Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CCNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 87.4 %

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (10 g), β-alanine methyl ester monohydrochloride (5.99 g), acetic acid (4 mL) and sodium triacetoxyborohydride (10.9 g) in dichloroethane (400 mL) was stirred overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (12.0 g, 87%) as a colorless oil.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12]>C(O)C>[C:1]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])(=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)C(C)O
Solvent: CCO
Product: CC(O)C(=O)NC(C)(C)CO
Temperature: 112.5 °C

Procedure:
15 g of ethyl lactate and 10 g of 2-amino-2-methyl-1-propanol were mixed and subsequently heated to 110-115° C. for 3.5 hours. During the reaction, the ethanol formed was distilled off. After the reaction, the excess of ethyl lactate was removed by vacuum distillation (bottom temperature: 160° C., 7 mbar), using a vigreux column. 15.5 g of residual brown viscous liquid was collected, which was confirmed to be pure N-lactoyl 2-amino-2-methylpropanol by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:10]([OH:20])=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[CH3:27][O-].C[O-].[Mg+2].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[C:10](=[O:20])[N:11]([CH3:27])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:22]
Reactant: C[O-]
Reactant: COC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (18.00 g, 47 mmol) in DMF (200 mL) was added magnesium methylate (96.08 mL, 95 mmol), and the reaction was warmed for 1 hour and cooled. The reaction was treated with iodomethane (17.66 mL, 283 mmol) and stirred at 45° C. overnight. At this time, LCMS showed the reaction incomplete, and an additional equivalent of iodomethane (2.95 mL, 48 mmol) was added. The reaction was again stirred for 4 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between chloroform and 1N HCl. The aqueous layer was washed twice more with chloroform. The organic fractions were extracted with 10% sodium bisulfite, and the bisulfite layer was washed twice with chloroform. The combined organic layers were washed with 5% aqueous HCl and brine, dried over sodium sulfate and concentrated in vacuo to afford the product as a black oil. This material appears quite clean by NMR and HPLC, but is highly colored.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:23]([O:28][CH2:29][CH3:30])(=[O:27])[C:24]#[C:25][CH3:26].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:25]([CH2:24][C:23]([O:28][CH2:29][CH3:30])=[O:27])[CH2:26][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Yield: 50 %

Procedure:
A solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl but-2-ynoate (0.40 mL) and tributylphosphine (0.40 mL) in a mixed solvent of tetrahydrofuran (16 mL)-toluene (8 mL) was stirred at 50° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-1:1) to give the title compound (0.33 g, yield: 50%) as a pale-yellow oil. A part of the oil was crystallized from ethyl acetate-hexane to give pale-yellow crystals. MS: 464 (MH+). melting point 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCCCN
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCNC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d (500 mg, 1.23 mmol) was suspended in THF/methanol (10 ml/20 ml), N-hexylamine (149 mg, 1.48 mmol) and Cyanoborohydride-IRA400 (1.0 g, 3.0 mmol) were added and the reaction mixture was stirred at 50° C. overnight. Excess amine was scavenged with Ameba-PS (415 mg, 0.50 mmol) by shaking for 2 h. The resins were filtered off, solvent removed in vacuo and the obtained residue purified by column chromatography on silica gel using a step gradient of 2.5% methanol in DCM and 5% methanol in DCM. Fractions with Rf=0.28 (5% methanol in DCM, ) were collected and evaporated to dryness (Note: Up to 1% conc. NH3 (13.5 M) may be added during the chromatography to reduce loss of material). The residue was dissolved in DCM (10 ml) and 1 NHCl in ether (3 ml) added. After aging at room temp for 1 h the precipitate was filtered off and dried in vacuo. The hydrochloric salt of sulfonamide 4-chloro-N-(4-{[4-(hexylamino)-1-piperidinyl]sulfonyl}benzyl)benzamide 7 was isolated as off-white powder (260 mg, 36%) in >95% purity. M/Z APCI 492.0 (M+1), 490.2 (M−1). 1H-NMR (DMSO-d6) (HCl salt) δ 9.39 (t, 1H, H-N5, 3J=5.92 Hz), 8.97 (m, br, 2H, H-N16), 7.99 (d, 2H, 3J=8.65 Hz, H-C2,3), 7.75 (d, 2H, 3J=8.20 Hz, H-C8,9), 7.61 (m, 4H, H-C1,4,7,10), 4.61 (d, 2H, 3J=5.92 Hz, H-C6), 3.73* (d, 2H, 2J=11.84 Hz, Heq-C11,15), 3.07 (m, br, 1H, H-C13), 2.83 (m, br, 2H, H-C17), 2.29* (m, 2H, Hax-C12,14), 2.10* (d, br, 2H, 2J=11.90 Hz, Hax-C11,15), 1.71-1.54* (m, 4H, Heq-C12,14 and H-C18), 1.36-1.23 (m, 6H, H-C19,20,21), 0.89 (t, 3H, 3J=6.60 Hz, H-C22)
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[Li]CCCC>C1COCC1>[CH2:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:3]#[CH:2]
Reactant: COc1ccc(CC=C(Br)Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To a stirred solution of Compound 75 (478 mg, 1.56 mmol) in THF (6 ml) was added n-BuLi (1.94 ml, 3.28 mmol), at -78° C. under N2, then warmed up to 0° C., and stirred for 5 h. The mixture was quenched by the addition of NH4Cl aq., and extracted with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 76 (213 mg, 94%) as a colorless oil.
Reaction SMILES: [C:1]([O:7][CH2:8]N1C2N=CN=C(C3C=NN(C(C4CCCC4)CC(N)=O)C=3)C=2C=C1)(=O)C(C)(C)C.CC([O-])(C)C.[K+].[NH2:39][C:40]1[C:45]([CH:46]=O)=[C:44]([Cl:48])[N:43]=[CH:42][N:41]=1>C1COCC1>[Cl:48][C:44]1[N:43]=[CH:42][N:41]=[C:40]([NH2:39])[C:45]=1[CH:46]=[CH:1][O:7][CH3:8]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Reactant: Nc1ncnc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(N)ncnc1Cl
Temperature: -2 °C
Reaction time: 1 h

