Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]#[N:27]>CN(C)C=O>[CH2:28]([CH:25]([N:20]1[CH:21]=[C:17]([C:15]([NH:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[N:18]=[CH:19]1)[C:26]#[N:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCC(Br)C#N
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C#N)n1cnc(C(=O)NC(c2ccccc2)c2ccccc2)c1
Yield: 49.8 %

Procedure:
To a solution of 1.67 g of 4-{[(diphenylmethyl)amino]carbonyl}-1H-imidazole in 100 ml of dimethylformamide were added 5.03 g of potassium fluoride on alumina. With stirring, 1.35 g of α-bromo-octanonitrile were added. The solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. NMR indicated a mixture of starting material with desired product, so the residue was dissolved in 200 ml of acetonitrile, and 1 g of α-bromooctanonitrile and 5 g of potassium fluoride on alumina was added. After stirring at room temperature for 2 days, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over SiO2 and the appropriate fractions combined and concentrated in vacuo to provide 1.2 g of the desired titled intermediate oil. MS: M+ =400
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:30])[CH3:29])/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:30])[CH3:29])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 5.6 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4.5 g, 9 mmol) was reacted with 1-(5-Fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (63 mmol) in toluene to give title compound as a white solid (Yield: 300 mg, 5.5%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH2:20][NH:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([C:4]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][NH:24][C:22]([NH:21][CH2:20][C@@H:16]3[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:12]4[CH:32]=[CH:33][C:34]([Cl:35])=[C:10]([Cl:9])[CH:11]=4)[CH2:15]3)=[O:23])[CH2:27][CH2:28]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(C(=O)C2CC2)CC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Cyclopropanecarbonyl chloride (0.014 ml) was added to a solution of Intermediate 18 (0.54 g) and N,N-diisopropylethylamine (0.063 ml) in dichloromethane (2 ml). The solution was stirred for 3 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo and the residue was further purified using a silica gel solid phase extraction cartridge (1 g Varian Bond Elut) eluting with 0–1% methanol in ethyl acetate, to give the title compound as a clear gum (0.023 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[OH:22][N:20]1[C:4]2[CH:3]=[CH:2][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:12][C:13](=[O:14])[C:15]1=[O:16]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ccccc3ccc2n(O)c1=O
Yield: 64.4 %

Procedure:
A solution of 0.5 g (1.36 mmol) 4-bromo-1-ethoxalylamino-2-nitronaphthalene in 30 ml tetrahydrofuran was added 10 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 50 mg 5% Pd-C as a catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid and recrystallization (dimethylformamide-water) of the precipitated product gave 0.2 g (65%) 4-hydroxy-benzo[f]quinoxaline-2,3(1H,4H)-dione. M.p. 270° C. decomp. 1H-NMR (DMSO-d6 : 12.1 (1H, broad s), 8.6 (1H, m), 7.7 (5H, m). MS (m/e): 228 (M+, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[Cl:20])(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1Cl
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
To a round-bottom flask, was added 5-bromo-2-chloropyridin-3-amine (0.2 g, 1.0 mmol, Asymchem Laboratories, Morrisville, N.C.) in THF (10 mL). To this solution, sodium bis(trimethylsilyl)amide (1M in THF, 3 mL, 3 mmol, Aldrich, St. Louis, Mo.) was added and the mixture was stirred for 5 minutes. Then 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.7 g, 3 mmol, Aldrich, St. Louis, Mo.) was added to the mixture and the suspension was stirred at 25° C. for 15 h. The mixture was diluted with H2O. The organic layer was collected by extracting the water with DCM (3×). The combined organic was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1 to 30% EtOAc/CH2Cl2) gave N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide (0.190 g, 49% yield) as a tan oil. MS (ESI positive ion) m/z: 401 (M+1).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1.[Cl-].ClC=[N+](C)C.ClC1C(C(OCC)=O)=CN=C(C2C=CC=C([N+]([O-])=O)C=2)N=1.[NH2:49][NH2:50]>CCOCC.CCCCCC>[NH:49]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1)[NH2:50]
Reactant: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1O
Reactant: NN
Agent: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1NN
Yield: 33 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.9 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 33% of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.8 g, 6 mmol) with citraconic anhydride in analogy to Example 21, to afford 80% (0.5 g) of the title compound; m.p. 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH3:13][C:14]1([OH:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:17]2[CH2:18][CH2:19][C:14]([OH:20])([CH3:13])[CH2:15][CH2:16]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N2CCC(C)(O)CC2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (1.66 g, 8.0 mmol), 4-methyl-piperidin-4-ol (1.21 g, 8 mmol) and sodium carbonate (1.74 g, 16.0 mmol) in methanol (8 mL) was stirred for 1 h at 20° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was subsequently washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude title compound (1.70 g, 72%) as light yellow solid. MS ISP (m/e): 286.1 [(M+H)+].
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C[OH:35].O>C1COCC1>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CO
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C#N)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)c1cccc(OCc2cccc(C=O)c2)c1
Yield: 30 %

