Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[O:17])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: COc1ccn(-c2nc(C)c(C(=O)O)s2)c(=O)c1
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3cccnc3)s2)c(=O)c1
Yield: 58 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 58% yield: mp 200-202° C. (dichloromethane/methanol); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 8.60-8.59 (m, 1H), 8.52-8.51 (m, 1H), 7.51-7.68 (m, 1H), 7.29-7.24 (m, 1H), 6.30 (t, J=5.8 Hz, 1H), 6.17 (dd, J=8.1, 2.6 Hz, 1H), 5.96 (d, J=2.6 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H), 3.82 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 162.4, 162.1, 153.6, 152.6, 149.2, 149.0, 135.7, 133.7, 131.4, 123.6, 121.8, 103.9, 96.2, 56.0, 41.4, 17.3; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:21]3[N:20]=[C:18]([NH2:19])[NH:17][C:15](=O)[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[SiH3][NH:23][SiH3].FC(F)(F)S(O[SiH3])(=O)=O.C(O)(C)C.[OH-].[NH4+].O>CS(C)=O.CO.C1(C)C=CC=CC=1>[CH:12]1[N:11]([CH:2]2[O:10][CH:7]([CH2:8][OH:9])[CH:5]([OH:6])[CH:3]2[OH:4])[C:21]2[N:20]=[C:18]([NH2:19])[N:17]=[C:15]([NH2:23])[C:14]=2[N:13]=1
Reactant: [SiH3]N[SiH3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=S(=O)(O[SiH3])C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: Nc1nc(N)c2ncn(C3OC(CO)C(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a 2 L stainless steel Parr bomb was added guanosine hydrate (100 g, 0.35 mol, Aldrich), hexamethyl) disilazane (320 mL, 1.52 mol, 4.4 eq.), trimethyl) silyl triflouromethanesulfonate (8.2 mL), and toluene (350 mL). The bomb was sealed and partially submerged in an oil bath (170° C.; internal T 150° C., 150 psi) for 5 days. The bomb was cooled in a dry ice/acetone bath and opened. The contents were transferred with methanol (300 mL) to a flask and the solvent was evaporated under reduced pressure. Aqueous methanol (50%,1.2 L) was added. The resulting brown suspension was heated to reflux for 5 h. The suspension was concentrated under reduced pressure to one half volume in order to remove most of the methanol. Water (600 mL) was added and the solution was heated to reflux, treated with charcoal (5 g) and hot filtered through Celite. The solution was allowed to cool to 25° C. The resulting precipitate was collected, washed with water (200 mL) and dried at 90° C./0.2 mmHg for 5 h to give a constant weight of 87.4 g (89%) of tan, crystalline solid; mp 247° C. (shrinks), 255° C. (dec, lit. (1) mp 250-252° C.); TLC homogenous (Rf 0.50, isopropanol-ammonium hydroxide-water 16:3:1); PMR (DMSO), δ 5.73 (d, 2,2-NH2), 5.78 (s, 1, H-1), 6.83 (br s, 2,6-NH2).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[N:32]=[C:31]4[N:23]([C:24]5[CH2:25][CH2:26][CH2:27][C:28]=5[C:29]([O:33][CH3:34])=[N:30]4)[CH:22]=2)(Br)[C:14]3=[O:39])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[CH3:34][O:33][C:29]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:23]2[C:31](=[N:32][C:21]([CH:20]=[C:15]3[C:14](=[O:39])[N:13]4[CH:16]3[S:17][CH:18]=[C:12]4[C:10]([OH:11])=[O:9])=[CH:22]2)[N:30]=1
Reactant: [H][H]
Reactant: COc1nc2nc(C(OC(C)=O)C3(Br)C(=O)N4C(C(=O)OCc5ccc([N+](=O)[O-])cc5)=CSC43)cn2c2c1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: COc1nc2nc(C=C3C(=O)N4C(C(=O)O)=CSC34)cn2c2c1CCC2

Procedure:
6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (966 mg, 1.4 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 100 mg of product was collected.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl.CC[O:17][CH2:18][CH3:19]>>[CH2:7]([C@H:9]1[CH2:10][CH2:11][C@H:19]([CH:18]=[O:17])[CH2:7][CH2:8]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1cc[nH+]cc1
Reactant: CCOCC
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C=O)CC1

Procedure:
A solution of 59.0 g. of trans-4-n-pentylcyclohexane carbinol in 100 ml. of ether is added to a suspension of 125 g. of pyridinium chlorochromate in 900 ml. of methylene chloride and the mixture is stirred at room temperature for 2 hours. The mixture is then diluted with 400 ml. of ether, stirred for a further 15 minutes and the solution is decanted off from the tarry precipitate. The precipitate is back-washed with ether. The combined organic solutions are filtered through a Florisil column. The trans-4-n-pentylcyclohexane carboxaldehyde obtained after evaporation of the filtrate is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F-:14].[K+].CN(C)C=O.O>C(Cl)Cl>[F:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1F

