Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:13][C:12]2[S:11][CH2:10][CH2:9][N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)[C:7](=[O:30])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].OO.S([O-])(O)=[O:34].[Na+]>C(O)(=O)C>[C:1]([C:4]1[S:13][C:12]2[S:11](=[O:34])[CH2:10][CH2:9][N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:29]=4)[CH2:22][CH2:23]3)[C:7](=[O:30])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc2c(s1)SCCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)S(=O)CCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.0 g of 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno[3,2-f]-1,4-thiazepin-5(4H)-one in 20 ml of acetic acid was added to 1.0 g of 30% hydrogen peroxide and the mixture was stirred for 20 hours at room temperature. Then, the mixture was poured into ca. 3% aqueous sodium hydrogen sulfite solution and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crude crystals were recrystallized from ethanol to give 1.5 g of 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno[3,2-f]-1,4-thiazepin-5(4H)-one 1-oxide as white crystals, melting at 103°-106° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:1][N:2]([C:44](=[O:45])[C:43]1[CH:47]=[C:39]([CH2:38][C:32]2[C:33](=[O:37])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[C:30](=[O:53])[C:31]=2[CH3:52])[CH:40]=[CH:41][C:42]=1[O:48][C:49](=[O:51])[CH3:50])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CNc1ccc(OC)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
N-Methyl-4-methoxyaniline (0.220 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.142 g, 0.288 mmol, 54%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][NH:9][CH3:10].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19](Cl)=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][N:9]([CH3:10])[C:19](=[O:20])[O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC1COCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC1COCCO1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (4.83 g, 29 mmol) was dissolved in 100 mL dichloromethane. Benzyl chloridocarbonate (4.9 mL, 35 mmol) and triethylamine (10 mL, 72 mmol) were added. The solution was stirred at ambient temperature. After 12 hours, the solution was concentrated, then diluted with ethyl acetate, and washed with saturated sodium bicarbonate and water. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by silica chromatography (0-100% ethyl acetate/hexanes gradient) to afford the title compound (racemic mixture).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:13]([N:16]([CH:19]([CH3:21])C)CC)([CH3:15])C.N1CCCC1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:16]2[CH2:13][CH2:15][CH2:21][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (0.83 g, 2.73 mmol) in tetrahydrofuran (10 mL) under argon was added diisopropylethylamine (0.525 mL, 3.00 mmol) followed by pyrrolidine (0.183 mL, 2.73 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between diethyl ether and aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was triturated with diethyl ether/heptane at −20° C. to provide the title compound (0.56 g, 67% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:2]1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl (2-(1H-indol-3-yl)ethyl)carbamate (4.70 g, 18.01 mmol) in anhydrous THF (50 mL) was added sodium hydride (800 mg, 20 mmol, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at room temperature for 15 min, iodomethane (2.84 g, 20 mmol) in THF (15 mL) was added slowly at 0° C. The resulting mixture was stirred at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (0.6% MeOH in DCM) to afford the title compound (4 g, 14.6 mmol, 80% yield) as a brown solid. MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CC=CCN
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(SC)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 32, 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-(methylthio)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21](OC(C)(C)C)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH2:38][NH:39][CH3:40].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21]([N:39]([CH3:40])[CH2:38][C:30]3[N:29]([CH3:28])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](Cc2ccccc2)C1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](Cc1ccccc1)N2
Yield: 99 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-benzyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.1 mmole), 1-methyl-2-(methylaminomethyl)indole (0.34 g, 2.1 mmole), Et3N (0.59 mL, 4.2 mmole), HOBt H2O (0.28 g, 2.1 mmole), and EDC.HCl (0.41 g, 2.1 mmole), the title compound (0.97 g, 100%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 80-90% EtOAc/hexanes): MS (ES) m/e 467.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]=[CH:9]1.OO.[OH-].[Na+].[O:18](C1CC(=O)C(SCCCCCCCC)=C1)[Si](C(C)(C)C)(C)C>CO>[O:13]1[CH:12]2[CH:11]1[C:10](=[O:18])[CH2:9][CH:8]2[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: CCCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: O=C1C=CC(OC2CCCCO2)C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(OC2CCCCO2)C2OC12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
One gram of 4-(2-tetrahydropyranyloxy)cyclopent-2-en-1-one was dissolved in 20 ml of methanol, and 10 ml of 30% hydrogen peroxide was added at room temperature. Then, with ice cooling, 3 ml of a 2 N aqueous solution of sodium hydroxide was added slowly. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was post-treated in the same way as in Example 1, (1). The resulting crude product was chromatographed on a thin layer plate with cyclohexane/ethyl acetate (=7/3) to afford 730 mg of 2,3-epoxy-4-(2-tetrahydropyranyloxy)cyclopentan-1-one in a yield of 84%. The product had the following spectral data.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH2:22]([O:29]CCN)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCOCc1ccccc1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(NCCOCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 2-(benzyloxy)ethanamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.24 (1H, s) 8.15 (1H, s) 7.99 (1H, d, J=5.47 Hz) 7.76 (1H, d, J=5.27 Hz) 7.44 (1H, d, J=5.47 Hz) 7.16-7.32 (5H, m) 6.78 (1H, d, J=5.27 Hz) 6.41 (1H, d, J=3.32 Hz) 4.44 (2H, s) 3.48-3.56 (2H, m) 3.39-3.47 (2H, m)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:15][Si:16]([CH3:42])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.CCOCC>[CH3:42][Si:16]([CH3:15])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperdine, 2.5 ml. of triethylamine and 0.6 g of 4-(dimethylamino)pyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.1 g. of 4-[14-(trimethylsilyl)tetradecylamino)-benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized to yield the product as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:6][S:7]([O:1][CH2:2][C:3]([CH3:4])=[O:5])(=[O:9])=[O:8]
Reactant: CC(=O)CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)COS(C)(=O)=O

