Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH2:21]Cl)=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:21][CH:20]=[CH:19][C:18]2[CH:23]=[CH:24][C:15]([O:14][CH2:13][O:12][CH3:11])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: COCOc1ccc(C=CCCl)cc1[N+](=O)[O-]
Reactant: Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C=CCSc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Under a current of argon, a solution having 251 mg of sodium hydride suspended in 10 ml of tetrahydrofuran and 906 mg of p-chlorothiophenol added thereto as kept cooled with ice were stirred for 30 minutes and the produced mixture and a solution of 1.62 g of 4-methoxymethoxy-3-nitrocinnamyl chloride in 5 ml tetrahydrofuran added thereto were stirred at normal room temperature for 14 hours. The resultant reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum. The concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (5:1 V/V) eluate, 1.77 g of 5-[3-(4-chlorophenylthio)-1-propenyl]-2-methoxymethoxy nitrobenzene was obtained in the form of a colorless oily substance. The yield was 77%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)C(=O)O
Yield: 89.4 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 129) (110 mg, 0.20 mmol) and sodium hydroxide (1M, 0.8 ml, 0.8 mmol) by a procedure analogous to that described in example 51, yielding ((E)-(S)-3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (92 mg, 88%) as a colourless solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][C:14]=2[Cl:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-azidophenyl)thiazol-2-amine (1.18 g, 5.43 mmol) in DMF (18 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (0.746 g, 5.59 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into water (100 mL). The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)-5-chlorothiazol-2-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78 °C.) solution of 1,4-dibromobenzene (33 g, 139.8 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (59.0 mL, 146.8 mmol, 2.49 M in hexane) dropwise. The viscous solution was stirred at −78° C. for 45 min, and cyclopentanone (13.6 mL, 153.8 mmol) was then added dropwise over 30 min. The resulting solution was stirred at −78° C. for 1 h and was then quenched by the addition of 0.5M HCl (200 mL) and ethyl acetate (200 mL). The layers; were separated, and the organics were washed with water (1×100 mL), brine (1×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 5% ethyl acetate in hexane to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.71-1.76 (m, 2 H), 1.78-1.88 (m, 6 H), 4.85 (s, 1 H), 7.39-7.43 (m, 2 H), 7.44-7.49 (m, 2 H).
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2Br)[O:3][CH2:2]1.CON(C)[C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][C:16]([C:8]2[CH:9]=[CH:10][C:5]([CH:4]3[O:12][CH2:1][CH2:2][O:3]3)=[CH:6][CH:7]=2)=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Brc1ccccc1C1OCCO1
Reactant: CON(C)C(=O)CC1CCCCC1
Product: O=C(CC1CCCCC1)c1ccc(C2OCCO2)cc1
Yield: 84 %

Procedure:
Following the procedure of Example D, 11 g (0.048mole) of p bromobenzaldehyde ethylene acetal and 8.9 g of the product of Example I were combined to give after chromatography on silica gel using 15% ethyl acetate/hexane 11 g of the title compound (84% yield).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C([Zn]CC)C.ICI.[CH3:16][CH2:17][O:18][C:19]([C@@H:21]1[CH2:25][CH:24]=[CH:23][N:22]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC>[CH2:17]([O:18][C:19]([C@@H:21]1[CH2:25][C@H:24]2[C@H:23]([CH2:1]2)[N:22]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:20])[CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Agent: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ICI
