Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[C:3]1(=NN)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(N=C(N(C)C)N(C)C)(C)(C)C>CCOCC>[I:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: II
Reactant: NN=C1CCCc2ccccc21
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CCOCC
Product: IC1=CCCc2ccccc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of I2 (14 g, 56 mmol) in ether (100 mL) added slowly at 5° C. over a 50 minute period to a solution of (3,4-dihydro-2H-naphthalen-1-ylidene)-hydrazine (4.5 g, 28 mmol, prepared from α-tetralone and hydrazine) and tert-butyl-tetramethylguanidine (43 g, 251 mmol, prepared from tetramethylurea, triphosgene, and tert-butylamine) in ether (100 mL). After the addition is complete, the mixture is stirred for 30 minutes and the ether (100 mL) is removed. The residue is heated for 1 hout at 90° C. and then cooled to room temperature. The mixture is diluted with ether and washed successively with 1N HCl, aq. Na2S2O3, aq. NaHCO3, and then saturated brine. The organic layers are dried, concentrated, and purified by flash chromatography (elution with hexane only) to give 6.4 g 4-iodo-1,2-dihydro-naphthalene: 1H NMR (CDCl3) 7.42 (d, 1H), 7.26-7.14 (m, 2H), 7.01 (d, 1H), 6.83 (t, 1H), 2.84 (t, 2H), 2.39-2.32 (m, 2H).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]1=[O:24].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>C1(C)C=CC=CC=1>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:35])(=[O:36])[N:37]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21
Yield: 70 %

Procedure:
A suspension of the compound of Example 18G (39 mg, 0.10 mmol) and 2-aminobenzenesulfonamide (17 mg, 0.10 mmol) in toluene (1 mL) was warmed at reflux for 2 h. The solution was cooled and concentrated in vacuo to afford a yellow foam which was purified by flash chromatography eluting with ethyl acetate in hexane to afford the title compound (33 mg, 0.07 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]#[N:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:34]1[C:29]([CH2:28][N:15]2[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=4)=[CH:12][CH:11]=3)[C:14]2=[O:31])=[N:30][N:36]=[N:35]1
Reactant: N#CCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2nnn[nH]2)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 220 °C

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetonitrile (21.8 mg, 0.046 mmol) in DMF (1.0 mL) are added NaN3 (60 mg, 0.92 mmol) and NH4Cl (49 mg, 0.92 mmol). The reaction mixture is heated at 220° C. for 15 min in a microwave reactor. After cooling down to room temperature and removal of the solvent, the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.58-7.45 (m, 4H), 7.26 (d, 2H), 7.19 (d, 2H), 6.87 (m, 4H), 5.24 (dd, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 4.10 (t, 1H), 3.48 (dd, 1H); HPLC-MS calculated for C24H18ClF3N6O2 (M+H+) 515.1, found 515.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C=O)cc(F)c1Oc1ccc(C#N)cn1
Yield: 66.9 %

Procedure:
Using a method similar to Example 710, Step 2, using 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (Journal of Organic Chemistry (1986), 51(21), 4072-3.) (2.84 g, 16.7 mmol), 6-chloronicotinonitrile (2.31 g, 16.7 mmol) and K2CO3 (3.46 g, 25.0 mmol) gives 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinonitrile (3.04 g) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O

Procedure:
A solution of Example 73C (210 mg), potassium carbonate (150 mg), and pyrrolidine (113 μl) in dichloromethane was stirred for 3 days, treated with potassium carbonate (150 mg) and pyrrolidine (113 μL), stirred for 3 more days, and concentrated; and the concentrate was purified by flash column chromatography on silica gel with a methanol/dichloromethane gradient.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[C:35]([CH2:36][C:37](O)=[O:38])=[CH:34][CH:33]=[CH:32][N:31]=1>C(O)CCCC>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:14]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[CH2:36][C:37]2=[O:38])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCCCCO
Product: O=C1Cc2cccnc2N1c1ccc(OCc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g), 4-methylbenzenesulfonic acid hydrate (0.178 g), and (2-chloropyridin-3-yl)acetic acid (Journal of Medicinal Chemistry, 1990, 33, 2697-2706.) (1.61 g) in 1-pentanol (15 mL) was stirred at 140° C. for 24 h. After cooling to room temperature, the mixture was added to SiO2, and the mixture was concentrated and purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39 g) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[N:25](S(C3C=CC(C)=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:7]1)C.[OH-].[K+]>CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:7]=[C:8]2[C:17]1[NH:25][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1
Reactant: CCOC(=O)Cn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3cccnc3[nH]1)cn2CC(=O)O
Yield: 56.7 %

