Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:25])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[CH3:15]>C(O)C>[CH3:25][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24]
Reactant: CC(C)(N)CCc1ccccc1O
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC(C)(CCc1ccccc1O)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 156 mg (1.46 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 170 ml of 2-amino-2-methyl-4-(2-hydroxyphenyl)butane in 15 ml of absolute ethanol is heated at reflux for 6 hours. The reaction mixture is concentrated and the residue chromatographed on silica gel to give the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Fc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2cccc(F)c2)CC1
Reaction time: 16 h
Yield: 44.8 %

Procedure:
1.28 g (0.0127 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.0159 mol) of 3-fluoro-benzyl bromide and 5.0 ml (0.0349 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.19 g (36%) of 1-(3-fluoro-benzyl)-piperidin-4-ol was obtained as yellow crystals; m.p. 61°-62°.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]([CH3:27])=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:28]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]([CH3:27])=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:28])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1sc2nc(C)n(N)c(=O)c2c1C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1sc2nc(C)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c2c1C

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,5,6-trimethylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.77 (m, 12 H) 1.91-1.98 (m, 3 H) 2.08 (d, J=12.0 Hz, 1 H) 2.15 (d, J=12.0 Hz, 1 H) 2.35 (s, 3 H) 2.36 (s, 6 H) 10.76 (s, 1H); MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(O)C.Cl.N>[Fe].O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[C:13]([NH2:14])=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2cc([N+](=O)[O-])c(OC(F)(F)F)cc2s1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1nc2cc(N)c(OC(F)(F)F)cc2s1
Yield: 62.2 %

Procedure:
6-Trifluoromethoxy-5-nitro-2-benzothiazolamine (7.2 g), ethanol (25 cc), water (25 cc), iron powder (8.7 g) and concentrated hydrochloric acid (d=1.19) (1.1 cc) are heated to reflux for 2 hours. After returning to a temperature in the region of 20° C., the mixture is alkalinized with 28% strength ammonia solution (10 cc) and extracted 4 times with ethyl acetate (350 cc in total). The organic solution is evaporated at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The product obtained (6.4 g) is purified by chromatography on a column of silica (800 g; particle size: 0.063-0.200 mm), eluting with an ethyl acetate/cyclohexane mixture (90:10 by volume), and recrystallized in toluene (320 cc). 6-Trifluoromethoxy-2,5-benzothiazolediamine (4 g), m.p. 175° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([P:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Br:17])=[C:12]([CH3:18])[CH:11]=2)=[CH:4][C:3]=1[CH3:25].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[Br:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:10]([P:9](=[O:31])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[C:3]([CH3:25])[CH:4]=2)=[CH:11][C:12]=1[CH3:18]
Reactant: Cc1cc(P(c2ccccc2)c2cc(C)c(Br)cc2C)c(C)cc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(P(=O)(c2ccccc2)c2cc(C)c(Br)cc2C)c(C)cc1Br
Yield: 61.3 %

Procedure:
Monomer 1 (30 g, 63.0 mmol, 1 equiv.) was dissolved in methylene choride (200 ml) at room temperature. m-Chloroperoxybenzoic acid (MCPBA, 50 wt %, ca. 22 g, 63.0 mmol, 1 equiv) was then added portion wise. A small exotherm was noted. Once the addition was complete, thin layer chromatography revealed complete conversion after approximately 5 minutes. The crude product was extracted with aqueous sodium hydroxide (2 M) and the organic layer evaporated under reduced pressure to give the crude product as a white solid. Crystallisation from ethanol gave the title compound (19 g, 63%). GC-MS 99.6%, M+ 491 (expected M+ 491)); 31P-NMR (CDCl3) δ (ppm) 34.
Reaction SMILES: C[C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:3][CH2:4][C:5]1C=C[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.C(OCC)(=[O:26])/C=C/C>C1COCC1>[CH2:2]([N:3]1[C@@H:7]([CH3:8])[CH2:6][C:5](=[O:26])[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Reactant: C/C=C/C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1CC(=O)CN1Cc1ccccc1
Reaction time: 0.33 h
Yield: 158.3 %

