respectively, and by infrared absorption peaks, in potassium bromide, at about 2.87, 2.97, 4.48, 5.92, 6.03, 6.07, 6.23 and 6.45 μ and also by nuclear magnetic resonance peaks, in deuteropyridine, at approximately 1.92, 2.58, 2.97, and 8.72 parts per million.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:26])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH3:15]>C(O)C>[CH3:26][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(CCC(C)(C)N)cc1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: COc1ccc(CCC(C)(C)NC[C@H](O)c2ccc3nnnn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 509 mg (3.13 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 619 mg (3.21 mmol) of 2-amino-2-methyl-4-(4-methoxyphenyl)butane in 25 ml of absolute ethanol was heated at reflux for two hours and then stirred overnight at room temperature. The reaction mixture was concentrated and the residue chromatographed on silica gel (4:1:2 ethyl acetate:n-propanol:water with 1% NH4OH) to give 497 mg of product. Recrystallization from isopropanol afforded 357 mg of crystalline tetrazole, mp. 139-40° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1C=CC=CC=1>[O:11]1[CH2:12][CH2:13][N:8]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: C1COCCN1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: C1=C(N2CCOCC2)CCCC1

Procedure:
295g of cyclohexanone and 261 g of morpholine are dissolved in 800ml of benzene. After the whole has been dissolved, 1.5g of p. toluene sulphonic acid are added and the mixture is heated under reflux. The water formed is extracted continuously by azeotropic distillation. After 20 hours reflux, the remaining solvent is distilled off and the oily residue is recovered. 379 g of the enamine are so obtained, boiling under 2mm at 115° to 117°. The yield amounts to 76%.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)[C@@H]1CCCCN1
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared by a similar method to Preparation 42 from 2,6-dichloro-1,3-benzothiazole [see J. Ind. Chem. Soc., (1993), 10, 565-569] and ethyl (2S)-2-piperidinecarboxylate (471 mg) [see J.A.C.S. (1993), 115(22), 9925-9938] to afford ethyl (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylate as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Similar to Example 57, a mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (200 mg, 0.547 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinylamine (302 mg, 1.38 mmol), PdCl2 (dppf) (45 mg, 0.0551 mmol) and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 24 hrs. The mixture was cooled to room temperature, diluted with H2O, extracted with CH2Cl2 (4×), and the combined organic extracts were dried (Na2SO4), and the solvents removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/EtOAc (100:0 to 80:20) to CH2Cl2/MeOH (100:0 to 98.5:1.5), followed by recrystallization from CH2Cl2/MeOH/i-Pr2O gave 2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5′-bipyrimidine-2′-amine (157 mg, 66% yield): mp 281-285° C.; 1H NMR (DMSO-d6) δ 9.09 (s, 2H), 8.35 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (t, Jjw=52.8 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 2H), 3.82 (m, 4H), 3.77 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(OCC)(=O)[C:25]([O:27]CC)=[O:26]>>[C:17]1([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:9](=[O:23])[C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
40 g of Potassium t-butoxide was added to 150 ml of diethyl oxalate in small portions with stirring. After the initial exothermic reaction subsided, the reaction mixture was heated on a steam bath under nitrogen in order to dissolve solids. After cooling down to room temperature, 79 g of 4-biphenyl acetic acid methyl ester was added in one portion. The mixture was stirred at 60°-70° C. for 2 hours while low boiling material was removed under vacuum. On cooling to room temperature, the viscous residue was stirred with 200 ml of ether and 350 ml of water with cooling. The ether layer was separated and extracted once with 100 ml of water. The aqueous layers were combined, extracted once with ether, made acidic with concentrated HCl (cooling) and extracted with 2×300 ml of ether. Some solids did not dissolve in the ether layer and were filtered. The ether layer was then evaporated to dryness. and the semi solid residue was combined with the preceeding solids. A mixture of 160 ml of conc. HCl and 350 ml of acetic acid was added to the solids and heated under reflux for 21/2 hours. On cooling down to ca. 50° C. a solid preciptated, which was filtered and washed with 150 ml of water. The wet solid was stirred with 150 ml of acetonitrile for five minutes, then filtered and dried under high vacuum at room temperature for 3 hours. 42.2 g of the title compound m.p. 215°-218° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([O:1][CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[C:5]2[C:6]1=[O:7])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)CN1C(=O)c2ccc(O)cc2C1=O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A mixture of 1 g of 4-hydroxy-N-isobutylphthalimide, 0.85 cm3 of 2-bromopropane and 1.38 g of potassium carbonate in 5 cm3 of dimethylformamide is stirred at a temperature in the region of 60° C. for 17 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 70 cm3 of water and then extracted 3 times with 75 cm3 of ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.16 g of N-isobutyl-4-isopropyloxyphthalimide are thus obtained in the form of a white solid. (Rf=0.50, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20]>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:6]=2[CH:17]=1
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.400 g, 1.15 mmol) and 4-propoxy-piperidine (79KS66) (0.332 g, 2.29 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 3 days and at 70° C. for 1 day. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50→1:20) to give the title compound (108LM30-27) (0.263 g, 63%). 1H NMR (CDCl3) δ 6.96 (dd, J=9.7 Hz, J=2.9 Hz, 1H), 6.91 (dd, J=8.9 Hz, J=4.9 Hz, 1H), 6.66 (dt, J=8.9 Hz, J=2.9 Hz, 1H), 4.56 (ABq, J=15.5 Hz, J=31.7 Hz, CH2), 3.95 (dd, J=13.5 Hz, J=8.1 Hz, 1H), 3.88 (dd, J=13.5 Hz, J=4.7 Hz, 1H), 3.38 (t, J=6.7 Hz, CH2), 3.32-3.23 (m, 1H), 2.79 (bs, 1H), 2.62 (bs, 1H), 2.26-2.12 (m, 3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=952.8 Hz, 1H), 141.7 (d, J=9.2 Hz, 1H), 130.0 (d, J=42.4 Hz, 1H), 117.7 (d, J=38.4 Hz, 1H), 109.6 (d, J=93.2 Hz, 1H), 103.4 (d, J=114.4 Hz, 1H), 75.2, 69.8, 67.9, 63.7, 52.8, 52.0, 45.7, 31.8, 31.6, 29.5, 23.5, 17.1, 10.9; HPLC-MS (ammonium acetate) [M+H]+=365.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][NH2:31]>>[NH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:30][C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[O:21][CH3:20])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Nc1ccc(Sc2ccnc(Cl)c2)c2ccccc12
Product: COc1ccc(CNc2cc(Sc3ccc(N)c4ccccc34)ccn2)c(OC)c1
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of 4-(2-chloropyridin-4-ylthio)naphthalen-1-amine (1.40 g, 90% purity, 4.40 mmol) and (2,4-dimethoxyphenyl)methanamine (3.7 mL, 24 mmol) was heated together at 120° C. for 24 hr. The reaction mixture was loaded directly onto silica and purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 30-70%, gradient elution) to afford 4-(4-aminonaphthalen-1-ylthio)-N-(2,4-dimethoxybenzyl)pyridin-2-amine as a dark red oil (710 mg, 37%); Rt 1.74 min (Method 2); m/z 418 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10].C(OCC)C>ClCCl>[CH2:9]([S:11]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1cccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCS(=O)(=O)NCc1cccnc1
Reaction time: 18 h