Procedure:
Thirty-seven (37) mg of hydroxyacetone was dissolved in 2 ml of chloroform, and to which 0.078 ml of methanesulfonyl chloride was added. After stirring the reaction liquid at room temperature for 30 minutes, saturated aqueous sodium bicarbonate solution was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 1.98 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 1.16 g (6.25 mmol) of tert-butyl 1-piperazinecarboxylate, and 1.29 g (10 mmol) of DIPEA in 100 mL of THF was stirred at room temperature for 1 hr, and the solution was concentrated under vacuum. The residue was diluted with water (100 mL) containing 1 mL of acetic acid. The resulting precipitate was collected, washed with water, and dried to give 2.71 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (MeOH) 221-223° C.; 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 54.9; H, 5.9; N, 20.5%.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](O)=[O:21])=[CH:12]1>>[CH2:4]1[C:3]2([CH2:2][NH:1][C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:11][CH:12]=3)=[O:21])[N:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NCC12CCCN1CCC2
Product: O=C(NCC12CCCN1CCC2)c1c[nH]c2ccccc12

Procedure:
Following the procedure of example 1, 7a-Aminomethylhexahydro-1H-pyrrolizine is reacted with indole-3-carboxylic acid to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:11]=[N:10][N:9]=1
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.50 g of 5-(2-bromophenyl)-1H-tetrazole in 20 ml of CH2Cl2 is added 0.65 g of triphenylmethyl chloride followed by 0.37 ml of triethylamine. The solution is refluxed for 2.5 hours, cooled to room temperature and then washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography eluting with ethyl acetate/hexanes (1:5) to provide the desired product.
Reaction SMILES: Cl.NCCS.C(N(CC)CC)C.[C:13]([NH:20][C@H:21]([CH:23]=[O:24])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C)C=O>[C:13]([NH:20][C@H:21]([CH2:23][OH:24])[CH3:22])([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: NCCS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
6.82 g (60 mmoles) of cysteamine hydrochloride is dissolved in 50 ml of dimethylformamide, and the solution is neutralized with 8.4 ml of triethylamine. The solution is mixed with a solution of crude Boc-L-alaninal obtained by oxidizing 8.75 g (50 mmoles) of Boc-alaninol in 50 ml of dimethylformamide, and mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, the formed crystals are dissolved in ethyl acetate, the solution is washed with 10% citric acid and saturated aqueous sodium bicarbonate, and the ethyl acetate layer is dried. The solvent is distilled off under reduced pressure to obtain 4.93 g (42.6%) of the desired compound 9-A as white crystals. Melting point 81.0°-84.1° C. MS 232 (M+), 159 1H-NMR (CDCl3, δ) 1.24(3 H, d, J=6.6 Hz), 1.45(9 H, s), 2.1(1 H, br), 4.42(1 H, d, J=8.1 Hz)
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]([CH3:22])[N:15]([C:23](=[O:25])[CH3:24])[CH2:14][CH2:13][C:12]2=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1>[C:23]([N:15]1[CH2:14][CH2:13][C:12]2[C:11]3[C:19](=[CH:20][CH:21]=[C:9]([O:8][CH3:7])[CH:10]=3)[N:18]([C:26](=[O:28])[CH3:27])[C:17]=2[CH:16]1[CH3:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c1c(n2C(C)=O)C(C)N(C(C)=O)CC1