Procedure:
To a stirred solution of 20.394 g (96.513 mmol) of (S)-alpha-methyl-N-(phenylmethyl)-benzenemethanamine (from Example 5) in 400 mL of THF, cooled to 0° C., was added, over a 10 minute period, 38.61 g (96.525 mmol) of n-butyllithium, and the reaction was stirred for an additional 15 minutes. To this solution was added 10.00 mL (80.427 mmol) of ethyl crotonate with stirring over a 20 minute period, and the solution was stirred for an additional 20 minutes. The reaction was quenched by addition of an excess of saturated ammonium chloride solution, and the mixture was extracted with ether. The ether extract was washed with saturated brine, dried over MgSO4 and concentrated to give a colorless liquid. The crude product was chromatographed on silica gel, eluting with 1:4 ethyl acetate:hexane, and the solvent was removed to afford 24.10 g (92.1%) of the title product as a colorless oil. MS M/Z: 326 (M+H). NMR (CDCl3) δ: 1.13 (d, 3 H, J=7 Hz), 1.16 (t, 3H, J=7 Hz), 1.35 (d, 3H, J=7 Hz), 2.10 (dd, 1H, J=14 Hz, J=6 Hz), 2.36 (dd, 1H, J=14 Hz, J=6 Hz), 3.44 (m, 1H), 3.67 (d, 1H, J=14 Hz), 3.74 (d, 1H, J=14 Hz), 3.88-4.07 (m, 3H), 7.19-7.42 (10H). Anal calc. for C21H27NO2 : C, 77.50; H, 8.36 N, 4.30; found: C, 77.46; H, 8.37; N, 4.28.
Reaction SMILES: [CH3:1][C@H:2]1[C@:10]2([OH:24])[C@H:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@:4]2([OH:25])[C@@H:3]1[OH:26])[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3.C[C@H]1[C@]2(O)[C@H]3[C@@](O)(CC(CO)=C[C@H]2[C@@H]2C(C)(C)[C@]2(O)[C@@H]1O)[C:40](=[O:41])[C:39](C)=C3>>[CH3:1][C@H:2]1[C@:10]2([OH:24])[C@H:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@@H:5]2[C:6]([CH3:7])([CH3:8])[C@:4]2([OH:25])[C@@H:3]1[OH:26])[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3.[C:40]([O:21][CH2:20][CH3:18])(=[O:41])[CH3:39]
Reactant: CC1=C[C@H]2[C@@]3(O)[C@H](C)[C@@H](O)[C@]4(O)[C@H]([C@@H]3C=C(CO)C[C@@]2(O)C1=O)C4(C)C
Agent: CC1=C[C@H]2[C@@]3(O)[C@H](C)[C@@H](O)[C@]4(O)[C@H]([C@@H]3C=C(CO)C[C@]2(O)C1=O)C4(C)C
Product: CCOC(C)=O