Procedure:
A suspension of (methoxymethyl)triphenyl-phosphonium chloride (11, 276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to −2° C. and 1M KOtBu in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 hr at −2 to −3° C. The deep red-orange mixture was stirred for 1 hr at −2 to −3° C. 4-Amino-6-chloropyrimidine-5-carbaldehyde (10, 115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from −3 to 13° C. and a brown color developed. When the reaction temperature dropped to 10° C., the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred 42 hr. The reaction mixture was cooled to −2° C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2N HCl (4×250 mL) followed by 3N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 hr. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 hr to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12, 72.3 g, 136.2 g theoretical, 53.1%). The crude 12 was used in the following reaction without further purification. A sample of crude 12 (2.3 g) was purified by chromatography on silica gel, eluting with 0-35% EtOAc/heptane to give 1.7 g of pure 12 as a white solid, which is a 1:2 mixture of E/Z isomers. For 12: 1H NMR (DMSO-d6, 300 MHz) for E-isomer: δ ppm 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) and for Z-isomer: δ ppm 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H); C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[N:10]([C:12]([CH3:15])=[N:13][N:14]=2)[N:11]=1.[CH3:19]O>>[Cl:5][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[N:10]([C:12]([CH3:15])=[N:13][N:14]=2)[N:11]=1
Reactant: Cc1nnc2c(C(=O)O)cc(Cl)nn12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)nn2c(C)nnc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
Thionyl chloride (2.0 mL) was added to a solution of product 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (4.0 g, 18.5 mmol) in MeOH dropwise under cooled ice-bath. The resulting mixture was stirred at 80° C. for 16 hours and then cooled to room temperature and concentrated in vacuum. The crude product was purified by flash column chromatography (silica-gel, PE: EA=3:1) to give product methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow solid (3.0 g, 71.8%). 1H NMR (300 MHz, CD3OD) δ: 7.92 (s, 1H), 4.07 (s, 3H), 2.79 (s, 3H). LRMS (M+H+) m/z: calcd 227; found 227.
Reaction SMILES: [CH2:1]([C:3]1[S:23][C:6]2[NH:7][C:8](=[O:22])[N:9]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[N:42]=[C:41](C(Cl)(Cl)Cl)[O:40][N:39]=2)=[CH:28][CH:27]=1.C(=O)([O-])[O-:48].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:23][C:6]2[N:7]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:42][C:41](=[O:48])[O:40][N:39]=4)=[CH:28][CH:27]=3)[C:8](=[O:22])[N:9]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(-c3cnc4ccccc4c3)c(=O)[nH]c2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(-c3cnc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A mixture of 6-ethyl-3-quinolin-3-ylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.6 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.8 g), potassium carbonate (0.6 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 35%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].C(N(C(C)C)CC)(C)C.[Br:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][CH:10]=1)[O:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[CH2:23][Br:22])#[N:9]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: O=C(Cl)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCNC(=O)CBr)c1
Reaction time: 8 h

Procedure:
1.50 g (9.26 mmol) of 3-(2-aminoethoxy)benzonitrile and 1.77 ml (10.2 mmol) of diisopropylethylamine were dissolved in 15 ml of tetrahydrofuran. A solution of 0.92 ml (11.1 mmol) of bromoacetyl chloride in 5 ml of tetrahydrofuran was added to the obtained solution at 0° C., and they were stirred for 8 hours. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22](=[O:23])[NH:21][C:12]3[N:13]=[C:14](S(C)=O)[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][NH2:25]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22](=[O:23])[NH:21][C:12]3[N:13]=[C:14]([NH:25][CH3:24])[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3c(C)nc(S(C)=O)nc3[nH]c2=O)cn1
Reactant: CN
Solvent: C1COCCO1
Product: CNc1nc(C)c2cc(-c3ccc(OC)nc3)c(=O)[nH]c2n1
Temperature: 110 °C
Yield: 60.5 %