Yield: 22 %

Procedure:
N,N-Diethylaminopyridine (530 mg) and pyridine (1.1 mL) are added to a solution of 1-(6-methoxy-1 -methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1-ethanone (933 mg) in toluene (100 mL) and acetic anhydride (6 mL). The mixture is refluxed for 48 h. After evaporation of the toluene, the crude product is taken up in water and then extracted with dichloromethane and, after separation on silica gel (chloroform/methanol eluent), the 1-(2-acetyl-6-methoxy-1-methyl-2,3,4,9-tetrahydro-1 H-β-carbolin-9-yl) 1 -ethanone is obtained (22% yield).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[BrH:15].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:15][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH:1]1[CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Br
Reactant: CCOC(=O)C(=NOC1CC1)C(C)=O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CC1)C(=O)CBr
Temperature: 0 °C

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(358 mg) and pyridinium hydrobromide perbromide (633 mg) in acetic acid (2 ml) was heated at 50° C. for 30 minutes. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-bromo-2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(470 mg). To a solution of the compound obtained above in N,N-dimethylacetamide (2.2 ml) was added thiourea (126 mg) at ambient temperature. The mixture was stirred at the same temperature for an hour. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(177 mg) as a crystal.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[NH2:26][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 112.6 %

Procedure:
To 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (313 mg, 0.753 mmol) was added ammonium hydroxide (2 mL, 51.4 mmol) and 1,4-Dioxane (1 mL) to a 5 mL microwave vial and heated in microwave for 20 min. at 100° C. After total of 35 minutes the reaction was completed. The reaction was concentrated to give 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (336 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.60 (s, 1H), 4.71 (tt, J=5.40, 10.64 Hz, 1H), 4.08 (br. s., 2H), 2.91 (br. s., 2H), 1.81-1.94 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=154-158° C.). The reaction was monitored by tlc (Rf=0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 50-100% EtOAc/hexanes as the eluent.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14]Cl.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].CN(C=O)C>O>[C:16]([O:19][CH2:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=c1c(Br)c(CCl)nc2ccc(F)cn12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2ccc(F)cn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (10.60 g, 36.36 mmol), potassium acetate (4.283 g, 43.64 mmol), and DMF (138.5 mL) was stirred at 40° C. After 3 h, the mixture was concd under reduced pressure. To the residue was added water (200 mL) and the resulting precipitate was collected by filtration, washed with water (300 mL), and dried to give (3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (1H, dd, J=4.9, 2.7 Hz), 8.18 (1 H, ddd, J=9.8, 7.1, 2.8 Hz), 7.86 (1 H, dd, J=9.7, 5.4 Hz), 5.21 (2 H, s), 2.16 (3 H, s); Mass Spectrum (ESI) m/e=315.0 [M+1 (79Br)] and 316.9 [M+1 (81Br)].