Procedure:
3-Aminomethylpyridine (2.15 g, 19.88 mmol) was dissolved in 40 ml dichloromethane. Ethanesulfonyl chloride (2.56 g, 19.9 mmol) was added to the mixture and stirred for 18 h. To the resultant precipitate was added 40 ml diethyl ether and decanted from the solid. The solid was partitioned between a mixture of 100 ml dichloromethane/20 ml isopropyl alcohol and 20 ml of a saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase extracted twice with the 80/20 mixture of dichloromethane/isopropyl alcohol. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 8.67 (s,1H), 8.60 (d,1H,J=4 Hz), 7.90 (m,1H), 7.42 (m,1H), 5.77 (t,1H,J=6 Hz), 4.38 (d,2H,J=6 Hz), 3.07 (t,2H,J=8 Hz), 1.38 (t,3H,J=8 Hz). MS calcd. 200.2; MS (M+1) 201.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:18].[OH-].[NH4+]>C(O)C>[OH:1][CH2:2][C:3]1[NH:18][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: N
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(CO)[nH]cc1OCc1ccccc1

Procedure:
A mixture of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one (9.65 g, 41.59 mole), 95 ml of concentrated ammonia and 20 ml of ethanol were heated at reflux overnight. An additional 75 ml of ammonium hydroxide was added, the mixture was refluxed for 2 hours and cooled. The resulting brown solid was filtered and washed with water until the washings were neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:21]1[CH2:25][S:24][C:23](=[O:26])[NH:22]1>C(O)C>[CH3:12][N:3]([CH3:2])[C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][C:21]1[CH2:25][S:24][C:23](=[O:26])[N:22]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.4 g) containing N,N-dimethyl-L-isoleucinamide hydrochloride obtained in B) and triethylamine (49.5 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (16.3 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (6.2 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+:30]>C(O)C>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:25][CH:26]=1.[Na+:30]
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1

Procedure:
To a stirred, hot solution of 4.5 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid in 150 ml. absolute ethanol was added 2.2 ml. 10N sodium hydroxide. The solution was cooled and the precipitate was filtered off and dried to yield a light yellow solid, m.p. 350°-355° C. dec.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:13][PH:14](=[O:16])[CH3:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([P:14](=[O:16])([CH3:15])[CH3:13])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[PH](C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg, 0.13 mmol), XANPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623 g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C. for 18 h. The reaction mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was concentrated and purified by prep-HPLC to give the final product (0.16 g, 30% yield). MS/ES+: m/z=229.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl.Cl>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][N:8]([C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(n1)CCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1)N1CCc2nc(Cl)ccc2C1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a room temperature stirred suspension of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (50 mg, 0.24 mmol) in dichloromethane (2 ml) under a nitrogen atmosphere was added DIPEA (0.12 ml, 0.73 mmol) followed by cyclopropyl carbonyl chloride (24 μl, 0.27 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 ml) and 1M aq. HCl (2 ml). The organic layer was separated and washed with saturated aqueous NaHCO3 (15 ml) and brine (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure to provide the title compound (60 mg, 95%) which was used without further purification.