Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(C)C=CC=CC=1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C:12]2[S:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cccc3ccccc23)sc1C(=O)N1CCN(C(C)C)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cccc3ccccc23)sc1CN1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-isopropyl-piperazin-1-yl)-(4-methyl-2-naphthalen-1-yl-thiazol-5-yl)-methanone (25 mg, 0.066 mmol) in anhydrous THF (2.5 ml) is added a solution of alane-dimethylethylamine complex in toluene (0.5 M, 0.4 ml, 0.2 mmol, 3.0 eq.) dropwise at 0° C. The resulting mixture is stirred at rt overnight. The reaction is quenched with one drop of water, followed by one drop of 10 N sodium hydroxide solution and two more drops of water. The resulting mixture is diluted with EtOAc (10 ml), dried over magnesium sulfate, and concentrated. The residue is purified through PTLC (EtOAc/Et3N, 25:1) to give the desired product. 1H NMR (300 MHz, CDCl3) δ 8.78 (1H, dd), 7.89 (2H, m), 7.78 (1H, dd), 7.60˜7.45 (3H, m), 3.74 (2H, s), 2.76˜2.54 (9H, m, overlapped), 2.51 (3H, s), 1.06 (6H, d); LC-MS (M+1) 366.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[CH:7]=1.[C:21]([Si:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=1)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].C(N(CCCC)CCCC)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:25]([O:28][C:29]1[CH:34]=[C:33]([CH:11]2[CH:12]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:20])[CH2:9][N:10]2[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:32]=[CH:31][CH:30]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1C=CC(c2cc(Cl)ccc2F)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 65 °C

Procedure:
A deoxygenated mixture of tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3dihydro-1H-pyrrole-1-carboxylate (3-1, 1.100 g, 3.69 mmol, 1 equiv), tert-butyl(3-iodophenoxy)dimethylsilane (1.85 g, 5.54 mmol, 1.50 equiv), tributylamine (1.76 mL, 7.39 mmol, 2.00 equiv), triphenylarsine (0.453 g, 1.48 mmol, 0.400 equiv), and palladium acetate (0.166 g, 0.739 mmol, 0.200 equiv) in DMF (10 mL) was heated at 65° C. for 20 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×85 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 50% ethyl acetate in hexanes) to provide tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3-2) as an orange oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ 7.11-6.53 (m, 7H), 6.11 (s, 1H), 5.32 (m, 1H), 4.53 (m, 2H), 1.09 (s, 9H), 0.79 (s, 9H), 0.00 (s, 6H). LRMS m/z (M+H) 504.1 found, 504.2 required.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[C:12]2[CH2:21][C:22](=[O:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-].C(OCC)(=O)C>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[C:12]2[CH2:21][CH:22]([OH:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1nn(C(C)=O)c2ccc(OCc3ccccc3)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)n1nc(CC(C)O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
To a solution of the product from Step A (0.13 g, 0.4 mmol) in methanol (8 ml) was added NaBH4 (0.016 g, 0.4 mmol) and the mixture was stirred at room temperature for 20 min. A saturated aqueous solution of NH4Cl (20 ml) and ethyl acetate (20 ml) were added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with a saturated aqueous solution of NaCl (2×15 ml), dried (MgSO4), and evaporated to give an oil (0.12 g). MS(APCl) m/z 325 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[F:23][C:22]([F:25])([F:24])[C:21]([NH:20][CH2:17]/[CH:18]=[CH:19]/[C:2]1[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:3]=1)=[O:26]
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: OC1(CCc2cccc(Br)c2)CCCCC1
Product: O=C(NC/C=C/c1cccc(CCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-(3-bromophenethyl)cyclohexanol with N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gives (E)-2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)allyl)acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[N:14]=2)[C:10]([CH3:21])=[CH:9][C:8]=1[CH3:22])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:30][CH2:31][CH2:32][SH:33]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:33][CH2:32][CH2:31][NH2:30])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:10]([CH3:21])=[CH:9][C:8]=1[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCS
Reactant: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cc(SCCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (Compound 1-1) (5.0 g, 15.0 mmol) obtained in Example 1-1 was dissolved in N,N-dimethylformamide (125 ml), and then cesium carbonate (11.5 g, 150.0 mmol) and 2-aminoethanethiol (48.8 g, 150.0 mmol) were added thereto at room temperature. The resulting mixture was stirred at room temperature for three hours, and then diluted with ethyl acetate (500 ml). The solution was sequentially washed with water (500 ml, three times) and a saturated aqueous sodium chloride solution (500 ml). The washed organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate (20 ml) while heating, and n-hexane (60 ml) was added thereto. The mixture was stirred at room temperature for one hour. The precipitated crystals were collected by filtration. After washing with n-hexane (60 ml), the crystals were dried under reduced pressure to yield 5-[2-amino-6-(2-aminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid tert-butyl ester (4.4 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)(C)(C)C.[ClH:16].[CH3:17][O:18][NH2:19].Cl>CO.O1CCOCC1>[ClH:16].[CH3:17][O:18]/[N:19]=[C:9]1/[C@@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][CH2:10]/1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO/N=C1\CCCC[C@@H]1N
Yield: 127 %