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C. a solution of TFA (104 mmol, 2.0 eq) in DCM (50 mL) is added dropwise to a solution of diethylzinc (104 mmol, 2.0 eq) in hexane (104 mL) and DCM (100 mL). After 30 min a solution of diiodomethane (104 mmol, 2.0 eq) in DCM (50 mL) is added slowly to the white suspension. The mixture is stirred for 10 min and treated with a solution of (S)-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (52 mmol, 1.0 eq) in DCM (50 mL). After 5 min the mixture is allowed to reach RT, stirred for additional 2.5 h, cooled to 0° C. and treated slowly with TEA (18 mL). After 14 h a sat. aqueous NaHCO3 solution is added and the mixture is filtered through Celite. The residue is washed with DCM (100 mL) and the layers are separated. The organic layer is washed twice with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (heptane/EtOAc 9/1) to give the desired product as a pale yellow oil. LC-MS (basic): tR=0.90 min; [M+H]+=256.3.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].N1C=CC=CC=1.[CH2:10]([O:12][N:13]=[C:14]([CH2:18][C:19]([CH3:21])=[CH2:20])[C:15](=O)[CH3:16])[CH3:11]>O.CO>[CH2:10]([O:12][N:13]=[C:14]([CH2:18][C:19]([CH3:21])=[CH2:20])[C:15](=[N:3][OH:2])[CH3:16])[CH3:11]
Reactant: C=C(C)CC(=NOCC)C(C)=O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: C=C(C)CC(=NOCC)C(C)=NO
Yield: 81.8 %

Procedure:
By the method of Example 4, 211.3 g of hydroxylammonium chloride in 400 ml of water and 240 g of pyridine were reacted with 342.4 g of 5-methylhex-5-ene-2,3-dione 3-(O-ethyloxime) in 800 ml of methanol. This gave 305 g of the title compound as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:24][CH:25]=[CH2:26])[CH3:28])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Reactant: C=CCNC
Solvent: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 73.9 %

Procedure:
5.0 g (13.0 mmol) 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester were treated with 3.66 g (51.5 mmol) N-allyl-methylamine in 100 ml DMF at 50° C. for 30 min. The mixture was concentrated in vacuo, dissolved in Et2O and water. The inorganic layer was extracted with Et2O, and the combined organic phases were washed with water and dried over Na2SO4. Purification by column chromatography on silica gel with CH2Cl2/MeOH 10:1 yielded 3.6 g (74%) 6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 375 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](C(F)(F)F)=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24](O)=[O:25].C(N1CCN(C2SC(C(O)=O)=C(C)C=2)C1=O)C1C=CC=CC=1.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:24]([NH:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:25])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-benzyl-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 46% yield: mp 130-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.51 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.38-7.22 (m, 6H), 6.18 (t, J=5.6 Hz, 1H), 6.07 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.44 (s, 2H), 3.81-3.74 (m, 2H), 3.47-3.40 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 155.9, 149.2, 148.8, 142.6, 141.8, 135.9, 135.5, 128.8, 128.2, 127.9, 123.6, 118.9, 112.3, 48.1, 42.7, 41.5, 41.2, 16.1; MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/I)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[S:26]1[C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1>CN(C)C=O>[S:26]1[C:30](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2
Reactant: COC(=O)COc1ccc(OC/C=C(\I)c2ccc(Br)cc2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2cc3ccccc3s2)cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl (Z)-[4-[3-(4-bromophenyl)-3-iodoallyloxy]-2-methylphenoxy]acetate (760 mg, 1.47 mmol) and (benzo[b]thiophen-2-yl)-tributyltin (0.72 g, 1.7 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and the solution was degassed. 