Procedure:
To a solution of 6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (147 mg, 0.445 mmol) in 1,4-dioxane (2.5 mL) was added methylamine (1.1 mL, 2.0 M in THF, 2.2 mmol). The mixture was sealed and heated at 110° C. microwave for 10 min. The mixture was concentrated under reduced pressure to give a solid. The crude solid was washed with water and EtOAc, recrystallized from DMSO/EtOAc to give the title compound (80 mg, 61%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8](#[N:12])[CH2:9][C:10]#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH:9]([C:8]#[N:12])[C:10]#[N:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CCC#N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C#N)C#N

Procedure:
Pivaloyl chloride (60 g) and malononitrile (33 g) were dissolved in methylene chloride (500 ml) and were placed in a flask equipped with a stirrer and a dropping funnel. Triethylamine (100 g) was added slowly with cooling over a period of 45 minutes. The triethylamine hydrochloride was removed and the filtrate was concentrated to about half volume. The solution was poured onto ice, acidified strongly with concentrated hydrochloric acid and the resulting product was filtered off and air dried.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:10][CH2:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1.O.N>C(Cl)Cl>[CH3:2][S:3]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:12][CH2:13]1)=[O:42]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of 480 mg (1 mmol) of 3-[1-(3-methylthiobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro -2(1H)-quinazolinone HCl salt in 10 mL of methylene chloride was added 190 mg (1.1 mmol) of m-chloroperbenzoic acid at temperature of 0° C. to 10° C. The mixture was stirred for 10 hours at ambient temperature, mixed with water, adjusted to pH 10 with a aqueous ammonia and then extracted with chloroform. The organic layer separated was washed with brine, dried on sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 440 mg (0.96 mmol) of the title compound as an about 1:1 mixture of the diastereomers.
Reaction SMILES: [C:1]([O-])(=[O:4])[CH2:2]C.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=NN=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OC(=O)C)(=O)C>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([C:30]2[O:4][C:1]([CH3:2])=[N:33][N:34]=2)([N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:17][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Reactant: CCC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(C)o2)CCN(Cc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 100 ml r.b. flask was charged with 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (6.04 g, 13 mmol) and acetic anhydride (50 ml). The resulting mixture was stirred at 110° C. for 2 hours and concentrated in vacuo. The crude was dissolved in CH2Cl2 (100 ml), washed with 5% Na2CO3 (100 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, EtOAc/Hex 1:1) to give the product (4.20 g, 10.4 mmol) as a viscous oil: NMR (60 MHz, CDCl3) δ 0.90 (t, 3H, CH3CH2CO), 2.61 (s, 3H, oxadiazolyl CH3), 3.46 (s, 2H, benzyl CH2), 7.33 and 7.52 (2bs, 10H, phenyl H's). ##STR28##
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=3)=[N:10][N:9]([C:22](=[O:25])[CH2:23][CH3:24])[CH:8]([CH3:26])[CH2:7][C:6]=2[CH:27]=1.O.NN>CO.ClCCl.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:5]3[CH:4]=[C:3]([Cl:28])[C:2]([Cl:1])=[CH:27][C:6]=3[CH2:7][CH:8]([CH3:26])[N:9]([C:22](=[O:25])[CH2:23][CH3:24])[N:10]=2)=[CH:13][C:14]=1[CH3:21]
Reactant: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
4.2 g (10 mmoles) of (±)-4,5-dihydro-7,8-dichloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepine are dissolved in a mixture of 40 cm3 of methanol and 40 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from acetonitrile. Thus, 1.99 g (56%) of the title compound are obtained in the form of pale yellow solids melting at 106–108° C.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:33]([O:32][C@@H:9]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethyl pivalate (5.6 mg, 0.011 mmol) in THF and methanol (1.5 mL/0.5 mL) was added 2 M NaOH solution (0.5 mL, excess) at 0° C. The mixture was stirred at 50° C. for 3 hours, diluted with water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide the desired product (3.0 mg, 64%). LCMS-ESI+ (m/z): 427.3, 429.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][SH:20].CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][S:20][CH2:19][CH2:18][NH2:17])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(CN2CCCCC2)c1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: NCCSCc1cccc(CN2CCCCC2)c1
Yield: 68.4 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)benzenemethanol (10.8 g) and cysteamine hydrochloride (6.48 g) in concentrated hydrochloric acid (25 ml) was heated at 100° for 3 h. The cooled mixture was added to ether (500 ml) and treated with an excess of sodium carbonate. The organic solution was filtered and distilled to give the title compound as an oil (9.51 g) b.p. 175° (6×10-2 mm). TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.7.