Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: OB(O)c1ccc(F)cc1
Product: COC(=O)c1c(O)c2cc(-c3ccc(F)cc3)ccc2sc1=O

Procedure:
6-(4-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-fluorophenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.515 (s, 1H), 7.765 (d, 1H), 7.586 (m, 2H), 7.427 (d, 1H), 7.381-7.120 (m, 2H), 4.026 (s, 3H).
Reaction SMILES: [CH3:1]N(C)C(=O)C.[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CCCCCC>[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)[CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(NCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N(C)Cc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Under an argon stream, N,N-dimethylacetamide (351 ml, 5.0 v/w) was added to methyl 4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (70.3 g, 0.134 mol) obtained in Example 1(5) and potassium carbonate (73.9 g, 0.535 mol) was carefully added with stirring. After stirring the mixture at room temperature for 20 min., dimethyl sulfate (50.6 ml, 0.535 mol) was added. After stirring at 50° C. for 1 hr., potassium carbonate (18.4 g, 0.134 mol) and dimethyl sulfate (12.7 ml, 0.134 mol) were added and the mixture was stirred at 60° C. for 2 hr. After cooling to room temperature, n-hexane (422 ml, 6.0 v/w) was added, and the mixture was stirred for 1 hr. After ice-cooling, distilled water (562 ml, 8.0 v/w) was added. After stirring at room temperature for 1 hr., the resulting crystals were collected by filtration and washed with methanol (352 ml, 5.0 v/w) in a slurry form. Tetrahydrofuran (180 ml) was added to the obtained orange solid and insoluble materials were filtered off. The filtrate was concentrated to give the title compound (42.1 g, yield 58.3%) as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1
Reactant: CCN(CC)CCNC(=O)c1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Yield: 106.4 %