0.15 M solution of tri-t-butylphosphine in cyclohexane (1.2 mL, 0.18 mmol) and tris(dibenzylidenacetone)dipalladium chloroform complex (46 mg, 0.044 mmol) were added; the reaction solution was degassed again and then stirred under inert atmosphere at 50° C. for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with 10% aqueous solution of potassium fluoride (50 mL), water (2×50 mL) and brine (2×30 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95:5-90:10) yielding methyl (Z)-[4-[3-(benzo[b]thiophen-2-yl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[N:27]=[C:26]([O:25][CH3:24])[N:43]([CH3:44])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1nc2cc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cnc2n1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 71.1.1) to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.24-8.20 (m, 1H), 8.17-8.13 (m, 1H), 8.13-8.08 (m, 1H), 7.97-7.92 (m, 1H), 7.87-7.83 (m, 1H), 7.55-7.53 (m, 1H), 4.16 (s, 3H), 3.91 (s, 3H), 3.57 (s, 6H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:35])[CH2:8][C:9]([CH3:34])([CH3:33])[O:10]2)=[CH:5][CH:4]=1.[C:36](N1C=CN=C1)([N:38]1C=CN=C1)=O.CN.C(OCC)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:38][CH3:36])=[O:32])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:35])[CH2:8][C:9]([CH3:33])([CH3:34])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.0 g of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylic acid was dissolved in 25 mL of ethanol, added with 851 mg of 1,1′-cabonyldiimidazole and the reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled with an ice-water bath, added 1.81 mL of 40% methylamine aqueous solution thereto and stirred for 50 minutes. The reaction mixture was added with 40 mL of ethyl acetate and 20 mL of water and the organic layer was separated. The organic layer was washed with 20 mL of 10% sodium chloride solution and added with 8.5 mL of 1 N hydrochloric acid to adjust the pH to 7. The aqueous layer was discarded and the organic layer was washed with 10 mL of water. The organic layer was concentrated in vacuo, added with 3 mL of 1-propanol and concentrated again and the title compound was obtained.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:6][C:5]=2[CH:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Product: Cc1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.261 g, 1.57 mmol, Example 14b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.54 g, 1.6 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 216-217° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:26]([F:27])=[C:25]([F:28])[C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[C:6]([F:29])[C:5]=1[OH:30])([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:26]([F:27])=[C:25]([F:28])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:23][CH:24]=2)=[C:6]([F:29])[C:5]=1[OH:30]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1c(O)c(F)c(Oc2ccc(C(=O)O)cc2)c(F)c1F
Reaction time: 72 h
Yield: 93 %

Procedure:
50 g of benzyl 4-(4-nitro-3-hydroxy-2,5,6-trifluorophenoxy)benzoate prepared as described in Example 1 (0.12 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17].[C:23](Cl)(=[O:25])[CH3:24]>O1CCCC1>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)NC(=S)Nc1cc(Sc2ccccc2)ccc1N
Solvent: C1CCOC1
Product: COC(=O)NC(=S)Nc1cc(Sc2ccccc2)ccc1NC(C)=O
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-1-(3-methoxycarbonyl-2-thioureido)-5- phenylthiobenzene, as prepared according to Example XI, is dissolved in 20 ml. tetrahydrofuran and treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized from methanol, yielding 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-5-phenylthiobenzene.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[C:10]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]=2[C:5](=[O:28])[N:4]([CH2:29][CH2:30][CH2:31][O:32]C2CCCCO2)[C:3]1=[O:39]>Cl.CO>[OH:32][CH2:31][CH2:30][CH2:29][N:4]1[C:5](=[O:28])[C:6]2[C:10]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:25])[F:27])[CH:18]=3)[S:8][C:7]=2[N:2]([CH3:1])[C:3]1=[O:39]
Reactant: CC(C)CC(=O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl
Solvent: CO
Product: CC(C)CC(=O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCO)c(=O)n2C
Yield: 23.4 %

Procedure:
