Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:50][S:51]([CH2:54][CH2:55][OH:56])(=[O:53])=[O:52]>[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:56][CH2:55][CH2:54][S:51]([CH3:50])(=[O:53])=[O:52])=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCO
Reactant: Cc1c(Nc2ccc(I)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(Nc2ccc(OCCS(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 3 %

Procedure:
General procedure of coupling alcohol to aryl halides: A mixture of 4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (103 mg, 0.2 mmole), cesium carbonate (130 mg, 0.4 mmole), copper iodide (8 mg, 0.04 mmole), and 1,10-phenanthroline (14 mg, 0.08 mmole) in 2-methanesulfonyl-ethanol (3 mL) was heated under microwave irradiation at 150° C. for 1 hour. The crude mixture was purified by HPLC to provide Compound A95 as a yellow solid (3 mg, 3%). Exact mass calculated for C23H31FN4O6S 510.2, found 511.3 (MH+).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[O:19][CH:20]=2)[CH:14]=1.C(C#N)(C)=[O:29]>O=[Mn]=O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:29])[OH:22])[O:19][CH:20]=2)[CH:14]=1
Reactant: CC(=O)C#N
Reactant: O=C(Nc1cnn(Cc2coc(CO)n2)c1)OCc1ccccc1Cl
Agent: O=[Mn]=O
Agent: N#N
Product: O=C(Nc1cnn(Cc2coc(C(O)O)n2)c1)OCc1ccccc1Cl
Temperature: 55 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-hydroxymethyl-oxazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (238 mg, 0.65 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (317 mg, 3.28 mmol) and the reaction mixture was stirred at 55° C. for 4 h before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a brown oil. TLC: rf (EA)=0.48. LC-MS-conditions 02: tR=0.81 min; [M+H]+=379.22.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[C:15]([OH:17])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[NH:32][CH3:33]>C(Cl)Cl>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[N:32]([CH3:33])[C:15]([C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)c1nc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
To a suspension of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (1 eq, 0.38 mmol, 101 mg) in anhydrous DCM (3 ml), I drop of DMF was added, followed by 2M oxalyl chloride in DCM (1.7 eq, 0.65 mmol, 330 ul) dropwise. Effervescence was seen and the reaction was stirred at room temperature for 40 mins before evaporating in vacuo. The crude material was dissolved in DCM (3 ml) and 2-chloro-N-methyl aniline (2 eq, 0.76 mmol, 94 ul) was added. The reaction was stirred at room temperature for 16 hr and extracted into DCM, washed with aq K2CO3, the organic layer dried over MgSO4, filtered, and purified on silica (ISCO, gradient 0% ethyl acetate/petrol to 25% ethyl acetate/petrol) to give 326 as a white solid (42 mg, yield 30%). 1H NMR DMSO, 2.89-2.92 (2H, m), 3.43 (3H, s), 4.23 (2H, br. m), 7.02 (1H, d, J=8.4), 7.08 (1H, t, J=7.6), 7.26 (1H, t, J=8), 7.38-7.41 (2H, m), 7.48-7.51 (2H, m), 7.58 (1H, d, J=8.4). MS: (ESI+): MH+ 371, purity >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:38])[CH2:17][C@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=4)[CH2:11]3)[N:7]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:6]=2[CH:44]=1.ClCCl.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>CO.CC#N.O>[NH2:30][C@H:18]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]2[N:7]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:6]3[CH:44]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11]1)=[O:38].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccc(Cl)cc21

Procedure:
tert-Butyl (R)-4-((R)-3-(6-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (32E) (0.135 mmol max, crude oil) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (15-55% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-1-((R)-3-(6-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (99) as its trifluoroacetic acid salt and as a white flocculent solid (0.074 mmol, 0.047 g, 55% yield over 3-steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.54 (m, 1H) 1.68-2.11 (m, 5H) 2.61-2.77 (m, 3H) 2.88-3.44 (m, 9H) 3.71-4.04 (m, 2H) 4.07-4.23 (m, 1H) 4.25-4.39 (m, 1H) 4.49 (dd, J=36.51, 13.26 Hz, 1H) 7.21-7.31 (m, 1H) 7.44 (ddd, J=8.40, 4.61, 1.64 Hz, 1H) 7.47-7.56 (m, 2H) 7.61 (dd, J=17.43, 8.59 Hz, 1H) 7.71-8.06 (m, 5H). ESI-MS: m/z 519.4 (M+H)+,
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=[CH:26][C:27]#[N:28])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=[CH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Na+]
Product: C(=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12)c1nnn[nH]1