Procedure:
5.7 g (19.3 mmol) of 4-nitro-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is dissolved in 120 ml of tetrahydrofuran:ethanol 1:1>mixed with 2 g of palladium on carbon (10%×50% water) and hydrogenated for 1 hour at room temperature and normal pressure. After being drawn off on diatomaceous earth and after concentration by evaporation, 5.45 g of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH:27]([NH:30][C:38](=[O:40])[CH3:39])[CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
Stirred 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride (300 mg, 0.582 mmol) in 10 mL THF with triethylamine (0.293 mg, 2.91 mmol). Acetic anhydride (89 mg, 0.873 mmol) was added and the reaction was stirred for 40 minutes. The solution was concentrated down and purified by preperative HPLC to give N-{1-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]-4-piperidyl}acetamide (0.120 g, 46% yield): HPLC Retention time; 6.92 min. (Method B) M+1; 450.4
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]([NH2:11])=O)=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].N1C=CC=CC=1>O1CCOCC1>[CH2:1]([N:3]1[C:7]([CH2:8][C:9]#[N:11])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1CC(N)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCn1nc(C)cc1CC#N
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-acetamide (2.0 g, 11.96 mmol) was dissolved in dioxane (180 ml) followed by the addition of pyridine (1.89 g, 23.9 mmol). The resulting solution was cooled to 0° C. and TFM (2.76 g, 13.16 mmol) was added drop by drop. The suspension was then slowly warmed to rt and stirring was continued in total for 4 h. The volatiles were removed under reduced pressure, the residue was dissolved in DCM (150 ml), washed with water (2×100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. After flash-chromatography (silicagel; DCM/methanol=40/1), 1.58 g (88%) of (2-ethyl-5-methyl-2H-pyrazol-3-yl)-acetonitrile was obtained. LC-MS: tR=0.65 min; [M+H]+=150.18.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CN1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of toluene (10 mL), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (300 mg, 0.64 mmol, 1.00 equiv), 2-methyl-2-(4-methylpiperazin-1-yl)propanal (541.45 mg, 3.18 mmol, 5.00 equiv), and piperidine (108.29 mg, 1.27 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:MeOH (5:1). The crude product (70 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H2O (0.5% TFA)/CH3CN=10% increasing to H2O (0.5% TFA)/CH3CN=40% within 10 min; Detector, UV 254 nm. This resulted in 46.4 mg (12%) of 2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile as a white solid. LC-MS-PH-PBF-003-96-0: (ES, m/z): [M+H]+ 625
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]([C:14]([C:16]2([CH3:31])[CH2:19][CH2:18][N:17]2[C:20](=[O:30])[NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[O:15])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:14]([C:16]2([CH3:31])[CH2:19][CH2:18][N:17]2[C:20](=[O:30])[N:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[CH3:36])=[O:15])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:32][CH:33]=1
Reactant: Cc1cc(C)cc(NC(=O)N2CCC2(C)C(=O)N(CCCC(=O)O)Cc2ccc(Cl)cc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(N(C)C(=O)N2CCC2(C)C(=O)N(CCCC(=O)O)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{(4-chloro-benzyl)-[1-(3,5-dimethyl-phenylcarbamoyl)-2-methyl-azetidine-2-carbonyl]-amino}-butyric acid, compound 200 (1 eq.) in DMF was added NaH (3 eq.). The reaction was stirred for 1 h at 20° C., then MeI (2.5 eq.) was added. The reaction was stirred for 15 h at 20° C. The crude was partitioned between aqueous HCl (0.1N) and EtOAc. The organic layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 4-((4-chloro-benzyl)-{1-[(3,5-dimethyl-phenyl)-methyl-carbamoyl]-2-methyl-azetidine-2-carbonyl}-amino)-butyric acid.
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=2[F:12])[N:3]=1.[I:17]CI.N(OCCC(C)C)=O>C1COCC1.CCOC(C)=O.[Cu]I>[F:12][C:8]1[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([I:17])=[N:3]2
Reactant: ICI
Reactant: COC(=O)c1cc(F)c2cnc(N)nc2c1
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c2cnc(I)nc2c1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
A suspension of methyl 2-amino-5-fluoro-quinazoline-7-carboxylate (4.28 g, 19.3 mmol, 1.00 equiv), CuI (1.81 g, 9.5 mmol, 0.49 equiv) and diiodomethane (7.80 mL, 96.8 mmol, 5.0 equiv) in THF (80 ml) was treated with isoamyl nitrite (7.80 mL, 58.1 mmol, 3.00 equiv) at ambient temperature, and the mixture heated to 60 ° C. After 18 h the reaction was cooled. The mixture was diluted with EtOAc (100 mL), filtered through a Celite® pad, and the dark green filtrate concentrated in vacuo to an oily residue (23.0 g) which was absorbed onto SiO2 and purified by flash chromatography eluting with an EtOAc/heptane gradient (0 to 30% EtOAc) to afford 3.54 g (55%) of methyl 5-fluoro-2-iodoquinazoline-7-carboxylate as a cream-white solid: 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.49 (s, 1H), 7.90 (d, J=9.5 Hz, 1H), 4.02 (s, 3H); LCMS: MH+333.0
Reaction SMILES: ClC(Cl)(Cl)C([NH:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=O>Cl>[NH2:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=CC(CCC(=O)OCC)NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Product: C=CC(N)CCC(=O)O
Yield: 139.4 %