Procedure:
A mixture of {5-methoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-indol-1-yl}-acetic acid ethyl ester [4.67 g, Reference Example 13(a)], methanol (250 mL) and aqueous potassium hydroxide (5M, 25 mL) were heated under reflux for 7 hours. The methanol was removed under reduced pressure and the residue was treated with water (20 mL) and the pH of this solution was adjusted to 7 by addition of concentrated hydrochloric acid. The resulting yellow solid was filtered and subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and methanol (7:3, v/v) to give the title compound (1.69 g) as a white solid. MS: 320(M−H+). HPLC (METHOD A): RT=6.67 minutes.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[C:24]=1[N+:30]([O-])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[Sn](Cl)Cl>C1COCC1.O.C(Cl)Cl>[C:36]([O:35][C:34](=[O:40])[NH:33][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][S:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[C:24]=1[NH2:30])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1cc[nH]c(=O)c1N
Reaction time: 22 h
Yield: 62.9 %

Procedure:
A solution of tert-butyl{(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-[(3-nitro-2-oxo-1,2-dihydropyridin-4-yl)sulfanyl]propan-2-yl}carbamate (44, 507 mg, 0.87 mmol) and ammonium acetate (1.1 g, 14.0 mmol) in THF (12 ml) and water (3 ml) was treated with anhydrous tin(II) chloride (1.04 g, 5.5 mmol) and the mixture stirred at +65° C. for 22 h. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification was performed in a chromatographic column on silicagel, eluted with 30% to 100% EtOAc in hexane to afford title compound (303 mg, 63% yield) as a light green solid. MS: m/z=576.2 (MNa+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([NH:74][C:75](=[O:76])[O:77][CH2:78][CH3:79])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CCOC(N)=O
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCOC(=O)Nc1ccc2c(c1)CN(c1cc(N3CCN(C)CC3)nc(N)n1)CC2
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (22.4 mg, 0.0556 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12.9 mg, 0.0222 mmol, Aldrich, Cat. No. 526460), palladium acetate (2.50 mg, 0.0111 mmol, Aldrich, Cat. No. 379875), cesium carbonate (36.2 mg, 0.111 mmol) and urethane (7.43 mg, 0.0834 mmol, Aldrich, Cat. No. 418331) in 1,4-dioxane (1 mL) was degassed with nitrogen and then heated at 120° C. for 20 h. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=412.2.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.C(O[CH2:22][O:23][CH:24]([CH2:30][O:31]C(=O)C)[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=O)C.N.OCC(CO)OCN1C=CN=C1[N+]([O-])=O.C([Sn](=O)CCCC)CCC.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(#N)C.C1(C)C=CC=CC=1>[C:27]([O:26][CH2:25][CH:24]([O:23][CH2:22][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])[CH2:30][OH:31])(=[O:29])[CH3:28]
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: CCCC[Sn](=O)CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)OCC(CO)OCn1ccnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Nitroimidazole was subjected to trimethylsilylation by use of hexamethyldisilazane in acetonitrile, and the resultant compound and 2-acetoxymethoxy-1,3-diacetoxypropane were subjected to condensation by use of stannic chloride serving as a catalyst. The resultant product was deprotected by use of methanolic ammonia, to thereby obtain 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole. The thus-obtained 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (0.5 g) was refluxed for two hours together with dibutyl tin oxide (0.6 g) in anhydrous toluene in the presence of molecular sieves having a pore size of 4 Å. The solvent was removed under reduced pressure, and anhydrous methylene chloride (16 mL) and anhydrous tetrahydrofuran (4 mL) were added to the residue. The resultant mixture was cooled to 0° C., and acetyl chloride (171 mg) was added to the mixture, and then the mixture was stirred for 30 minutes. To the resultant reaction mixture, a sodium phosphate buffer having a pH of 7.1 (10 mL) was added, and the resultant mixture was subjected to filtration. The resultant residue was subjected to extraction with chloroform (10 mL×3), and the thus-obtained extract was mixed with the filtrate, and the mixture was separated, thereby obtaining an organic layer. The organic layer was dried over sodium sulfate, and then fractionated and purified through silica gel chromatography, to thereby yield the title compound, 1-[1-acetoxymethyl-2-(hydroxy)ethoxy]methyl-2-nitroimidazole (265 mg).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:21][CH:20]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cc3ccccc3c3ccccc23)cc1
Reaction time: 24 h
Yield: 72.2 %

Procedure:
In argon atmosphere, a mixture of 39.25 g (177 mmol) of 9-phenanthreneboronic acid, 50.0 g (177 mmol) of 4-bromoiodobenzene, 4.10 g (3.54 mmol) of tetrakis(triphenylphosphine)palladium (0), 400 ml of toluene, and 265 ml of a 2 M sodium carbonate aqueous solution was refluxed under stirring for 24 h. After the reaction, the reaction mixture was filtered and the aqueous phase was removed. The organic phase was washed with water and dried over magnesium sulfate, and then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 42.6 g (yield: 72%) of 9-(4-bromophenyl)phenanthrene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])C(C(F)(F)F)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[CH:28]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:42]([C:44]([F:47])([F:46])[F:45])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M93) (0.34 g, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (176 mg, 65%).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[S:20][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1>CO.Cl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[S:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2sc3ccncc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1sc2ccncc2c1Nc1ccc(I)cc1F
Reaction time: 2 h
Yield: 53 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (18 mg, 0.03 mmol) was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1 drop) added. The mixture was allowed to stir for 2 hours then evaporated to dryness to give a residue. The residue was partitioned between aqueous saturated NaHCO3 solution (10 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography (Si-SPE, DCM:MeOH, gradient 98:2 to 92:8) to afford the title compound as a yellow solid (8 mg, 50%). LCMS (method A): RT=6.32 min, M+H+=504. 1H NMR (d4-MeOH, 400 MHz) 8.56 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 7.87 (d, J=5.7 Hz, 1H), 7.45 (dd, J=10.5 Hz, 1.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.61 (dd, J=8.5 Hz, 8.5 Hz, 1H), 3.89-3.94 (m, 1H), 3.76-3.85 (m, 2H), 3.45-3.54 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:25])[C:18]([O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:19]
Reactant: CC(=O)CC(=O)OCC1CC1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CC1