Procedure:
To a solution of 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzonitrile (10.0 g.) in THF was added diisobutylaluminum hydride (15 g.) and the reaction was refluxed overnight. Methanol (10.2 ml) was slowly added followed by water (5.7 ml). The mixture was filtered and the filtrate was concentrated to an oil. The oil was dissolved in chloroform. The solution was washed with 5% aqueous hydrochloric acid (4 times), dried (MgSO4) and concentrated to an oil (3.0 g., 30% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][F:28])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1.CCOC(C)=O>CCO.[Pt]>[F:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH2:9])=[C:6]([O:12][CH3:13])[CH:5]=3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(CCF)CC2)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[2,5-Bis(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(2-fluoroethyl)piperazine (1.36 g, 3.43 mmol) was taken up in EtOH (50 mL) and EtOAc was added to help with solubility. The catalyst, 5% sulfided platinum on carbon (140 mg) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (1.2 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1H), 6.28 (s, 1H), 4.53 (t, J=4.9 Hz, 1H), 4.41 (t, J=4.9 Hz, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.61 (s, 3H), 3.15 (s, 2H), 2.57 (t, J=4.8 Hz, 1H), 2.49-2.51 (m, 1H), 2.45-2.48 (m, 6H), 2.42 (d, J=13.4 Hz, 4H), 2.17 (t, J=11.3 Hz, 1H), 1.73 (d, J=11.0 Hz, 2H), 1.46 (qd, J=11.7, 3.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Methyl 2′-methyl-2-nitro-1,1′-biphenyl-4-carboxylate, prepared in step 1 (2.5 g, 9.2 mmol) was dissolved in dry THF (20 mL) and cooled to 0° C. To this solution was added lithium hydroxide (1.15 g, 27.6 mmol) in water (5 mL) and the mixture was stirred at RT for 4 h. The solvents were concentrated and the aqueous residue was washed with EtOAc. The aqueous layer was separated and acidified with 1.5N HCl to pH 2-3 and extracted with DCM. DCM was washed with water and dried over sodium sulphate and evaporated under reduced pressure to obtain the title compound as a yellow solid (1.6 g, 70%). 1H NMR: (DMSO-d6, 400 MHz) δ 13.67 (bs, 1H), 8.49 (s, 1H), 8.26-8.24 (d, 1H), 7.58-7.56 (m, 1H), 7.35-7.32 (m, 2H), 7.27-7.12 (d, 1H), 7.10 (d, 1H), 2.09-1.99 (s, 3H). LC/MS (Method A): 255.9 (M−H)−. HPLC (Method B) Rt 1.79 min (Purity: 99.16%).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11]>C1COCC1.C(O)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][C:3](=[O:5])[CH3:4])=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 0° C. suspension of sodium hydride (853 mg, 21.8 mmol, 60% oil dispersion) in THF (13 mL) is added ethyl acetate (2.03 mL, 20.8 mmol). The reaction is stirred at room temperature for 1 h. A solution of 4-methoxyacetophenone (1.56 g, 10.4 mmol), dibenzo-18-crown-6 (62 mg, 0.016 mmol) and ethanol (2 drops) in THF (13 mL) is added dropwise and the reaction mixture is heated to reflux. After 3 h, the reaction is cooled to room temperature, quenched with saturated aqueous NH4Cl, and concentrated under reduced pressure. The residue is partitioned between EtOAc (200 mL) and water (50 mL). The aqueous layer is extracted with EtOAc (200 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated. The residue is purified via chromatography (0 to 20% EtOAc/Hexanes) to yield the title compound (1.62 g, 81%). GC-ES/MS m/e 192
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1cccc(SC(C(=O)O)C(=O)O)c1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: COc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 130°-131° C. 1H NMR (400 MHz, DMSO-d6) δ 3.69 (s, 3H), 6.69 (dd, 1H), 6.72 (dd, 1H), 6.89 (s, 1H), 7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C([Li])CCC.CON(C)[C:17](=[O:33])[CH2:18][C:19]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:19]2([CH2:18][C:17]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=3)=[O:33])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:26][CH:27]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COc1ccc(C2(CC(=O)N(C)OC)CCCCC2)cc1
Agent: [Li]CCCC
Product: COc1ccc(C2(CC(=O)c3ccnc(C)c3)CCCCC2)cc1

