Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:38])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:29]3[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:16]=1.C([O-])(O)=O.[Na+]>CCO.Cl>[NH:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[O:14][CH2:13][CH:12]([OH:38])[CH2:11][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[C:29]=2[N:28]=[CH:27]1
Reactant: C[Si](C)(C)CCOCn1cnc2c(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(COc1cccc(-c2cccc3[nH]cnc23)c1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)phenoxy)propan-2-ol (265 mg, 0.5 mmol) in EtOH (20 mL) and conc. HCl (1 mL) was stirred at 80° C. overnight. The reaction was adjusted to pH 9 by aq. NaHCO3. The mixture was then extracted with DCM and the combined organic layers dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by pre-HPLC to afford the desired product (50 mg, Yield 25%). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.35 (s, 2H), 7.65 (br.s, 2H), 7.49 (m, 1H), 7.21 (dd, J=7.6 Hz, 1H), 7.12-7.06 (m, 5H), 4.53-4.39 (m, 3H), 4.14 (s, 2H), 2.83-2.57 (m, 6H). LCMS (m/z): 400.1 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:31])[C@H:20]([N:28]=[C:29]=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1>[CH3:17][O:18][C:19](=[O:31])[C@H:20]([NH:28][C:29]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[O:30])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1ccc(COc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc(COc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
4-Phenoxymethylphenylmethanol 4 (0.857 g, 4.0 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.026 g, 5.0 mmol) and 4-dimethylaminopyridine (DMAP) (10 mg) were combined, heated until molten, and stirred for 20 min. Upon cooling, the residue was purified by chromatography to give about 1.6 g of (R)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid methyl ester 6.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:8]([NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]O>S(=O)(=O)(O)O.O>[CH3:26][O:15][C:14](=[O:16])[CH2:13][NH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
A solution of {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid (30 mg, 0.08 mmol) in methanol (5 mL) was treated with concentrated sulfuric acid (4 drops). The reaction was heated to 80° C. for 8 h. At this time, the reaction was cooled to 25° C. and diluted with water (10 mL). This solution was extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL) and water (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid methyl ester (21 mg, 68%) as a white solid:mp 134.5-136.6° C.; EI-HRMS m/e calcd for C18H22Cl2N2O4 (M+) 400.0957, found 400.0970.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)O
Yield: 99.7 %

Procedure:
To a solution of 3.2 g (12.1 mmol) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate in 50 ml of methanol, 1.01 g (24.2 mmol) of sodium hydroxide and 10 ml of water were added and the mixture was heated under reflux for 24 hours. After distilling the solvent off under reduced pressure and adding 50 ml of water, the mixture was washed with 50 ml of diethylether. The aqueous layer was made acidic by adding a concentrated hydrochloric acid, and then the mixture was extracted three times with 50 ml of diethylether. After washing with water and with a saturated aqueous sodium chloride, the organic layer was dried over with anhydrous magnesium sulfate and the solvent was distilled off to obtain 3.02 g (yeld:100%) of 2-benzyloxyimino-3-methoxyiminobutyric acid as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].S(OC)(O[CH3:17])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. 1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hours. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hours. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford 1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%). 1H NMR (300 MHz, CDCl3) δ 7.23-7.31 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 3.52 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
To a solution of 100 mg (0.345 mmol) of (2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate in tetrahydrofuran (3 mL) was added water (3 mL), followed by cooling to 0° C., and 15.2 mg (0.362 mmol) of lithium hydroxide monohydrate was added, followed by stirring at the same temperature for 15 minutes. The reaction mixture was washed with ethyl acetate, and the aqueous layer was made acidic with saturated aqueous sodium dihydrogen phosphate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and subsequently the solvent was concentrated under reduced pressure to afford 93.1 mg of the title compound as a colorless foamy solid (yield 98%). Instrumental data were consistent with those of Example 9.
Reaction SMILES: [K].[C:2]([NH:6][S:7]([C:10]1[CH:18]=[C:17]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[CH2:25][CH3:26]>C(#N)C.C(OCC)(=O)C>[C:2]([NH:6][S:7]([C:10]1[CH:18]=[C:17]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH2:25][CH3:26])=[O:13])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)c(S(=O)(=O)NC(C)(C)C)c1
Reactant: CCBr
Agent: [K]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(=O)N(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
A suspension of 3.0 g (8.2 mmol) of the potassium salt of 2-tert-butylsulfamoyl-4-dimethylcarbamoylbenzoic acid, and 0.21 g (0.79 mmol) of 1,4,7,10,13,16-hexaoxacyclooctane in 25 ml of acetonitrile was stirred at room temperature for half an hour, and 890 mg (8.2 mmol) of bromoethane were then added. The mixture was subsequently heated under reflux for 6 h and then allowed to cool to room temperature. For work-up, the reaction mixture was diluted with ethyl acetate and extracted with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate, filtered off and concentrated. This gave 2.31 g (79% of theory) of ethyl 2-tert-butylsulfamoyl-4-dimethylcarbamoylbenzoate as a colorless solid of m.p. 101 to 102.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O.[H][H]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccccc2Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccccc2Cl)cc1
Yield: 70 %