Procedure:
To a solution of 2.13 g ((S)-2-oxo-cyclohexyl)-carbamic acid tert-butyl ester in 10 ml methanol was added 0.46 g O-methylhydroxylamine hydrochloride and the mixture was heated to reflux for 18 h. To the resulting yellow solution was added 2.0 ml of a 4M solution of hydrochloric acid in dioxane and the mixture was refluxed for 30 min. The reaction mixture was evaporated and dried under high vacuum. The semisolid residue was triturated under acetonitrile. The solid was collected by filtration and dried to constant weight under high vacuum to yield 1.25 g of the title compound as white crystals. MS (EI): 142 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([N:22]=[C:23]=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:23](=[O:24])[NH:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cc(O)ccc21
Reactant: CCCCCCCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Reaction time: 0.33 h

Procedure:
A solution of 1-methyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.490 g., 3 mmol) in dry dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.072 g., 3 mmol) in dry dimethylformamide (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then heptyl isocyanate (0.58 g., 3 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (37° C.). The reaction mixture was quenched with water (0.2 ml), diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2n; yield: 0.60 g. (65.6%), m.p. 60° C., C18H28N2O2; 1NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.30-1.56 (m, 10H), 1.95-2.05 (m, 2H), 2.68 (t, 2H), 2.86 (s, 3H), 3.15-3.26 (m, 4H), 6.52 (d, 1H), 6.70-6.86 (m, 2H); IR vmax (KBr) (cm−1) 758, 899, 1160, 1226, 1318, 1390, 1503, 1621, 1718, 2861, 2930, 3348, 3759, MS: m/z: 305 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a stirred solution of 3.1 grams (0.011 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in 5 ml of concentrated sulfuric acid was added dropwise 0.9 ml (0.011 mole) of 70% nitric acid. Upon completion of addition the reaction mixture was stirred for two hours at ambient temperature then was poured into ice-water. The mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 2.8 grams of 1-(4-chloro-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 80°-81° C. The reaction was repeated several times.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15](C([O-])=O)=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].Cl>O1CCOCC1.O>[C:18]1([NH:17][C:16]2[C:5]3[CH:4]=[CH:3][C:2](=[O:1])[N:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:6]=3[S:14][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Agent: Cl
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc2c(Nc3ccccc3)csc2n1-c1ccccc1
Temperature: 70 °C
Yield: 53.6 %

Procedure:
To a solution of the compound of Example 14 (200 mg) in 1,4-dioxan (10 mL) was added 2M HCl(aq) (0.5 mL) and the reaction mixture heated at 70° C. for 1 h. The reaction was diluted with water (30 mL), extracted with EtOAc (3×20 mL) and the EtOAc extracts dried (MgSO4) and concentrated in vacuo. The crude residue was purified by chromatography on silica (0-5% EtOAc in DCM) to give the title compound as a white solid (90 mg). δH (DMSO-d6) 8.21 (1H, bs), 7.96 (1H, d, J 9.6 Hz), 7.63-7.47 (3H, m), 7.43-7.36 (2H, m), 7.25-7.11 (2H, m), 7.10-7.03 (2H, m), 6.82-6.71 (1H, m), 6.46 (1H, d, J 9.6 Hz), 6.44 (1H, s). LCMS (ES+) RT 3.54 minutes, 319 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=2)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(N)cc1OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(OC)c(OCc3ccccc3)c2)ccc1OCc1ccccc1
Reaction time: 12 h
Yield: 71 %

Procedure:
N,N-1,3-Diisopropyl carbodiimide (0.40 g, 3.36 mmol) was added to a solution of 1-benzyloxy-2-methoxy-5-aminobenzene (0.771 g, 3.36 mmol), 4-benzyloxy-3-methoxy benzoic acid (0.87 g, 3.36 mmol) and 1-hydroxybenzotriazole (0.454 g, 3.36 mmol) in N,N-dimethylformamide (15 ml) and stirred for 12 hrs. The product was precipitated by diluting with a mixture of ethyl acetate/hexane (1:1) (120 ml). Filtration of the reaction mixture provided 1.12 g of 4-Benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide. Yield 69%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][N:23]=[C:22]([S:31][CH3:32])[N:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:24]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][N:21]=[C:22]([S:31][CH3:32])[N:23]=2)[N:7]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)c(-n2nc(C(C)(C)C)cc2N)c1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1cnc(SC)nc1Nc1cc(C(C)(C)C)nn1-c1cc(C)ccc1C
Temperature: 110 °C
Yield: 41.9 %

