Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[O:21]1CCOCC1>>[Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(Br)c(O[Si](C)(C)C(C)(C)C)c2n1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=O)nc12
Temperature: 80 °C
Reaction time: 32 h
Yield: 89 %

Procedure:
A slurry of SeO2 (0.869 g, 7.83 mmol) and 1,4-dioxane (20 mL) was warmed to 80° C. and then the product from Step B (2.3 g, 6.53 mmol) was added as a 1,4-dioxane solution (20 mL). The mixture was stirred at 80° C. for 32 hours. The mixture was cooled to ambient temperature and filtered through GF/F filter paper and the residual solid was washed with CH2Cl2. The filtrate was concentrated and purified by passing through a silica gel plug, eluting with 50% CH2Cl2/hexane to provide 2.14 g (89%) of the product as a yellow/orange solid.
Reaction SMILES: C([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:5](C(O)=O)[C:4]=1[CH2:16][CH3:17])#N.[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:16]([C:4]1[CH:3]=[C:12]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11]2)[CH:5]=1)[CH3:17]
Reactant: CCc1c(C#N)c2cccccc-2c1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc2cccccc-2c1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
3.7 g (16.4 mmol) of the above-obtained 1-cyano-2-ethylazulene-3-carboxylic acid was separated into two parts, i.e., about 1 g and a remaining part. 30 ml of 75% sulfuric acid was added to the first part, i.e., about 1 g of 1-cyano-2-ethylazulene-3-carboxylic acid and heated to 90° C., and thereafter gradually supplied with the remaining part of 1-cyano-2-ethylazulene-3-carboxylic acid. The mixture was heated at 90° C. for 2 hours and further at 120° C. for 2 hours. The obtained reaction solution was added to an aqueous solution containing 35 g of sodium hydroxide and extracted with a mixed solution of hexane and ethyl acetate. An organic phase of the extract was removed under a reduced pressure. The resultant crude product was purified by silica gel column chromatography, to obtain 1.71 g of 2-ethyl azulene (yield: 67%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 63.4 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoyl]piperidine (0.292 g, 0.538 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.737 g, 1.34 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. 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=2:1) to obtain the titled compound (0.175 g, 0.341 mmol, 63%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:6])[CH:4]=[CH2:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])(=O)C>O>[CH2:3]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])[CH:4]=[CH2:5]
Reactant: C=CCS
Reactant: CCC1C(=O)NC1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1NC(=O)C1CC
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3.2 g of sodium hydroxide in 40 ml of water under an argon atmosphere were added 8 ml of allyl thiol (about 85% pure). After 20 minutes of further stirring, a solution of 12.5 g of 4-acetoxy-3-ethylazetidin-2-one in 20 ml of water was added and the mixture was stirred for a further 15 minutes, and then extracted into dichloromethane. The organic extracts were washed with water, were dried over MgSO4, and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compounds as a yellow oil (3.2 g).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-ethyl 3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 17, (14.0 g, 45.9 mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphere of nitrogen at room temperature overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.
Reaction SMILES: [Mg].C1(S([N:11]2[C:26]([CH2:27][CH3:28])=[C:15]3[CH2:16][CH:17]([N:23]([CH3:25])[CH3:24])[C:18]4[CH2:19][O:20][CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12]2)(=O)=O)C=CC=CC=1>CO.C(Cl)(Cl)Cl>[CH2:27]([C:26]1[NH:11][CH:12]=[C:13]2[CH:22]=[CH:21][O:20][CH2:19][C:18]3[CH:17]([N:23]([CH3:25])[CH3:24])[CH2:16][C:15]=1[C:14]2=3)[CH3:28]
Reactant: CCC1=C2CC(N(C)C)C3=C2C(=CN1S(=O)(=O)c1ccccc1)C=COC3
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC1=C2CC(N(C)C)C3=C2C(=CN1)C=COC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Magnesium (turning) 246 mg was added to compound (55) in methanol 9 ml and the mixture was stirred at room temperature for 3 h. Ice was added to the reaction mixture which was diluted with chloroform. The insoluble materials were filtered off through cerite and the filtrate was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (2:1) to give the titled compound as a pale yellow oil 97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 236-237° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:27]N1C(=O)CCC1=O>>[Br:27][CH2:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Product: CCOC(=O)c1nc(CBr)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Yield: 71.5 %

Procedure:
Following a procedure similar to that described in Preparation 42(ii), but brominating 6.6 g of diethyl 2-methyl-1-(4-nitrobenzyl)imidazole-4,5-dicarboxylate [prepared as described in step (i) above] with 3.9 g of N-bromosuccinimide, 5.75 g of the title compound were obtained as a syrup.