Procedure:
18.6 gm of 4-(2'-chloro-4-biphenylyl)-4-hydroxybutyric acid (obtained by acidifying 20 gm of its sodium salt and extraction with ethyl acetate) were hydrogenated in 200 ml of glacial acetic acid in the presence of 2 ml of perchloric acid and in the presence of palladium/barium sulfate (5%) at room temperature and at a hydrogen pressure of 5 atmospheres. After filtration, the solvent was evaporated and the residue admixed with water; the crystalline acid was collected and dried. Yield: 70% of theory; m.p. 60°-61° C. (from petroleum ether). Melting point of the cyclohexylamine salt: 143°-144° C. (from water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)=O)=[C:4]([NH:16][CH3:17])[CH:3]=1.CC(O)=O>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)[N:16]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a stirred solution of N-(4-bromo-2-(methylamino)phenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH3CN (20 ml) was added glacial AcOH (2 ml) at room temperature, and then mixture was heated at reflux for 3 h. The mixture was then cooled to room temperature, concentrated in vacuo, and poured into ice-cold saturated NaHCO3 (100 ml). The mixture was extracted with EtOAc, and the extract was washed with water (100 ml) and brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.0 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])=[C:4]([CH3:22])[CH:3]=1.[NH2:23][C:24]([NH2:26])=[O:25].Cl.O1CCOCC1>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:26][C:24](=[O:25])[N:23]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[C:14]4[CH3:20])[CH:9]=2)=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1cc(N)ccc1C(=O)/C=C/c1ccc2[nH]nc(C)c2c1
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 110 °C