Procedure:
In analogy to example 151, step 1, 4-bromo-2-methylpyridine was reacted first with n-butyllithium and later with N-methoxy-2-[1-(4-methoxy-phenyl)-cyclohexyl]-N-methyl-acetamide to give the title compound as a light yellow oil, MS (ESI+): m/z=324.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[C:10]([Cu])#[N:11]>CN(C=O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)ccc1C#N
Yield: 60 %

Procedure:
A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4]Br.[C-]#N.[Na+].C[N:20](C)[CH:21]=[O:22]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][N:20]=[C:21]=[O:22]
Reactant: Cc1ccc(-c2ccccc2)cc1CBr
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)cc1CN=C=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
3.0 g (11.6 mmol) of 2-methyl-5-phenylbenzyl bromide (produced in the same manner as in Reference Production Example 1 (5)) was dissolved in 5 ml of anhydrous N,N-dimethylformamide, and to this solution was added 1.13 g (17.3 mmol) of sodium cyanide, and the mixture was stirred for 3 hours at 100° C., to obtain a 2-methyl-5-phenylbenzyl isocyanate solution. To this solution was added 5 ml of toluene, then, the solution was cooled to 0° C., and to this was slowly dropped 550 mg (11.9 mmol) of methylhydrazine. Further, the mixture was stirred for 3 hours at room temperature, and to this reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, then, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluant: ethyl acetate/methanol=9/1 (v/v)), to obtain 1.24 g of 2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23](Br)[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:35]C(C)([O-])C.[K+].CB(O)O.C(O)(=O)C>CN(C)C=O.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>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23]([CH3:35])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(C)c1
Temperature: 160 °C
Yield: 48.3 %

Procedure:
A mixture of {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetra-hydro-indazol-1-yl}-acetic acid ethyl ester (70 mg, 0.123 mmol, prepared as described above in example 2-1), tetrakis(triphenylphosphine)palladium(0) (1 mg, 0.012 mmol), potassium tert-butoxide (2.5 mg, 0.29 mmol), methylboronic acid (12 mg, 0.184 mmol) in N,N-dimethylformamide (1.5 ml) was heated in a microwave oven at 160° C. for 30 minutes, then acidified to pH 6 by addition of acetic acid. The resulting precipitate was filtered through a glass funnel to afford {4-[6-(4-chloro-phenoxy)-5-methyl-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 48%) as a white solid. MS cald. for C23H25ClN4O5S 504, obsd. (ESI+) [(M+H)+] 505.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:36])[O:9][CH2:10][C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]=[CH:18][C:17]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[O:25])=[C:16]3[OH:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C#C>C(Cl)Cl.[Pd]>[C:1]1([NH:7][C:8](=[O:36])[O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]=[CH:18][C:17]([C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:25])=[C:16]3[OH:35])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)OCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.67 h
Yield: 11 %

Procedure:
A mixture of 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynyl phenylcarbamate from Example No. 150 (100 mg) and Pd/C (10%, 20 mg) is dissolved in 80 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 25 psi H2 and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. The reaction is complete in 40 min . The reaction mixutre is filtered over celite to remove the palladium. The filtrate is condensed. The mixture is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 11.3 mg (11%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 100.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1 N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, S.1 mmol) in 25 ml of 4M hydrochlorio acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d 6): 7.13 (d,J=9 Hz, IH, ArH), 7.62 (D,J=9 Hz, IH, ArH), 7.72 (d,J=5 Hz, IH, ArH),