Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH:45]([CH2:47][CH3:48])[CH3:46])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH:45]([CH2:47][CH3:48])[CH3:46])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C(C)CC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C(C)CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-butyl) imidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (550 mg) in dichloromethane (1.5 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (299 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-butyl)imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (350 mg) (Compound 352) as yellow amorphous.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:24][C:21]([F:22])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-(2-trifluoromethylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (1.413 g, 4.000 mmol) in dichloromethane (40.0 mL) was added trifluoroacetic acid (6.0 mL, 80.00 mmol). The resulting mixture was stirred at ambient temperature for 24 hours and then quenched with a saturated aqueous solution of Na2CO3 (10.0 mL). The organic phase was washed with water (20.0 mL), brine (20.0 mL), dried over MgSO4 and then concentrated in vacuo. The obtained crude product was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1>C(OCC)(=O)C.CCCCCC>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][CH3:5])=[O:15])=[CH:17][CH:18]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Thionyl chloride (1.33 mL) is added dropwise to methanol (30 mL) under ice-cooling and the solution is stirred for 10 minutes. To the solution is added 4-hydroxycinnamic acid (3.0 g) and the mixture is stirred at room temperature for 4 days. The reaction mixture is concentrated and the residue is diluted with ethyl acetate (50 mL), washed successively with a saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is re-crystallized from ethyl acetate/n-hexane to methyl 4-hydroxycinnamate (2.86 g, yield; 88%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:34]1[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccncc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with pyridin-4-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H19N2O3 (M+H): 335.1390. Found 335.1402
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[I-].[Na+].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38]Br)=[O:36])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38][N:2]([CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH3:1])=[O:36])=[CH:31][CH:30]=1
Reactant: CNCC(O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=S(CCBr)c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCS(=O)c1ccc(F)cc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A suspension (50 ml) of 6-(3-methylamino-2-hydroxypropoxy)carbostyril (3.0 g), sodium iodide (11.8 g), triethylamine (2.2 ml) and 2-(4-fluorophenylsulfinyl)ethyl bromide (3.9 g) in dimethylformamide is heated with stirring at 80°-90° C. for 5 hours. After concentration under reduced pressure, the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol:ammonium hydroxide=200:10:1-150:10:1) and recrystallized from dichloromethane-diethylether to give 6-[3-{[2-(4 -fluorophenylsulfinyl)ethyl]-N-methylamino}-2-hydroxypropoxy]carbostyril (0.7 g), as white powder, m.p. 126°-129° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.O.[C:34](=O)(O)[O-:35].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[C:16]([CH:34]=[O:35])[CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccccc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
1.0 g of N-[4-(trifluoromethyl)phenyl]-2-(2-methoxyphenyl)acetamide was dissolved in 10 mg trifluoroacetic acid, and 0.46 g hexamethylene tetramine was added, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was returned to room temperature, water and ethyl acetate were added, and sodium bicarbonate was further added until the pH reached 8. The reaction solution was extracted with ethyl acetate, washed with brine and dried over anhdydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 0.7 g of N-[4-(trifluoromethyl)phenyl]-2-(5-formyl-2-methoxyphenyl)acetamide as a colorless oil from fractions eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: FC(O)CCCCCCCCCCC.C(O)CCCCC/C=C\CCCC.C(O)CCCCCCC/C=C\CC.[CH2:41]([OH:55])[CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:41]([OH:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].[CH2:41]([OH:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]/[CH2:53][CH3:54]
Reactant: CCCCCCCC/C=C\CCCCO
Agent: CC/C=C\CCCCCCCCO
Agent: CCCC/C=C\CCCCCCO
Agent: CCCCCCCCCCCC(O)F
Product: CC/C=C/CCCCCCCCCCO
Product: CCCCCC/C=C\CCCCCCO

Procedure:
In accordance with the foregoing procedures but where, in place of 1-fluorododecanol there is utilized (Z)-7-dodecenol; (Z)-9-dodecenol; (Z)-5-tetradecenol; (Z)-7-tetradecenol or (E)-11-tetradecenol there are obtained the corresponding (Z)-7-dodecenoic, (Z)-9-dodecenoic, (Z)-5-tetradecenoic, (Z)-7-tetradecenoic, (Z)-11-tetradecenoic or (E)-11-tetradecenoic acids respectively.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].C(Cl)Cl.C(O)(=O)C>CCOC(C)=O>[Br:1][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([F:3])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 95 %

Procedure:
Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of 66.49A (4.79 g, 28.1 mmol) in a 1:1 mixture of DCM (20 mL) and acetic acid (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc, and then the resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the white solid 66.49B was obtained 6.69 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, m), 7.75 (1H, dd, J=10.6, 2.0 Hz), 6.12 (1H, s), 3.94 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH2:26][CH2:25]1>>[CH:20]1([NH:23][C:15]([C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:41]([C:37]5[CH:36]=[C:35]6[C:40](=[CH:39][CH:38]=5)[N:32]([CH2:31][CH2:30][N:27]5[CH2:26][CH2:25][O:24][CH2:29][CH2:28]5)[CH:33]=[CH:34]6)=[O:42])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:19][CH:18]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc2c(ccn2CCN2CCOCC2)c1
Reactant: NC1CC1
Product: O=C(Nc1ccc2c(ccn2-c2ccc(C(=O)NC3CC3)cc2)c1)c1ccc2c(ccn2CCN2CCOCC2)c1