Procedure:
To a solution of (E)-1-(4-amino-2-methylphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (0.480 g, 1.64 mmol) in EtOH (5 mL) were added urea (0.900 g, 15 mmol) and 4N HCl/dioxane (5 mL, 20 mmol). The reaction mixture was heated to 110° C. for 17 hours, cooled down and concentrated in vacuo. The product was purified by SiO2 flash chromatography (ethyl acetate to 60:40 ethyl acetate/methanol) and preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate), followed by concentration in vacuo and lyophilization to afford the title compound as an acetate salt (58 mg, 11%). 1H NMR (400 MHz, d6-DMSO): δ 8.6 (s, 1H), 8.15 (d, 1H), 7.54 (d, 1H), 7.20 (d, 1H), 7.01 (s, 1H), 6.49 (m, 2H), 5.56 (s, 2H), 2.54 (s, 3H), 2.3 (s, 3H), 1.89 (s, 1H); MS (EI) for C19H17N5O: 332.3 (MH±).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][OH:33])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:49](Br)[CH:50]=[CH2:51]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][O:33][CH2:51][CH:50]=[CH2:49])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5ccccc5CO)nn4)nn23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1ccccc1-c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.052 g, 0.082 mmol) in DMF (3 mL) was added 60% NaH (8.23 mg, 0.206 mmol) at 0° C. After 10 min allyl bromide (0.071 ml, 0.823 mmol) was added at once and stirred for 30 min at 0° C. and 1 h at rt. Then, quenched with EtOH, diluted with ether (50 mL), washed with water (3×5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as yellow paste which was used in the next step without purification. LCMS (M+H)=672.7.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:37][C:38]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[C:9]([NH:11][C@H:12]([C:19]([NH:21][C@H:22]([C@H:30]1[O:34][C:33](=[O:35])[C@H:32]([CH3:36])[CH2:31]1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH2:47]>CO>[CH2:1]([C@H:8]([CH2:37][C:38]([N:40]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1)=[O:39])[C:9]([NH:11][C@H:12]([C:19]([NH:21][C@@H:22]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[C@@H:30]([OH:34])[CH2:31][C@@H:32]([CH3:36])[C:33]([NH:47][CH3:46])=[O:35])=[O:20])[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)[C@@H](CC(=O)N2CCOCC2)Cc2ccccc2)OC1=O
Solvent: CO
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.313 mmole) of (3R, 5S)-5-[(1S)-1{N-[2(R)-benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-alanyl}amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H) -one [prepared as described in Preparation 21(a) above] in 2 ml of methanol was added, whilst ice-cooling, to 2.5 ml of a 40% by volume methanolic solution of methylamine, and the mixture was allowed to stand at room temperature for 1 hour. At the end of this time, any excess of the methylamine and the methanol were removed by distillation under reduced pressure. The resulting residue was dissolved in 4 ml of ethyl acetate, and the solution was allowed to stand overnight at room temperature to deposit crystals. These were collected by filtration to afford 150 mg of the title compound as white crystals, melting at 130°-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 8.09 mmol) in CH2Cl2 (75 mL) was added TFA (50 mL). The reaction was complete after 45 minutes After evaporating the solvents in vacuo, the crude material was diluted with CH2Cl2 and neutralized by adding a 1 N aqueous NaOH solution. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol as a solid (2.09 g, 84%). LC/MS: m/z 321.3 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Cl:14][C:9]1[CH:8]=[C:7]([CH2:6][C@@H:5]([NH:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([I:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(3,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.06 min. MS (ESI−): mass calcd. for C24H17Cl2IN4O5S, 669.93; m/z found, 669/671 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.85 (s, 1H), 9.00,(d, J=1.8, 1H), 8.92 (d, J=1.7, 1H), 8.54 (dd, J=7.4, 1.2, 1H), 8.33-8.31 (m, 1H), 8.07 (d, J=1.5, 1H), 7.91-7.87 (m, 1H), 7.47-7.22 (m, 3H), 6.98 (dd, J=8.2, 2.0, 1H), 6.87 (d, J=8.3, 1H), 6.37 (d, J=7.7, 1H), 4.92-4.88 (m, 1H), 3.23 (dd, J=14.2, 5.9, 1H), 3.14 (dd, J=14.1, 6.1, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
NaBH4 (1.18 g, 31.1 mmol) was added carefully in portions (exothermic) to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (3.54 g, 8.9mmol), NiCL2.6H2O (1.06 g, 4.4 mmol), MeOH (100 mL) and THF (50 mL) at 0° C. The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was concentrated onto silica gel and flash chromatography afforded 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (2.93 g, 90%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.46 (m, 2H), 6.27 (dd, J=8.5, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.44-3.38 (m, 2H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.61-2.54 (m, 6H complicated by DMSO peak), 2.35-2.26 (m, 1H), 1.80-1.77 (m, 2H), 1.56-1.46 (m, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:29][C:30]#[N:31])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:59])(=O)=O)CCCCCCCCCCCCCCC>>[C:30]([CH2:29][CH:10]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:59])(=[O:7])=[O:6])#[N:31]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCCl
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCI

Procedure:
1-(3-Chloropropylsulfonylamino)-2-cyanomethyl-3-hexadecyloxypropane IIIn1 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](Br)[CH3:18])=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)c1ccc(C(=O)c2cccs2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C

Procedure:
A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 10 parts of α-bromo-α-methyl-p-tolyl 2-thienyl ketone and stirring at 60° C is continued for 4h.30. The reaction mixture is poured onto water and the products ae extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>C(O)C>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[CH2:2]1
Reactant: Nc1ccccc1S
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cc(C2=Nc3ccccc3SC2)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.51 g of 2-aminothiophenol and 50 ml of ethanol is heated to boiling under reflux for 1 hour. The reaction mixture is then cooled to room temperature, whereupon the crystals are removed by filtration under suction. There is obtained 5-(2H-1,4-benzothiazin-3-yl)-3-nitropyrocatechol of m.p. 302°-304° (from N,N-dimethylformamide/methanol).