Procedure:
Following the procedure of Example 56, N-benzyl-5-benzyloxy-3-(2-cyanovinyl)indole is reacted with the sodium azide to give N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indole. (m.p. 178°-180° C. (dec.))
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].FC(F)(F)C(O)=O.[CH2:20]([N:27]([CH2:33]OC)[CH2:28][Si](C)(C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(OCC)(=O)C>[CH2:20]([N:27]1[CH2:33][CH2:9][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Reaction time: 2 h
Yield: 139.4 %

Procedure:
2-Fluoro-1-nitro-4-vinyl-benzene (360 mg, 2.15 mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (70 μl, 0.88 mmol) was added, followed by slow addition of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (633 mg, 2.67 mmol). Stirring was continued for 2 h at room temperature. Another portion of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (300 mg, 1.26 mmol) was added and stirring continued for another 30 minutes. The reaction mixture was diluted with ethyl acetate (25 ml), washed with aqueous NaHCO3 (15 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (900 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-25%). Fractions containing the product were combined, the solvent evaporated to yield an oil (550 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:21]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]([OH:13])[CH3:21])=[N:7]2
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde (0.4405 g, 1.537 mmol) in THF (14.95 mL, 1.537 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.024 mL, 3.073 mmol) dropwise at 0° C. and the mixture was then allowed to warm to room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, dd, J=8.4, 1.2 Hz), 8.06 (1H, dd, J=7.6, 1.4 Hz), 7.87 (1H, dd, J=8.4, 7.6 Hz), 7.56-7.71 (3H, m), 7.37-7.46 (1H, m), 5.50 (1H, d, J=6.1 Hz), 5.04-5.13 (1H, m), 1.48 (3H, d, J=6.3 Hz); LC-MS (ESI) m/z 303.1 [M+H]+.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si:14]([O:21][CH2:22][C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][NH:30][C:31](=[O:47])[C@H:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=2[CH3:46])[C@@H:33]([OH:35])[CH3:34])=[O:28])=[CH:25][CH:24]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[Si:10]([O:35][C@@H:33]([CH3:34])[C@@H:32]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=1[CH3:46])[C:31]([NH:30][NH:29][C:27](=[O:28])[C:26]1[CH:48]=[CH:49][C:23]([CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:24][CH:25]=1)=[O:47])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 135 %

Procedure:
Imidazole (3.99 g, 58.55 mol) and TBDMS-Cl (5.29 g, 35 mmol) were added sequentially to a pre-cooled (0° C.) solution of 4-((tert-butyldimethylsilyloxy)methyl)-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (6.22 g, 11.71 mmol) in DMF (300 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, whereupon the solution was poured into H2O (120 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (200 mL). This organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (10.2 g). This crude product was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.CCN(CC)CC.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCNC1CCc2cccc(OC)c2C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 60 mg (0.27 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) and 0.11 mL Et3N (0.79 mmol) in 5 mL dry CHCl3 was cooled in an ice bath. After adding 0.05 ml (0.41 mmol) 2-thienylacetic acid chloride (A3-1: W═Cl, Cy=2-thienyl) to the mixture the ice bath was removed and the reaction was stirred for 2 hrs at room temperature. In a second step further 0.05 mL (0.41 mmol) of 2-thienylacetic acid chloride (A3-1) were added and the reaction stirred for 20 hrs. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and finally extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 40/1 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2nccn2O)cc1
Agent: Cl
Product: COc1ccc(-c2nccn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, crystals).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:31](Cl)(=[O:33])[CH3:32].[Cl-].C(N(CC)CC)C>O.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH:30]=3)=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncncc2C2=CCNCC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1

Procedure:
To a round bottom flask was added (1H-benzo[d]imidazol-2-yl)(4-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yloxy)phenyl)methanone (60.8 mg, 0.153 mmol) with DCM (1 mL) under nitrogen. With stirring, acetyl chloride (12 μL, 0.168 mmol) was added dropwise to a yield a suspension that quickly became a solution. After complete addition of the chloride, triethylamine (32.0 μL, 0.229 mmol) was added in one aliquot. The reaction was diluted with water after 10 minutes and extracted with dichloromethane before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a yellow oil. It was purified by column chromatography (2M NH3/MeOH/DCM). The resulting oil was resolubilized in dichloromethane and flushed through a plug of silica to yield 1-(4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a pale yellow oil. MS (ESI, pos. ion) m/z: 440.2 (M+1). IC50 (uM) ++++.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])(=[O:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O)C.[OH-].[K+]>C(OCC)(=O)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[CH:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])=[O:3]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)c1c(C)n(CCN2CCOCC2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(C(=O)C=Cc2ccccc2F)c2ccccc2n1CCN1CCOCC1