Procedure:
A suspension of ethyl 4-trichloroacetoamido-5-hexenoate (0.3 g, 1 mmol) in 6 N HCl (10 mL) was heated under reflux 6 H. Then the mixture was concentrated in vacuo, diluted with water (10 mL), washed twice with Acoet, and dried in vacuo to give the title product (0.18 g, 100%). NMR, TLC (NH4OH:EtOH, 3:7) are identical with those of an authentic sample of 4-amino-5hexenoic acid.
Reaction SMILES: [C:1]1([N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[C:24](O)(=[O:26])C>>[C:1]1([N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:24]=[O:26])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(N(Cc2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
N,N-diphenylbenzylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL), and hexamethylenetriamine (1.12 g, 7.96 mmol) was added thereto, followed by stirring at 90° C. for 12 hours. The reaction liquid was cooled to room temperature, a 6 mol/L sodium hydroxide aqueous solution and water were added thereto, and then the product was extracted with chloroform. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=20/1→10/1), to obtain 4-(N-phenylbenzylamino)benzaldehyde (742 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH2:34]([O:41][CH2:42]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][CH2:42][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)s1)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (750 mg, 1.54 mmol) in anhydrous DMF (7.5 mL) at ambient temperature was added NaH (37 mg, 1.54 mmol, 60% dispersion in mineral oil). After stirring for 20 minutes a solution of benzyloxymethylchloride (241 mg, 1.54 mmol) in anhydrous DMF (0.75 mL) was added. After 2 h of stirring at room temperature the reaction was quenched with H2O (5 mL) and diluted with EtOAc. The organic layer was separated and washed with H2O (3×10 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and evaporated. The crude material was purified by silica gel chromatography (0 to 10% EtOAc in pet ether) to afford 3-(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea as an off white solid (550 mg, 59%), mp 101-104° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.82 (s, 1H), 7.37-6.99 (m, 5H), 6.65 (d, J=4.0 Hz, 1H), 6.17 (s, 1H), 5.71 (s, 2H), 4.97 (q, J=8.5 Hz, 4H), 4.60 (s, 2H); ESIMS m/z 605 ([M+H]+). Also isolated was a by-product 1,3-bis(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (11) as a pale yellow gum (65 mg); 1H NMR (400 MHz, Aceton) δ 7.29-7.05 (m, 10H), 6.87 (d, J=4.0 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 2H), 5.23 (s, 2H), 4.75 (q, J=8.7 Hz, 4H), 4.69 (s, 2H), 4.52 (s, 2H); ESIMS m/z 618 ([M−PhCH2O]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21]([CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:22][S:23][CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:19][C:20]2[C:21]([CH2:25][N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])=[CH:22][S:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-(4-Bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, and DIPEA in CH3CN gave 2-(4-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-thiophen-3-ylmethyl)-isoindole-1,3-dione as a white foam. Deprotection with H2NNH2H2O using General Procedure E gave the free base as a pale yellow solid. Conversion to the HBr salt gave COMPOUND 396 as a beige solid. 1H NMR (D2O) δ 2.43 (s, 6H), 3.88 (s, 2H), 3.99 (s, 2H), 4.31 (s, 4H), 7.29 (d, 1H, J=3 Hz), 7.48 (d, 1H, J=3 Hz), 7.79 (dd, 2H, J=6.0, 7.8 Hz), 8.31 (d, 2H, J=7.8 Hz), 8.55 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.39, 36.42, 53.37, 54.95, 126.10, 127.73, 128.48, 132.21, 134.97, 137.81, 139.23, 148.51, 150.64; ES-MS m/z 353 (M+H). Anal. Calcd. for C20H24N4S.3.2HBr.5H2O: C, 37.63; H, 4.77; N, 8.78; S, 5.02; Br, 40.05. Found: C, 37.52; H, 4.62; N, 8.68; S, 4.95; Br, 40.21.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=2)[C:8]1=[O:26])[CH3:6])C.[OH-].[Li+]>O.O1CCCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:26])[N:7]([CH:5]([CH3:6])[C:4]([OH:27])=[O:3])[CH2:16][CH2:15]2
Reactant: CCOC(=O)C(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid ethyl ester (0.087 g, 0.234 mmol) (example 2) and lithium hydroxide (0.0062 g, 0.258 mmol) in water and tetrahydrofuran (1:1 v:v, 9 mL) was stirred at room temperature for 2 h. The THF was evaporated and the mixture acidified to pH 3-4 with 0.1N HCl. After extraction with ethyl acetate, drying of the organic layer with MgSO4, filtration and evaporation a white solid was obtained (0.080 g, 99%). MS: m/e=342.1 (M−H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[N:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][CH:16]=1.O>CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[N:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1nc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 73.4 %