Reaction SMILES: [C:1]([CH:8]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:30][CH3:31])=[CH:12][C:11]=1[CH2:32][CH2:33][CH3:34])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([CH:8]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:30][CH3:31])=[CH:12][C:11]=1[CH2:32][CH2:33][CH3:34])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)O)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)O)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 3-[4-(1-carbo-t-butoxy-1-phenylmethoxy)-3propylphenylmethyl]-5-carboxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (47 mg, 0.087 mmol) in CHCl3 (3 mL) was added TFA (0.5 mL) at -20° C. The solution was warmed to rt and was stirred at rt for 12 hours. After evaporation of the solvent the crude mixture was purified by flash chromatography eluted with CHCl3 /MeOH/AcOH (90:5:5) to give 31 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:19]I>C1COCC1.CCOC(C)=O>[CH3:19][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(Nc2cccnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccnc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
NaH (61 mg, 2.5 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (6 mL) was added. The slurry was cooled to 0° C. and compound 15 (500 mg, 2.33 mmol, 1.00 eq) was added as a solution in THF (6 mL). After stirring at 0° C. for 30 minutes methyl iodide (159 μL, 2.54 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 340 mg (64%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=2.7 Hz, 1H), 8.35 (dd, J=4.7, 1.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.66-7.64 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.60 (t, J=2.3 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.42 (dd, J=8.3, 4.7 Hz, 1H), 7.32 (dd, J=8.3, 2.5 Hz, 1H), 3.37 (s, 3H); ES-MS [M+1]+: 230.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CC(C)(C)OC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.50 g, 1.9 mmol), tert-butyl 6-bromohexanoate (1.25 g, 4.9 mmol) and potassium carbonate (0.54 g, 3.9 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.75 g, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13].[O:16]=[C:17]1[CH2:22][S:21][CH2:20][CH2:19][S:18]1>CO.CC(C)=O>[SH:18][CH2:19][CH2:20][S:21][CH2:22][C:17]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13])=[O:16]
Reactant: NCCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reactant: O=C1CSCCS1
Solvent: CC(C)=O
Solvent: CO
Product: O=C(CSCCS)NCCNC(=O)Cn1ccnc1[N+](=O)[O-]
Yield: 37.5 %

Procedure:
N-(2-Aminoethyl)-(2-nitroimidazol-1-yl)acetamide (40 mg, 0.23 mmol) in methanol (0.5 cm3) was added to 2-oxo-1,4-dithiane (40 mg, 0.27 mmol) in acetone (0.2 cm3) under an atmosphere of dry nitrogen. The mixture was left at room temperature and monitored by n.m.r. spectroscopy until the reaction was complete. The bulk of the solvent was removed, and the resulting material purified by reverse phase h.p.l.c. using aqueous methanol as the eluant. The pure N-{2-[(2-mercaptoethylthio)acetylamino]ethyl}-(2-nitroimidazol-1-yl)acetamide (30 mg) was isolated as a pale yellow solid.
Reaction SMILES: Cl[CH:2]([C:12](=O)[CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>C(O)C>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[CH2:3][C:2]1[S:31][C:30]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)=[N:32][C:12]=1[CH3:13]
Reactant: CC(=O)C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3ccc(Cl)c(Cl)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(3,4-dichloro-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 85 mg (93%) of the title compound as a brown solid. MS ISP (m/e): 4.59.3/461.2/460.3/462.2 (100/74/35/20) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (s, 1H), 7.37 (d, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7.03 (d, 1H), 6.89 (d, 1H), 6.86 (s, 1H), 3.93 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccc(CO)c12
Solvent: ClCCl
Product: Cc1cccc2cccc(C=O)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1-L 4-neck equipped with an overhead stirrer, a condenser and a thermocouple was charged with 8-methyl-1-napthalenemethanol (18.5 g, 0.107 mol) in CH2Cl2 (500 mL) and stirred at room temperature under N2. Solid Mn(IV)O2 (61 g, 0.7 mol) was carefully added and the reaction was stirred at room temperature for 3 h, then at 40° C. for 6 h and then at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (500 mL), filtered and the filtrate was washed with 1N HCl and then dried over MgSO4. The resulting crude material was purifed using silica gel chromatography (8/2 hexane/ethyl acetate) to yield 8-methyl-naphthalene-1-carbaldehyde as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:18]
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenyl-propane (1.5 g-see Preparation 4), 1-(N-methylamino)-3-phenylpropane (0.746 g), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 48 hours and then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×40 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.93 g.
