Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>[Pd]>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:10]([CH:9]=[C:8]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=5)[N:7]=4)[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:29]=[N:28][CH:27]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cncc(F)c3)cc1OCC2

Procedure:
5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted under Suzuki palladium coupling conditions. The crude product was purified by reverse phase HPLC to give 241. LCMS: 406.2
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24](=[O:32])[CH2:23][CH2:22]2)[N:10]=1)C1C=CC=CC=1.C(OC1C2C(=CC=C(CO)C=2)N=C(N2CC3C=CC=CC=3S(=O)(=O)CC2)N=1)C1C=CC=CC=1.[O:66]1[CH2:69][C:68]([CH2:72][NH2:73])([CH2:70][NH2:71])[CH2:67]1>O>[NH2:71][CH2:70][C:68]1([CH2:72][NH:73][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=3)[N:12]=[C:11]([N:21]3[CH2:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[S:24](=[O:32])[CH2:23][CH2:22]3)[N:10]=2)[CH2:69][O:66][CH2:67]1
Reactant: O=S1CCN(c2nc(OCc3ccccc3)c3cc(CO)ccc3n2)Cc2ccccc21
Reactant: NCC1(CN)COC1
Agent: O=S1(=O)CCN(c2nc(OCc3ccccc3)c3cc(CO)ccc3n2)Cc2ccccc21
Solvent: O
Product: NCC1(CNc2nc(N3CCS(=O)c4ccccc4C3)nc3ccc(CO)cc23)COC1
Temperature: 160 °C

Procedure:
A mixture of [4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol and [4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol (700 mg, about 1.57 mmol) and oxetane-3,3-diyldimethanamine (700 mg, 6.03 mmol) was heated at 160° C. for 30 minutes. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL×3). The organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol, MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.139 (s, 1 H), 7.918 (s, 1 H), 7.71 (m, 2 H), 7.48 (m, 3 H), 7.316 (d, J=8 Hz, 1 H), 5.21 (m, 2 H), 4.75 (m, 2 H), 4.51 (m, 4 H), 4.369 (s, 3 H), 3.93 (brs, 1 H), 3.15 (brs, 2 H), 2.989 (s, 2 H), and [4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol, MS obsd. (ESI+) [(M+H)+] 470, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.197 (s, 1 H), 7.789 (m, 3 H), 7.62 (t, J=7.2 Hz, 1 H), 7.48 (m, 2 H), 7.316 (s, 1 H), 5.12 (m, 3 H), 4.48 (m, 8 H), 3.917 (s, 2 H), 3.569 (brs, 2 H), 2.951 (brs, 2 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14](Cl)[CH2:15][S:16][C@H:11]12)=[O:8].S([O-])([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Hg].[Pt]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Agent: [Pt]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
Fifty ml. of working fluid was prepared, containing 6.4 mg./ml. of 7-(thien-2-ylacetamido)-3-chloro-3-cephem-4-carboxylic acid in 0.25 molar pH 8 McIlvaine buffer containing 0.0375 molar tetrabutylammonium iodide. The McIlvaine buffer was prepared according to McIlvaine's article at Anal. Chem. 28, 1179 (1956). The measured pH of the working fluid was 7.3. It was transferred to the cathode compartment of an electrolysis cell having a mercury ring working electrode and a stirrer. The circular auxiliary electrode compartment was suspended over the mercury pool, and consisted of a platinum wire in toroidal shape over a 4% agar gel supported by a medium porosity sintered glass frit. The auxiliary fluid was saturated aqueous potassium sulfate. The cell was stoppered, and a deaerating frit, pH electrode, reference electrode and a delivery tube through which 2 N sulfuric acid could be added were installed. The reference electrode was a Beckman fiber-junction saturated calomel electrode.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:10]([CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:24])[N:10]2[CH3:23])=[CH:19][CH:18]=1
Reactant: CN1C(=O)N(Cc2ccccc2)CC1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)N(Cc2ccccc2)CC1Cc1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of the product from step (a) (2.2 g), 10% Pd/C (400 mg) and 2N aqu. HCl (4.3 ml) in ethanol/water (27.8 ml, 3:5 v/v) was hydrogenated at room temperature and atmospheric pressure for 24 hours (uptake ca 200 ml). The mixture was filtered through celite, the residue washed with hot water and the filtrate evaporated in vacuo to give the desired product as a white solid (2.1 g).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl.O>CCCCCCCC>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH3:19]
Reactant: CCCCCCCCC(O)(CC(CC)CCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCCCC
Solvent: O
Product: CCCCCCCCC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.37 mL) was added dropwise to 7-([2,2′-bithiophen]-3-yl)-5-ethylpentadecan-7-ol (IId) (1.59 g, 3.79 mmol) in 50 ml n-octane under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Id) (0.852 g, 57%). 1H-NMR (CDCl3): δ=7.12 (d, J=4.8 Hz, 2H), 6.93 (d, J=4.8 Hz, 2H), 1.90 (t, 2H), 1.82 (m, 2H), 1.28-1.12 (m, 5H), 1.00-0.74 (m, 16H), 0.62 (t, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O>[Pd].C(OCC)(=O)C>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Under argon, 5.4 g of 10% palladium on carbon were added to a solution of 72.0 g (254 mmol) of tert-butyl (2E)-3-(4-chloro-3-nitrophenyl)acrylate in 1.0 liters of ethyl acetate. The suspension was stirred at RT under a hydrogen atmosphere at standard pressure for 7 h. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 38 g (58% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:36][CH:35]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 41.6 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (500 mg), 4-(4-methylpiperazin-1-yl)aniline (300 mg), methanesulfonic acid (201 μl), and N-methylpyrrolidone (2 mL) was heated in a microwave reaction device at 200° C. for 1 hour. To the reaction mixture was added 4-(4-methylpiperazin-1-yl)aniline (150 mg) and the mixture was heated at 200° C. for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain 6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (308 mg) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH2:24][OH:25])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:24]=[O:25])=[CH:16][CH:17]=1
Reactant: OCC1=C(c2ccc(Cl)cc2)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=CC1=C(c2ccc(Cl)cc2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.1 g, 8.63 mmol) in dichloromethane (30 ml) at −78° C. was added dimethylsulfoxide (6.12 mL, 86 mmol). The mixture was stirred at −78° C. for 30 minutes, and then a solution of Example 8C (1.2 g, 5.75 mmol) in dichloromethane (10 mL) was added. The mixture was stirred at −78° C. for two hours before the addition of triethylamine (10 mL). The mixture was stirred overnight and the temperature was allowed to rise to room temperature. The mixture was diluted with ether (300 mL) and washed with water, brine and dried over Na2SO4. Evaporation of solvent and column purification (5% ethyl acetate in hexane) gave title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH3:35])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added methyl chloroformate (2.7 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 12%). LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][O:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][O:8][CH:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cocc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cocc1C(=O)O