Procedure:
A mixture of 1-chloro-2,6-dinitrobenzene (30 grams), anhydrous potassium fluoride (35 grams), and dimethylformamide (50 ml.) is refluxed for twenty-four hours. The reaction mixture is poured into water (250 ml.) and extracted with ether (3 × 100 ml.). The combined ether extracts are dried with anhydrous sodium sulfate. Removal of the solvent leaves brown solid. Chromatography of the solid on silica gel with methylene chloride as the elutant gives a light yellow solid after recrystallization from pentane-methylene chloride. (20.30 grams, melting point 59°). Mass spectrum (70 ev) mol. ion 186 m/e.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14](NC)=[O:15]>>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:14]([NH:13][CH3:12])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: CNC(=O)NC
Product: CNC(=O)N(CCO)Cc1ccccc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyl ethanolamine (3 g, 0.0198 mol) and N,N′-dimethyl urea was stirred at 130° C. overnight. The reaction mixture was cooled to RT and the crude product was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to yield 3.5 g of the sub-title compound as a liquid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@H:22]([C:27]([OH:29])=O)[CH2:23][CH2:24][S:25][CH3:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.[CH2:31]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C=O>[CH2:31]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:27](=[O:29])[C@H:22]([CH2:23][CH2:24][S:25][CH3:26])[NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 102.9 %

Procedure:
N-t-butyloxycarbonyl-L-methionine dicyclohexylamine salt (44.36 g, 103 mmole), L-proline benzylester hydrochloride (2490 g, 103 mmole) and HOBT (13.92 g, 103 mmole) were dissolved in methylene chloride (400 ml), and WSC hydrochloride (19.75 g, 103 mmole) were added thereto at -30C. The mixture was stirred for 2 hours at less than 0° C., N,N-dimethylformamide (100 ml) was added thereto, and stirred further overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-t-butyloxycarbonyl-L-methionyl-L-proline benzylester (yield: 46.27 g, 100%)
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](Cl)=[O:50]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:49]([C:48]1[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=1)=[O:50]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[C:11]([F:25])[CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:34]3[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[CH:35]=3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][C:11]=1[F:25]
Reactant: Fc1cc(Oc2nccnc2Cl)ccc1Nc1nc2ccccc2s1
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C1C=C(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)c(F)c2)CCC1
Temperature: 140 °C

Procedure:
A mixture of N-(4-(3-chloropyrazin-2-yloxy)-2-fluorophenyl)benzo[d]thiazol-2-amine (2098 mg, 5.63 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1000 mg, 4.50 mmol), dichlorobis(triphenylphosphine)palladium(ii) (316 mg, 0.450 mmol), and sodium carbonate (1432 mg, 13.51 mmol) in DME/H2O/EtOH (7:3:2, 36 ml) was heated to 140° C. for 3 h. Water (100 ml) was added and the reaction mixture was extracted with EtAOc (3×100 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded 3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone. MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:31]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2Cl)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4Cl)cc23)cc1