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]4)=[C:26]([CH3:46])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:47])C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH3:43][C:42]([CH3:45])([CH3:44])[CH2:41][CH2:40][N:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]([N:14]3[CH2:13][CH2:12][C:11]4[N:10]=[C:9]([CH3:47])[NH:8][C:17]=4[C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]3=4)=[O:23])=[CH:25][C:26]=2[CH3:46])[CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCN(CCC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Yield: 20 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-methanone from Example E70.3 (98 mg, 0.15 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (98 mg) for 8 h. The mixture was filtered through glass-fibre paper and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (17 mg, 20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[S:9][C:10]([C:13]2([OH:20])[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:25][CH:24]([NH:26][C:27]([CH2:29][NH:30][C:31](=[O:42])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:28])[CH2:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[S:9][C:10]([C:13]2([OH:20])[CH2:18][CH2:17][CH:16]([N:22]3[CH2:25][CH:24]([NH:26][C:27](=[O:28])[CH2:29][NH:30][C:31](=[O:42])[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=4)[CH2:23]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of [5-(1-Hydroxy-4-oxo-cyclohexyl)-thiazol-2-yl]-carbamic acid tert-butyl ester, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([O:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: C/C=C/C(=O)Nc1cccc(O)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)Nc1cccc(OC(=O)Nc2ccc(Cl)c(Cl)c2)c1
Temperature: 55 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 17.7 parts of 3'-hydroxycrotonanilide and 18.8 parts of 3,4-dichlorophenyl isocyanate. The reaction mixture is heated to about 55°C and one part of triethylamine is added. An additional 100 parts of ethyl acetate is added and the reaction mixture heated at reflux for about one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 31 parts of 3'-(3,4-dichlorophenylcarbamoyloxy)crotonanilide, m.p. 193°-194°C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])[N:12]=1)=[O:10].Cl>C1COCC1>[NH2:17][C:16]1[C:11]([C:9]([CH:1]2[CH2:3][CH2:2]2)=[O:10])=[N:12][C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])=[CH:14][N:15]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(C(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added to a solution of 3-amino-6-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazine-2-carboxylic acid methoxy-methyl amide (Intermediate C) (0.058 mg, 0.14 mmol) in anhydrous THF (3 ml) under N2. The orange solution is stirred at room temperature for 2 hours after which time a 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added. The orange solution is stirred at room temperature for 1 hour. 1M HCl (15 ml) is added, and the product extracted into EtOAc (30 ml), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, 33-50% EtOAc in iso hexane) yields the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-6) δ 8.63 (1H, s), 7.92 (2H, bs), 7.79 (1H, s), 7.70-7.63 (2H, m), 3.64-3.62 (4H, m), 3.49-3.43 (1H, m), 2.90 (4H, bs) 2.54 (3H, s), 1.09-1.01 (4H, m); MS m/z 403 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].N(CC)CC.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]2[NH:38][N:37]=[N:36][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: O=C(CCCCCCc1ccccc1)N[C@@H](CCc1nnn[nH]1)Cc1ccc(OCc2ccccc2)cc1
Yield: 219.9 %

Procedure:
A mixture of (65) (74 mg, 0.16 mmol), NaN3 (103 mg, 1.58 mmol) and Et2NH.HCl (173 mg, 1.58 mmol) in toluene (1.5 mL) was heated at reflux for 48 h. The organic phase was decanted, and the remaining gum washed several times with CH2Cl2. The washings were filtered (Celite™), and the organic phases combined. Evaporation of the solvent under reduced pressure afforded a brown gum (180 mg) which was chromatographed on a C-18 reverse phase column to provide (66) (29 mg, 36%). 1H NMR (500 MHz, d4-MeOH) δ 7.43-7.07 (m, 12H), 6.9 (d, 2H, J=8.6 Hz), 4.99 (s, 2H), 4.15-4.04 (m, 1H), 3.03-2.86 (m, 2H), 2.79 (dd, 1H, J=5.7, 13 Hz), 2.65 (dd, 1H, J=8.7, 13 Hz), 2.54 (t, 2H, J=7.6 Hz), 2.12-2.00 (m, 3H), 1.90-1.78 (m, 1H), 1.50-1.36 (m, 2H), 1.33-1.10 (m, 4H). 13C NMR (125 MHz, d4-MeOH) δ 176.2, 158.9, 156.2, 143.9, 138.8, 131.9, 131.3, 129.5, 129.4, 129.3, 128.8, 128.5, 126.6, 115.8, 71.0, 51.5, 41.1, 37.2, 36.8, 33.5, 32.5, 30.0 (two superimposed), 27.0, 21.3. ESMS 512 (M+H)+.