Procedure:
500 mg (2.65 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 798 mg (2.65 mmol) of cyclopropylmethyl 3-oxobutanoate, 38 μl (0.66 mmol) of acetic acid and 66 μl (0.66 mmol) of piperidine in 25 ml of anhydrous dichloromethane are heated after addition of 4 Å molecular sieves (1.5 g) under reflux for 24 h. After cooling, the suspension is filtered with suction and the filtrate is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC. 650 mg (74% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:12].[C:21]([O:28][CH2:29][CH3:30])(=[O:27])[C:22]([O:24]CC)=O>CCOCC>[CH2:29]([O:28][C:21](=[O:27])[C:22](=[O:24])[CH:11]([CH3:12])[C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:30]
Reactant: CCC(=O)C1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C(=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
LHMDS solution (39.3 mL, 39.3 mmol, 1M in hexanes) was added to 200 mL of diethyl ether and the mixture was cooled to −78° C. Cyclohexyl ethyl ketone (5.0 g, 35.7 mmol) dissolved in 50 mL of ether was added dropwise, and the resulting mixture was stirred at −78° C. for 1 h. Diethyl oxalate (5.6 mL, 41.1 mmol) was then added dropwise, and the cooling bath was removed and the mixture was allowed to come to room temperature. After the mixture was stirred for 16 h, 1M hydrochloric acid (200 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×100 mL) and the combined organic layers were dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-20% EtOAc/hexanes) to give 5.36 g of the title compound. MS: (−) m/z 239.33 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:17]([O-])=O>CO.[Pd]>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH2:17]
Reactant: Cc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(OCCN2CCOCC2)cc1N
Reaction time: 8 h

Procedure:
To the mixture of 4-(2-(4-methyl-3-nitrophenoxy)ethyl)morpholine (532 mg, 2 mmol) in MeOH (50 mL) was added 10% Pd/C (250 mg). The mixture was stirred under an atmosphere of H2 (balloon) overnight. The contents of the reaction mixture were then filtered and concentrated in vacuo to give the title product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9]CC2C=CC=CC=2)=[CH:4][C:3]=1[O:17][CH3:18].[H][H]>C(O)(=O)C.[Pd]>[Cl:8][C:7]1[CH:6]=[C:5]([OH:9])[CH:4]=[C:3]([O:17][CH3:18])[C:2]=1[Cl:1]
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)cc(Cl)c1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(O)cc(Cl)c1Cl
Yield: 25.9 %

Procedure:
To a solution of 2,3-dichloro-5-benzyloxyanisole (3.4 g, 0.02 mole) in acetic acid (60 ml) was added 5% palladium on carbon (2.0 g) and the mixture hydrogenated using a Parr apparatus at 20 p.s.i. of hydrogen for 3 hours. The catalyst was removed by filtration and the acetic acid evaporated at reduced pressure. The residue was dissolved in ether, extracted with 2N sodium hydroxide acidified, extracted into ether, washed with water, brine, dried over magnesium sulfate and the solvent removed by evaporation in vacuo to give 1.0 g of 3,4-dichlor-5-methoxyphenol which melted at 119°-120° C.
Reaction SMILES: OO.[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[O:12]B(O)O>S([O-])(O)=O.[Na+]>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12]
Reactant: Cc1cc(F)c(F)c(OB(O)O)c1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Product: Cc1cc(O)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under cooling with an ice bath, 53.1 g of aqueous hydrogen peroxide was slowly added dropwise to the compound (3) having been dissolved in 300 mL, followed by stirring at room temperature for 3 hours. Under cooling with an ice bath, 100 mL of a saturated sodium hydrogensulfite aqueous solution was added dropwise thereto to terminate the reaction. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated sodium hydrogensulfite aqueous solution and a saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to obtain 22.7 g of 2,3-difluoro-5-methylphenol (4).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:16])([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(OCC(F)(F)F)c1N
Reaction time: 4 h
Yield: 103.2 %

Procedure:
To a mixture of 2-nitro-3-(2,2,2-trifluoroethyl)oxytoluene (4.12 g) and ethyl acetate (30 ml) was added a catalytic amount of 10% palladium/carbon. Then, the mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed from the reaction solution by filtration, and the filtrate was concentration under reduced pressure to yield the title compound (3.71 g).