Procedure:
Following a procedure similar to that described in Example 20A above, 14.75 g. (0.0516 mole) of 3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml. of ethanol in the presence of 3.44 g. (0.061 mole) of potassium hydroxide pellets and the product, in the form of the free base, recrystallized from ethyl acetate to give 10.0 (54%) of 3-(2-fluorocinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole. m.p. 113°-116° C.
Reaction SMILES: C([N:8]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][CH:10]([O:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1)[CH2:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:32]([NH:8][CH2:9][CH:10]([O:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1)[CH2:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1

Procedure:
5 g of 4-[3-(N-benzyl-tert-butylamino)-2-nicotinoyloxypropoxy]oxindole are debenzylated with hydrogen in 25 cc of tetrahydrofuran, in the presence of 1 g of a palladium catalyst (10% of palladium on charcoal). The title compound is obtained, the dihydrochloride thereof having a M.P. of 215°-218°.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=[O:4].[Na+].Cl>CCOC(C)=O>[F:13][C:2]([F:1])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)c1ccc(F)cn1
Yield: 95.1 %

Procedure:
To sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 step B (1 g, 4.69 mmol) were added EtOAc (50 mL) and 4 N HCl (50 mL) and the mixture was shaken. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure to afford 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid (852 mg, 95%) as an oil that solidified upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.88-8.03 (m, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[O:11][N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:8][OH:7])[CH:13]=2)[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1
Reactant: FC(F)(F)c1cc(-c2cc(COC3CCCCO3)no2)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]isoxazole (Example 323A) (0.590 g, 1.49 mmol) in DCM (15 mL) was added TFA (1.5 mL). The reaction is stirred at rt overnight. Solvent and excess TFA were removed in vacuo. The residue was purified by radial chromatography (0-60% EtOAc-hexanes gradient) to afford the title compound (0.320 g, 69% yield): MS (ES) m/z 312 (M+1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:7]=1[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13]Br>O1CCCC1.C(Cl)Cl>[CH:1]1([NH:4][CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:8][C:7]2[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:6]=2[F:5])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCC#CCNC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of cyclopropylamine (1.10 ml, 15.8 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (530 mg, 1.58 mmol) in tetrahydrofuran (8 ml). The cloudy reaction mixture was stirred for about thrity minutes. The reaction mixture was then cooled to 0° C., and held at this temperature for about four hours, at which time no starting material remained, as determined by thin layer chromatography. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 1 M potassium carbonate (10 ml). The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by preparative high performance liquid chromatography, affording 362 mg (73%) of the title intermediate as a clear oil.
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:23])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[ClH:24]>CCOC(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[O:23])=[CH:17][CH:18]=1
Reactant: Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccn(Cc2cccc(Cl)c2)c1=O
Solvent: CCOC(C)=O
Product: O=c1c(O)cccn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pyridin-2-one, 2, (2.36 g, 10 mmol) in EtOAc (25 mL) as added 5 M HCl (25 mL) with vigorous stirring at room temperature. The reaction was monitored by TLC for the disappearance of starting material and was complete within 30 minutes. The organic layer was decanted and the aqueous phase extracted with dichloromethane (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was recrystallized from dichloromethane. The yield was nearly quantitative. 1H NMR (360 MHz, DMSO-d6) δ ppm 5.12 (2H, s); 6.13 (1H, t, J=7.04); 6.71 (1H, dd, J=7.04, 1.59); 7.23-7.28 (2H, m); 7.36-7.43 (2H, m); 9.10 (1H, br. s).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=3)=[N:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: CCCCCCCOc1ccc(-c2ncc(C=CCCCCCCCC3CCCC3)cn2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc(-c2ncc(CCCCCCCCCC3CCCC3)cn2)cc1

Procedure:
A solution of 1.86 g of 5-(9-cyclopentyl-non-1-enyl)-2-(4-heptyloxy-phenyl)-pyrimidine in 35 ml of toluene is hydrogenated with 0.24 g of 5% palladium/charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. Recrystallization from ethanol of the crude product obtained after filtration and concentration of the filtrate yields pure 5-(9-cyclopentyl-nonyl)-2-(4-heptyloxy-phenyl)-pyrimidine.