Procedure:
463 mg of potassium carbonate and 224 mg of 1-methylpiperazine are added to a solution of 484 mg of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine in 4.45 ml of DMSO. The reaction medium is heated for 1 hour at 105° C. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 460 mg of 1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazine in the form of a yellow solid.
Reaction SMILES: C([CH:3]([C:22]([OH:24])=[O:23])[N:4]([CH2:15][P:16]([S:20][CH3:21])([S:18][CH3:19])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH3:26]COCC>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:20][CH3:21])([S:18][CH3:19])=[S:17])[CH2:3][C:22]([OH:24])=[O:23])[CH3:26]
Reactant: CCC(C(=O)O)N(CP(=S)(SC)SC)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(SC)SC

Procedure:
Ethyl-N-[bis(methylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (5.9 g.) was dissolved in 11 ml. of 35% hydrobromic acid in acetic acid and stirred for one hour. Ether was added to the reaction solution which precipitated ethyl-N-[bis(methylthio)phosphinothioylmethyl]glycine hydrobromide salt as an oily liquid. This oil was washed three more times with additional ether. The material was suspended in benzene and treated with propylene oxide which effected almost complete solution. The solution was then concentrated to an oil at 0.5 torr. The oil thus recovered was chromatographed on 25 g. of silica gel employing diethyl ether as the eluant to yield ethyl-N-[bis(methylthio)phosphinothioylmethyl]glycine (1.46 g.) as an oil, ND25 =1.6002.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:6][C:7](=O)[CH3:8])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:8][C:7]1[S:16][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:6]=1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOc1sc(C)nc1CC(C)C

Procedure:
A one liter three-neck flask equipped with a stirrer, condenser, and heating mantle is charged with 31.4 g (0.156 mole) of N-acetylleucine ethyl ester, 34.7 g (0.156 mole) of phosphorus pentasulfide, and 250 ml of chloroform, and the mixture is heated under reflux for 24 hours while care is taken to exclude moisture. The reaction mixture is then cooled and made basic with 10% aqueous potassium hydroxide.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a solution of ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (90 mg, 0.195 mmol) in DCM (3 ml) at room temperature is added TFA (1 ml, 12.98 mmol). The reaction is stirred at room temperature. The mixture is concentrated to give N-((2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoyl)-methanesulfonamide. Next, this crude is added a half solution of 2-benzyl-2H-tetrazole-5-carbonyl chloride (131 mg, 0.588 mmol) in DCM at 0° C. and is followed by half of TEA (0.109 mL, 0.782 mmol). And then after half hour, the other half reagents are added into the reaction. The reaction is warmed up slowly to room temperature. The reaction is quenched by brine and is extracted with DCM. The combined organic layer i washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 50% ACN—H2O (0.1% NH4OH) over 10 min by X-bridge phenyl column] provides 2-Benzyl-2H-tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. HPLC retention time=1.50 minutes (condition C), MS (M−1)=545.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10](Cl)=[N:11]2.Cl>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[CH:10]=[N:11]2
Reactant: COC(=O)COc1cc(C)cc2nc(Cl)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)COc1cc(C)cc2ncc(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 40 °C
Reaction time: 17 h

Procedure:
A mixture of [2-chloro-3-(4-chlorobenzyl)-4,7-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), palladium (10 wt. % on activated carbon, 0.020 g), ethanol (7.0 mL) and 1.0 M aqueous hydrochloric acid (1.5 mL) was stirred at 40° C. for 17 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washed with ethanol and the filtrate concentrated under reduced pressure to afford title compound, 0.18 g.