Procedure:
Characterization of phorbol and 4α-phorbol. White needles of phorbol-ethyl acetate solvate (8.9 mg; 0.34% w/w; m.p. 230° C.) were obtained after crystallization from ethyl acetate, which exhibited identical thin-layer chromatography and mass spectral characteristics to an authentic sample of the compound.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C12(N)CC(CC1)CC2.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[CH:3]12[CH2:4][CH:8]([CH:7]=[CH:2]1)[CH2:9][CH:10]2[CH2:11][NH:6][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: C1CCOC1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: NC12CCC(CC1)C2
Solvent: CCOCC
Product: CS(=O)(=O)NCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Into a dry 500 ml round bottom flask equipped with a magnetic stirrer, condenser and an addition funnel was added 75 ml of dry distilled tetrahydrofuran, 32 g (0.41 moles) of pyridine and 50 g (0.41 moles) of norbornyl amine. The reaction mixture was cooled to 0° C. To the mixture was added via the additional funnel 47 g (0.41 moles) of methanesulfonyl chloride and the reaction mixture was stirred overnight. The reaction mixture was filtered to remove the pyridinium hydrochloride salt and the filtrate was rotovaped to remove tetrahydrofuran, resulting in a solid. The solid was dissolved in diethylether, and the resulting solution was extracted several times with deionized water. After treating with decolorizing carbon and drying over anhydrous sodium sulfate, the solution was filtered and the solvent was removed by rotary evaporation. The solid product was recrystallized from toluene and dried under reduced pressure in 76% yield, mp 60-62° C. The product was identified by 1H and 13C NMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[N:20][OH:21])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CSc1ncc(C=O)c(OCc2ccccc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CSc1ncc(C=NO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde (S20, 223 mg) in pyridine (4.0 mL), hydroxylamine hydrochloride (95.8 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde oxime (S21, 233 mg).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:15]1[CH:19]=[C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[N:16]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 417.2 g, 2.15 mol, 1.05 equiv) and 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 645 g, 2.04 mol) in acetonitrile (4.9 L) was added DBU (30.5 mL, 0.204 mol, 0.1 equiv) drop wise at room temperature. The resulting reaction mixture was then stirred at room temperature for 3 h. After about 1 h, a clear, brown solution was obtained. When LCMS showed that no starting material remained, silica gel (SiO2, 1 Kg) was added and the mixture was concentrated to dryness under reduced pressure. This material, which contains the crude desired product (15), was then loaded onto a pre-packed silica column (SiO2, 2.5 Kg) and the column was eluted with 60-80% of ethyl acetate/heptane. The fractions containing the pure desired product (15) were combined and concentrated under reduced pressure to give the desired product as thick oil which was then stirred in heptane at room temperature until crystallization occurred. The solids were collected by filtration and washed with heptane to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 1014.9 g, 1039.7 g theoretical, 97.6% yield) as white solids. For 15: 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.80 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.50 (d, 2H, J=9.3 Hz), 4.21 (d, 2H, J=9.3 Hz), 3.66 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 1.40 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), −0.12 (s, 9H) ppm; C25H35N7O3Si (MW, 509.68), LCMS (EI) m/e 510 (M++H) and 532 (M++Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A suspension of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (400 mg) and potassium carbonate (300 mg) in DMF (5 ml) was mixed with 4-fluoronitrobenzene (290 mg). After 2 hours, the reaction mixture was poured into water, and the resulting precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified after concentration by chromatography. The product with the molecular weight of 319.36 (C16H21N3O4); MS (ESI): 320 (M+H+) was obtained in this way.
Reaction SMILES: CS(C)=O.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([O-:7])=[O:6].C(O)(=O)C.[BH4-].[Na+]>O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(Oc2ccccc2)c1
Reaction time: 0.05 h
Yield: 68.1 %

Procedure:
To a dimethyl sulfoxide (30.0 mL) solution of 1-((E)-2-nitro-vinyl)-3-phenoxy-benzene (3.60 g, 14.9 mmol) described in Manufacturing Example 64-1-1 and acetic acid (3.00 mL) was added sodium borohydride (902 mg, 23.8 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 3 minutes. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduce pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (2.47 g, 68.1%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:8][CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:29].ClC1C=CC=CC=1C1C2C=C(CC)SC=2N2N=C(C(N)=[O:53])N=C2CN=1.ClC1C=CC=C(C(OO)=O)C=1>>[CH3:1][C:2]1[C:6]2[C:7]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N+:8]([O-:53])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)=[O:16])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:29]
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1CN=C2c1ccccc1Cl
Reactant: Cc1sc2c(c1C)C(c1ccccc1)=NCc1nc(C(=O)N3CCCCC3)nn1-2
Agent: O=C(OO)c1cccc(Cl)c1
Product: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)N3CCCCC3)nn1-2