Procedure:
Compound 960 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 1-(2-morpholinoethyl)-1H-indole-5-carboxylic acid. [M+H]+ calcd for C33H33N5O3: 548.26; found 548.13.
Reaction SMILES: [CH2:1]([P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].[Br:15][C:16](Br)=[N:17][OH:18]>C(OCC)(=O)C.O>[Br:15][C:16]1[CH2:3][CH:2]([CH2:1][P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[O:18][N:17]=1
Reactant: ON=C(Br)Br
Reactant: C=CCP(C)(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(C)(=O)CC1CC(Br)=NO1

Procedure:
20 g (0.135 mol) of ethyl allyl(P-methyl)phosphinate are dissolved in 570 ml of ethyl acetate, 49.7 g (0.6 mol) of sodium bicarbonate in 115 ml of water are added and, while stirring vigorously, a solution of 40.6 g (0.2 mol) of dibromoformaldoxime in 115 ml of ethyl acetate is slowly added dropwise. The product is isolated in the form of an oil, 15 g from the ethyl acetate phase, and a further 19 g from the aqueous phase by extraction with dichloromethane at pH 2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:45])C1C=CC(CO)=CC=1>>[CH3:34][O:35][C:36](=[O:45])[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:28][CH:29]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Reactant: COC(=O)c1ccc(CO)cc1
Product: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and 4-hydroxymethyl-benzoic acid methyl ester (CAS Reg. No. 6908-41-4). Brown sticky solid (15%). MS (Turbo Spray): m/z=386.2 (M+H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:12](=O)[CH3:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[N:17]=[C:18]([C:24]2S[CH:26]=[CH:27][CH:28]=2)S[C:20]=1[C:21](=O)[CH3:22].[NH3:29]>>[CH3:15][C@@H:16]1[CH2:20][CH2:21][CH2:22][N:17]1[CH2:18][CH2:24][C:28]1[CH:2]=[C:1]2[C:7](=[CH:26][CH:27]=1)[N:29]=[C:12]([C:9]1[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:11][CH:10]=1)[CH:13]=[CH:6]2
Reactant: N
Reactant: CC(=O)c1cnc(-c2ccccc2)s1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3cnc(-c4ccccc4)s3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G substituting 1-(2-phenyl-thiazol-5-yl)-ethanone (Arcadi, A., et al. Eur. J. Org. Chem. 1999, 11, p. 3117-3126) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.10 Hz, 3H), 1.46 (m, 1H), 1.78 (m, 2H), 1.95 (m, 1H), 2.24 (q, J=8.82 Hz, 1H), 2.39 (m, 2H), 3.01 (m, 2H), 3.13 (m, 1H), 3.29 (td, J=8.48, 2.71 Hz, 1H), 7.47 (m, 3H), 7.61 (m, 2H), 7.81 (d, J=8.48 Hz, 1H), 8.03 (m, 3H), 8.12 (d, J=8.48 Hz, 1H), 8.38 (s, 1H); MS (DCI-NH3) [M+H]+ at 400.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3].C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN1CCCC1=O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][N:45]([CH:2]([C:4]5[CH:5]=[C:6]6[C:11](=[CH:12][CH:13]=5)[N:10]=[CH:9][CH:8]=[N:7]6)[CH3:3])[CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(Br)c1ccc2nccnc2c1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1ccc2nccnc2c1)N1CCN(c2cccc3[nH]c(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 6-(1-Bromo-ethyl)-quinoxaline (0.2 g,0.084 mMol) in N-methyl-pyrrolidinone (3 mL) and diisopropylethylamine (0.029 mL, 0.1 7 mMol) was added 2-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole (0.028 g, 0.084 mMol) and the mixture stirred overnight. Upon arrival the solution was diluted with ethyl acetate (200 mL) and washed with water (4×75mL) and brine (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 5% methanol in dichloromethane yielded 38 mg (92% yield) of 6-(1-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-yl}-ethyl)-quinoxaline as a racemate. This material was separated into the (R) and (S) enantiomers by chiral HPLC using a Chiralcel-OD 250×4.6 mmcolumn with an isocratic 90:10 acetonitrile:ethanol eluant. The first peak had a (+) chirality by CD and a retention time of 5.86 and the second peak a (−) chirality by CD and a retention time of 6.941. The fractions were concentrated and freeze dried to obtain 10 mg of each enantiomers. NMR,MS,and analytical HPLC were identical. 1H NMR (DMSO-d6): δ=12.67 (s, 1H), 8.94 (dd, 2H, J=8.8, 1.8 Hz), 8.11 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 8.02 (d, 2H, J=8.5 Hz), 7.95 (dd, 1H, J=8.7, 1.7 Hz), 7.53 (d, 2H, J=8.6 Hz), 7.02 (m, 2H), 6.47 (dd, 1H, J=7, 1.4 Hz), 3.81 (q, 1H, J=6.8 Hz), 3.58 (br s, 4H), 2.75 (br s, 2H), 2.61 (br s, 2H), 1.49 (d, 3H, J=6.8 Hz), 1.32 (s, 9H). LC/MS (Method A), rt=1.07 mins., purity=99%, calculated mass=490, [M+H]+=491,[M−H]−=489. HPLC (Method C): rt=9.2mins., purity=94% @ 210-370 nm and 95.3% @ 304 nm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][C@H:16]([O:18][CH3:19])[C@@H:15]([O:20][CH3:21])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:21][O:20][C@@H:15]1[C@@H:16]([O:18][CH3:19])[CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CO[C@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)C[C@@H]1OC
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: CO[C@H]1CN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C[C@@H]1OC