Procedure:
A solution of 235 gm of furan-3,4-dicarboxylic acid diethyl ester and 62.1 gm of potassium hydroxide in 800 ml of 60% ethanol was stirred for 2 hours at room temperature, and then the solvent was distilled off in vacuo. The residue was acidified by carefully adding an aqueous KHSO4 solution dropwise thereto, while stirring, and the monoester was extracted with methylene chloride and crystallized from ethyl acetate/petroleum ether.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C@@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=2[N:7]2[C:25]([CH3:28])=[N:26][N:27]=[C:6]12.[OH-].[Na+]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=3[N:7]3[C:25]([CH3:28])=[N:26][N:27]=[C:6]3[C@H:5]([CH2:4][C:3]([OH:29])=[O:2])[N:11]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of methyl[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (for a preparation see Reference compound G)(7.4 g, 18.1 mmol) in THF (130 mL) at room temperature was added 1N NaOH (36.2 mL, 36.2 mmol). The reaction mixture was stirred at this temperature for 5 h before being quenched with 1N HCl (36.2 mL) and concentrated in vacuo. Water is then added and the aqueous layer was extracted with DCM (×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (7 g, 98% yield) as a pale yellow solid.
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15](C)=[CH:14][C:13]=1[Cl:20].[H-].[CH2:24]([Al+]CC(C)C)C(C)C.CO>C1COCC1>[Cl:18][C:17]1[C:16]([CH3:24])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:21]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CON(C)C(=O)c1ccccc1Nc1c(Cl)cc(C)cc1Cl
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a magnetically stirred 0° C. solution in dry THF (25 mL) of N-methoxy-N-methyl-2-[(2,6-dichloro-4-methylphenyl)amino]benzamide (3.8 g, 11.2 mmol), prepared as in step 1, was added dropwise diisobutylaluminum hydride (1.0M in THF, 24.6 mL) and the reaction mixture was stirred at ambient temperature for 16 hours. Methanol (5 mL) was added dropwise and the mixture was stirred for 15 minutes until a white precipitate had formed. The reaction mixture was concentrated, the residue was taken up in methanol (10 mL), the insoluble white solid was filtered, and the filtrate was evaporated in vacuo and then purified by chromatography on silica gel (5:1 hexane/CH2Cl2) to provide 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (1.98 g; 63%) and over reduced alcohol side product (0.70 g; 22%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[O:27]=[C:28]1[N:32]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:11][CH:12]3[O:25][C:16]4=[C:17]5[C:21](=[CH:22][CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:24])[CH2:18]5)[CH2:37][CH2:38]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CN2CCC(n4c(=O)[nH]c5ccccc54)CC2)CO3)N1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.04 g, 2.77 mmole) and 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine (2.71 g, 12.5 mmole) were combined in 40 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. The reaction was cooled and taken into 400 ml of 1:1 hexane/ethyl acetate. This was washed with 200 ml of water, with 200 ml of saturated brine, dried over MgSO4, filtered and concentrated to yield an oil. This oil was column chromatographed on silica gel using 1% methanol/CH2Cl2 as eluant to give the free base of the title compound as a yellow oil (0.65 g, 53%). This oil was crystallized from ethanol with the addition of a solution of fumaric acid in hot ethanol to give 0.61 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, hemihydrate, m.p. 262°-263.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH2:8][CH3:9].[CH2:17]([O:19][C:20](=[O:25])[CH:21]=[C:22](Cl)[CH3:23])[CH3:18]>O1CCCC1>[CH2:17]([O:19][C:20](=[O:25])/[CH:21]=[C:22](/[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:7][CH2:8][CH3:9])\[CH3:23])[CH3:18]
Reactant: CCCc1ccccc1O
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1ccccc1O/C(C)=C/C(=O)OCC
Temperature: 23 °C
Yield: 41.9 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2-propyl-phenol (6.90 g, 0.051 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (5.20 g, 41%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22].[C:23](Cl)([CH3:25])=[O:24].N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.CCO>[C:23]([NH:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22])(=[O:24])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)c(F)c1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)c(F)c1C2
Reaction time: 5 h
Yield: 89.8 %