A solution of 1-methyl-5-(3-methylbutanoyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.053 mmol) in concentrated HCl (1 mL) and MeOH (5 mL) was stirred at RT for 1 h then concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-5-(3-methylbutanoyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 23.4% yield) as a white solid. 1H NMR (CDCl3) δ: 7.48-7.37 (m, 2H), 7.32 (s, 1H), 7.26-7.23 (m, 1H), 4.18 (t, J=6.1 Hz, 2H), 3.61 (s, 3H), 3.55 (dd, J=11.7, 6.3 Hz, 2H), 3.04 (t, J=7.0 Hz, 1H), 2.54 (d, J=6.6 Hz, 2H), 2.14 (dt, J=13.3, 6.7 Hz, 1H), 1.97-1.85 (m, 2H), 0.84 (d, J=6.7 Hz, 7H). LCMS: MH+ 485 and TR=3.100 min.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH2:8])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[C:35](Cl)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[C:35]([NH:8][C@H:4]4[CH2:5][CH2:6][CH2:7][O:2][CH2:3]4)=[C:30]3[CH:29]=[CH:28]2)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CCCOC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCCOC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
(S)-(Tetrahydro-pyran-3-yl)amine hydrochloride (40.7 g, 296.09 mmol) and N,N-diisopropylethylamine (130 mL, 760 mmol) were added to a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (100.0 g, 296.09 mmol) in ispropanol (1.0 L). The mixture was stirred at an internal temperature of 75° C. for 4 hours. The mixture was then allowed to cool down slowly and left still overnight. The resulting solid was collected by filtration and washed with cold isopropanol. The solid was then dried in a vacuum oven for 24 h to afford 114.0 g (95.7%) of (1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(S)-tetrahydro-pyran-3-yl-amine as a yellow solid. LCMS (Method D, ESI): RT=1.63 min, m+H=403.2; 1H NMR (400 MHz, DMSO) δ 9.21 (d, J=8.1 Hz, 1H), 8.92 (s, 1H), 8.13 (d, J=7.8 Hz, 2H), 7.77 (dt, J=25.1, 10.9 Hz, 2H), 7.66 (t, J=7.7 Hz, 2H), 7.02 (d, J=4.1 Hz, 1H), 4.28 (s, 1H), 3.88-3.65 (m, 3H), 3.56 (t, J=8.9 Hz, 1H), 2.00 (t, J=11.5 Hz, 1H), 1.93-1.63 (m, 2H), 1.53 (dd, J=9.4, 4.2 Hz, 1H), 1.28 (t, J=6.9 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]=1[CH3:8])=[O:2].C(O)(=O)C.C(Cl)(Cl)Cl.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:5]1[S:4][C:3]([CH:1]=[O:2])=[C:7]([CH3:8])[C:6]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C2CCCCC2)csc1C=O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)sc(Br)c1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 2-formyl-3-methyl-4-cyclohexylthiophene (4.1 g, 20 mmol, See Example 22) in 30 mL of a mixture prepared from acetic acid and chloroform (1:1), was added solid N-bromosuccinimide (5.3 g, 30 mmol) slowly in portions at 0° C. The reaction mixture was then stirred overnight at room temperature, poured into water, and extracted repeatedly with dichloromethane. The combined organic layers were washed with saturated NaHCO3 and brine solutions, and dried over anhydrous Na2SO4. After the solvent was removed by rotary evaporation, the remaining solid was purified by column chromatography using silica gel and a dichloromethane-petroleum ether (2:3) as eluant. The solvent was removed by rotary evaporation yielding 3.3 g white solid (57%). 1H NMR (CDCl3) δ 9.97 (s, 1, CHO), 2.88 (m, 1,cyclohexyl methane), 2.59 (s, 3,CH3), 1.87 and 1.34 m, 10, cyclohexyl)
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.[CH:12]1[CH:13]=[CH:14][C:15]2[N:20](O)N=[N:18][C:16]=2[CH:17]=1>CS(C)=O>[N:20]1[C:15]2[C:16](=[CH:17][CH:12]=[CH:13][CH:14]=2)[N:18]=[CH:2][CH:1]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Solvent: CS(C)=O
Product: c1ccc2nccnc2c1

Procedure:
Compounds of structure H may be prepared as illustrated in Scheme 2. Reaction of a carboxylic acid E with various hydrazides in the presence of EDCI and HOBt in DMSO yields quinoxaline F. Quinoxaline F may then be treated with phosphorus oxychloride to give quinoxaline G. Subsequent reaction of quinoxaline G with ammonia at elevated temperature then provides compounds H.