Procedure:
To a dried 15 mL tube was added 3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-amine (106 mg, 0.44 mmol), synthesized in the same manner as intermediate F, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (101 mg, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), BINAP (27 mg, 0.044 mmol), and Cs2CO3 (199 mg, 0.61 mmol). The flask was degassed followed by addition of toluene (2 mL), and the mixture was then heated to 110° C. for 20 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 45% to 90% acetonitrile in water to afford 81 mg (42%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.23 (s, 1H), 8.72 (s, 1H), 7.24 (dd, 2H), 7.16 (s, 1H), 6.78 (s, 1H), 4.20 (q, 2H), 2.64 (s, 3H), 2.38 (s, 3H), 2.04 (s, 3H), 1.34 (s, 9H), 1.28 (t, 3H);. ES-MS m/z 440.2 (MH+); HPLC RT (min) 4.66.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].[CH:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>CN(C=O)C>[C:40]1([C:37]2[CH:36]=[CH:35][CH:34]=[CH:39][CH:38]=2)[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:48])[NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=2)[CH2:6][N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[S:8]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[OH:19])(=[O:9])=[O:10])=[CH:44][CH:45]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide (60 mg, 0.12 mmol) in DMF (3 mL) was added 4-biphenyl isocyanate (23.7 mg, 0.12 mmol). The resulting mixture was stirred at rt. for 2 h under nitrogen. The mixture was concentrated and dissolved in MeOH, purified by preparative HPLC. The fractions containing the desired product were combined, concentrated and lyophilized to give white solid (50 mg, 60%).
Reaction SMILES: C(O)CCCCCCCO.COC1C=CC(CBr)=CC=1.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:25][CH:24]=1.COC1C=CC(COCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:39][CH:38]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1ccc(COCCCCCCCCO)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: COc1ccc(CBr)cc1
Agent: COc1ccc(COCCCCCCCC(=O)O)cc1
Agent: Cl
Product: COc1ccc(COCCCCCCCC(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1

Procedure:
The title compound, m/e=407.6 ([M−H]−), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 4-methoxy-benzyl bromide, leading to 8-(4-methoxy-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(4-methoxy-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(4-methoxy-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.83 g), (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.69 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.54 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.65 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 61%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([C:25]1([CH:28]([NH:31][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[C:29]#[N:30])[CH2:27][CH2:26]1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:25]1([C@H:28]([NH:31][C@H:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33])[C:29]#[N:30])[CH2:27][CH2:26]1)[CH3:10]
Reactant: C[C@H](NC(C#N)C1(C=O)CC1)c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl orthoformate (0.2 mL, 1.20 mmol) and p-toluenesulfonate monohydrate (1 mg, 0.0053 mmol) were added to an ethanol (2.5 mL) solution of 2-(1-formylcyclopropyl)-2-{[(1S)-1-phenylethyl]amino}acetonitrile (102 mg, 0.447 mmol). The resulting mixture was stirred at room temperature for 2 hours and 30 minutes and then, at 50° C. for 4 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic layer was washed with water and then, dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography, whereby the title compound was obtained as white crystals (40 mg, 30%, diastereomer ratio=81/19).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23](=[O:28])[CH:24]=[CH:25][CH2:26]Br)[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23](=[O:28])[CH:24]=[CH:25][CH2:26][N:2]([CH3:3])[CH3:1])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 2 h
Yield: 44 %

Procedure:
Twenty five milliliters of 2N dimethylamine in tetrahydrofuran were stirred and cooled in an ice bath, and a solution of 1.16 g (2.5 mmoles) of 4-Bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide in 20 mL of tetrahydrofuran and 10 mL of N,N-dimethylformamide was added dropwise. After stirring for 2 hours, 45 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate were added, and the layers were separated. The organic layer was extracted with 25 mL of brine, dried over sodium sulfate, and taken to an oil in vacuo. This was chromatographed on silica gel with 1:4 methanol methylene chloride to give 475 mg (44%) of the desired product, which melted at 215-217° C. Mass spectrum (m/e) M+2H 213.4, 214.4. M+H 426.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[H][H]>CO.[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(N(C)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 4 h

Procedure:
To a mixture of 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine (0.233 g, 0.751 mmol) in MeOH (10 mL) at RT was added a suspension of 10% palladium on carbon (0.0799 g, 0.751 mmol) in EtOAc (10 mL). The mixture was exposed to an atmosphere of hydrogen (balloon). After 4 h, the mixture was filtered over celite and concentrated in vacuo. The crude yellow foam, N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine, was advanced without further purification. MH+=281.2@1.21 min.