Procedure:
Each of 7,8-dimethyl-6-phenyl-2-piperdinocarbonyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine and 6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a]-[1,4]diazepine-2-carboxamide is treated with 70% m-chloroperbenzoic acid in the same manner as in a) to give 7,8-dimethyl-6-phenyl-2-piperidinocarbonyl-4H-thieno[3,2-f]-s-triazolo-[1,5-a][1,4]diazepine-5-oxide, as colorless prisms melting at 213° to 214° C. and 2-carbamoyl-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-5-oxide as colorless needles melting at 247° to 248° C, repectively.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC.[Cl-].[Li+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH:17]=[CH2:18])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1cnc(NC(=O)CCC(=O)OC)cn1
Temperature: 150 °C
Yield: 51 %

Procedure:
Methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.00 g, 3.47 mmol) was dissolved in toluene in a microwave vial and tributyl vinyl tin (1.22 g, 3.82 mmol), lithium chloride (0.178 g, 4.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.405 g, 0.347 mmol) were added. Argon was bubbling through the mixture for ca. 5 min and the vial was heated under microwave irradiation for 5 min at 150° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated. The product was purified by flash chromatography (AcOEt/cyclohexane: 1/99→99/1) to give methyl 4-oxo-4-[(5-vinylpyrazin-2-yl)amino]butanoate A32 (0.42 g, 1.8 mmol, 51% Yield). 1H NMR (400 MHz, CDCl3) 9.42 (1H, s), 9.15 (1H, s), 8.22 (1H, s), 6.72 (1H, m), 6.21 (1H, d), 5.48 (1H, s), 3.72 (3H, s), 2.78 (4H, m).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:15]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:16]4[C:21]([C:22]=3[C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[O:33])[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:15]([CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[C:16]4[C:21]([C:22]=3[C:23]([OH:25])=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[O:33])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Cn2c(=O)n(C3CC3)c3ccncc32)n(CCC(C)C)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(C(=O)O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Compound 18 (0.5 g, 1 mmol) was dissolved in THF (25 mL), lithium hydroxide (48 mg, 2 mmol) dissolved in water (5 mL) was added. The resulting mixture was stirred at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature then poured in water. The pH of the resulting mixture was adjusted to pH=4 by addition of a 1 M solution of hydrochloric acid. Then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol. The title compound 17 (400 mg, 94%) was isolated as a white powder. m/z=419 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26]OC)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=C(C)SC=3NC(=O)C3(CC3C)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH:24]3[CH3:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1C)C(=O)N2
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1C)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that racemic (1S,2R)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one was used as starting material. LRMS (M+H)+: 383 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 4H), 2.59 (s, 3H), 2.39 (s, 3H), 1.96-2.02 (m, 1H), 1.58 (s, 3H), 1.39 (d, J=6.18 Hz, 1H), 1.04 (d, J=5.95 Hz, 1H), 0.79 (d, J=5.49 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]#[N:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]#[N:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: N#CCc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74.5 mml) and 10% Pd—C (300 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for 5 h. Pd—C was removed via filtration and the filtrate was evaporated to give (6-amino-1H-indol-3-yl)-acetonitrile (B-9) (1.1 g, 90%). 1H NMR (DMSO-d6) δ 10.4 (br s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 6.52 (s, 1H), 6.42 (dd, J=8.4, 1.8 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 2H); ESI-MS 172.1 m/z (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[F:19][C:16]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1C(F)(F)F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Under argon, 2-trifluoromethylphenyl 4-hydroxyphenyl ketone (959 mg) obtained in Example 145 and 4-dimethylaminopyridine (484 mg) were added to xylene (7 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (805 mg) was added, and the admixture was then refluxed with heat overnight. The reaction mixture was treated in the same manner as described in Example 130 to obtain 899 mg of the title compound (yield: 55%).