Procedure:
The title compound was prepared from (3S,4S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C MS: 437.4 (MH+); HPLC Rf: 4.432 min.; HPLC purity: 98%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]([NH2:36])(=[O:35])[CH:33]=[CH2:34]>CN(C=O)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>[OH:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2](/[CH:34]=[CH:33]/[C:32]([NH2:36])=[O:35])=[CH:7][CH:6]=1)[N:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][CH2:11]2
Reactant: C=CC(N)=O
Reactant: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)/C=C/c1ccc(C2c3ccc(O)cc3CCN2c2ccccc2)cc1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 1-(4-iodo-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.234 mmol), triethylamine (0.163 ml, 1.17 mmol), and acrylamide (0.082 g, 0.351 mmol) in DMF (2 ml), under an atmosphere of N2, was added Pd(PPh3)4 (0.014 g, 0.012 mmol). The solution was heated to 100° C. overnight, then cooled to RT and diluted with water (20 ml). The aqueous mixture was extracted with EtOAc (3×10 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 5% MeOH/CH2Cl2) to give the desired product (0.030 g, 0.089 mmol, 35% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([O:13]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:12].[OH-].[K+].C(O)C.Cl>O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([OH:13])=[O:12]
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)C1=Cc2ccccc2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)O)C1=Cc2ccccc2C1

Procedure:
A mixture of m-phenoxybenzyl 2-(2-indenyl)-3-methylbutanoate (8 mmol), potassium hydroxide (24 mmol), ethanol (25 ml) and water (4 ml) is heated to reflux for about 3 hours. After cooling, the reaction is acidified with dilute hydrochloric acid. The mixture is extracted with ether, and the ether phase is washed to neutrality with saturated NaCl solution. Removal of solvent by evaporation yields 2-(2-indenyl)-3-methylbutanoic acid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.CO[CH:14]([O:25]C)[C:15]1[N:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][NH:22]2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[CH:29]=1.Cl>C1COCC1.C(Cl)Cl>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:35][C:1]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[C:15]([CH:14]=[O:25])[N:24]=3)[CH2:19][CH2:20][CH2:21]2)=[O:2])[CH:29]=1
Reactant: Nc1cc(Cl)c(Cl)cn1
Reactant: O=C(Cl)Cl
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(Cl)cn1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phosgene (20% solution in toluene, 0.186 ml, 0.353 mmol) in THF (2 ml) was added triethylamine (0.141 ml, 1.01 mmol). To the resulting white suspension was added a solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 70 mg, 0.336 mmol) in THF (2 ml) drop wise. The resulting yellow suspension was stirred at room temperature for 1 h. 4,5-dichloropyridin-2-amine (65.7 mg, 0.403 mmol) in THF (1 ml) was added to the mixture and stirred at room temperature for 16 h. The reaction mixture was filtered through a silica gel plug and washed with heptanes/EtOAc 1:1 (35 ml), the filtrate was concentrated. The residue was dissolved in dioxane (1 ml) and treated with HCl (4 M in dioxane, 1 ml, 4.0 mmol). The mixture was stirred at room temperature for 2 h, diluted with DCM and quenched with saturated aqueous NaHCO3. The org. layer was collected and the water layer was extracted with DCM. The combined org. layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was dissolved in acetonitrile/NMP/TFA, filtered through a syringe filter (0.2 μm) and purified by preparative reverse phase LC-MS (RP 1). The clean fractions were combined and lyophilized to obtain the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[N:7]=1.[CH3:28][CH2:29][N:30](C(C)C)C(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>O1CCOCC1.O>[CH2:29]([NH:30][C:19](=[O:20])[CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:5][CH2:4][C:3]3[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:2]=3[F:1])[CH:11]=[CH:10][N:9]=2)[CH:14]=[N:15]1)[CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Agent: CCN
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid I-2 (80 mg, 0.21 mmol, prepared by Procedure B), DIPEA (187 μL, 1.06 mmol) and TFFH (61 mg, 0.23 mmol) in dioxane (4 mL) was stirred for 10 min at room temperature. Ethylamine (2M in THF, 529 μL, 1.06 mmol) was added and the reaction was stirred for 2 h, then diluted with water and extracted with DCM. The organic layer was concentrated in vacuo and purified by prep. HPLC to afford N-ethyl-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-6 (8.8 mg, 0.02 mmol). LC-MS (Method B), RT=5.23 min. (ES+) 406.