Procedure:
A solution of 7-amino-4-bromo-9a-butyl-6,8-difluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one(0.131 g, 0.354 mmol) in CH2Cl2 (3 mL) was treated with AcCl (0.051 mL, 0.708 mmol) and pyridine (0.043 mL, 0.531 mmol). The resulting solution was stirred under a nitrogen atmosphere for 5 hours. This mixture was treated with NaOH (5N, 1 mL) and EtOH (6 mL), and stirred for 10 minutes. After being diluted with CH2Cl2, the mixture was dried over MgSO4, filtered through a pad of silica gel and rinsed with EtOAc. The filtrate was evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 50% EtOAc in hexanes, to afford 7-(acetylamino)-4-bromo-9a-butyl-6,8-difluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.131 g, 90%) as yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[N:14]=[N:15][N:16](S(C4C=CC(Cl)=CC=4)(=O)=O)[C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[N:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1nnn(S(=O)(=O)c3ccc(Cl)cc3)c1C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1nn[nH]c1C2
Temperature: 75 °C
Yield: 55.2 %

Procedure:
To 12,5-bis(4-chloro-benzenesulfonyl)-3,4,5,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (15 mg, 0.029 mmol) in THF (200 μL) was added H2O (100 μM) followed by 1M NaOH solution in H2O (100 μL). The mixture was heated at 75° C. for 3 hr. The mixture was partitioned between EtOAc/H2O. The organic layer was washed with brine, dried and concentrated. The residue was purified by prep TLC to 12-(4-Chloro-benzenesulfonyl)-3,4,5,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (5.3 mg, 0.016 mmol, 54% yield). MS (ES) m/e 339.0 (M+H)
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16]Cl)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[N+:20]([C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)([O-:22])=[O:21].[Br-].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[N:27]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccn[nH]1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc([N+](=O)[O-])n2)o1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole (243 mg, 0.88 mmol), 5-nitro-1H-pyrazole (100 mg, 0.88 mmol) and TBA bromide (57 mg, 0.18 mmol) in acetone (2.0 mL) was treated with K2CO3 (365 mg, 2.64 mmol) and the reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 01: tR=1.09 min, [M+H]+=353.02.