Procedure:
The title compound, light green solid (39 mg, 30%), MS (ISP) m/z=386.2 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 1 from 1-(2-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate L) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.[Cl-].[Na+].O>[CH2:14]([O:11][CH2:10][C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H](COCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of L-phenylalaninol (11.78 g) in THF (200 ml) was gradually added 60% sodium hydride (3.43 g) in oil at room temperature. Twenty minutes later, the reaction mixture was refluxed under heating for 1 hour. Then, the mixture was allowed to cool, followed by gradual addition of benzyl bromide (9.27 ml) under ice-cooling, and stirred at room temperature for 16 hours. The reaction mixture was added to saturated brine, and extracted with ether. The organic layer was extracted with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (14.5 g, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:40])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:29])=[O:28])[C:24]([O:35][CH3:36])=[CH:23][C:22]=3[O:37][CH2:38][CH3:39])=[N:9]2)=[CH:4][CH:3]=1.[C:41](Cl)([Cl:43])=[O:42]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:40])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:41]([Cl:43])=[O:42])[C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)(=[O:28])=[O:29])[C:24]([O:35][CH3:36])=[CH:23][C:22]=3[O:37][CH2:38][CH3:39])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[CH2:7][CH2:8][C:9]([C:11]1[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[CH:19]=[C:20]([Br:22])[S:21][C:13]=2[C:12]=1[OH:23])=[O:10].BrC1SC2C(O)=C(C(OCC)=O)C(=O)N(C)C=2C=1.BrC1SC(C(OC)=O)=C(NC)C=1.[H-].[Na+]>C1COCC1>[Br:22][C:20]1[S:21][C:13]2[C:12]([OH:23])=[C:11]([C:9](=[O:10])[CH2:8][CH2:7][C:2]([OH:3])=[O:1])[C:16](=[O:17])[N:15]([CH3:18])[C:14]=2[CH:19]=1
Reactant: Cn1c(=O)c(C(=O)CCC2OCCCO2)c(O)c2sc(Br)cc21
Agent: CCOC(=O)c1c(O)c2sc(Br)cc2n(C)c1=O
Agent: CNc1cc(Br)sc1C(=O)OC
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2sc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(3-(1,3-Dioxan-2-yl)propanoyl)-2-bromo-7-hydroxy-4-methylthieno[3,2-b]pyridin-5(4H)-one. To ethyl 2-bromo-7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxylate (800 mg, 2408 μmol, prepared in a manner similar to that described in Method 7 using methyl 5-bromo-3-(methylamino)thiophene-2-carboxylate (Method 6(b))) was added THF (24 mL) and sodium hydride (60% in oil; 963 mg, 24084 μmol). The resulting mixture was stirred for 1 hour at ambient temperature. 2-[2-(1,3-Dioxanyl)]ethylmagnesium bromide in THF (4.81 mL, 2408 μmol) was then added dropwise at ambient temperature, and the resulting mixture was stirred for 3 hours before it was quenched with water, acidified with 5 N HCl, filtered, washed with water, and dried in a vacuum oven. The crude product was purified via HPLC to give the title compound.
Reaction SMILES: C(O[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]([O:10]C)=O)CC.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:23]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]1=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CCCOC(=NNC(=O)OC)OCCC
Solvent: CO
Product: CCCOc1n[nH]c(=O)n1Cc1ccccc1
Reaction time: 5 h

Procedure:
In an autoclave, 2.04 g of methyl N′-dipropoxymethylenehydrazinecarboxylate (8.9 mmol) and 3.46 g of benzylamine (31.6 mmol) were initially charged in 25.8 g of methanol. After 5 hours at 110° C., the solvent was distilled off and the 4-methyl-5-propoxy-2,4-dihydro-1,2,4-triazol-3one was recrystallized from ethyl acetate. This gave 0.57 g (27%) of pure 4-benzyl-5-propoxy-2,4-dihydro-l,2,4-triazol-3-one.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=3[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-{[2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 139°-141° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with 1-pyrrolidinecarbonyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][C:26]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1C(F)(F)F
Temperature: 100 °C
Yield: 39.7 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 4-fluoro-2-(trifluoromethyl)benzyl bromide (204 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (2×25 mL), aqueous sodium thiosulfate, water, and brine. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50% ethyl acetate/petroleum ether, to give an orange oil. 1H NMR showed that this oil contained some dimethyl formamide. The oil was dissolved in ethyl acetate and the solution was washed with water (3×10 mL), dried (magnesium sulfate), filtered, evaporated, then co-evaporated with ethyl ether and dichlormethane, and held under high vacuum to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(4-fluoro-2-trifluoromethyl-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (63 mg, 40%) as a pale foam. APCI(+)-MS (M+H) 481.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCCCC(=O)OCc1nccc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCCCCC(=O)OCc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 300 mg (1.33 mMol) hexanoic acid 4-hydroxy-pyrimidin-2-ylmethyl ester, 487 mg (2.94 mMol) Et4NCl and 373 μl (2.94 mMol) N,N-dimethylaniline in 15 ml of acetonitrile, 1.22 ml (13.3 mMol) POCl3 are added. After stirring for 24 h at rt, the solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and sat. NaHCO3, the aq. layer separated off and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/ether 199:1→9:1→3:2) gives the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.26.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C-:19]#[N:20].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O.CO>[NH2:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]#[N:20]
Reactant: N#Cc1ccccc1
Reactant: [C-]#N
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#CC(N)c1ccccc1
Temperature: 0 °C
Yield: 29 %

Procedure:
20 millimoles (2.06 g) of benzonitrile are dissolved in 20 ml of anhydrous toluene, at 0° C., under an argon atmosphere. 30 millimoles of a toluenic solution 1.5 M of diisobutylaluminum hydride (20 ml) are added, dropwise, at this temperature. The temperature is maintained at 0° C. for 1 hour, then the reaction mixture is added with 50 ml of a normal solution of sodium cyanide in dimethylformamide. The mixture is maintained at room temperature for 3 hours while stirring, then hydrolyzed with 20 ml of methanol, and with pasty sodium sulfate. After purification of the so obtained α-aminonitrile by high pressure liquid chromatography on silica, with elution by an acid-base extraction, there are obtained 0.350 g of 2-amino-2-phenyl acetonitrile, with a yield of 29%.