Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1F.CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH2:16][CH3:17]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 96.4 μmol) was dissolved in DMF (200 μL). NaH (2776 μg, 115.7 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (22.6 μL, 192.8 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC (10-40%, 60 min, BDS) to yield the title compound as a mono-TFA salt oil (24.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO2, 304.08. found 304.0.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][C:13]2[NH:17][C:16]3=[CH:18][S:19][CH:20]=[C:15]3[N:14]=2)[CH:6]=1>C(#N)C>[OH:2][CH2:1][N:14]1[C:15]2=[CH:20][S:19][CH:18]=[C:16]2[N:17]=[C:13]1[S:12][CH2:11][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[CH:10]=[CH:9][N:8]=1
Reactant: C=O
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Solvent: CC#N
Product: COc1ccnc(CSc2nc3cscc3n2CO)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 0.7 ml of 37% strength aqueous formaldehyde solution in 3 ml of acetonitrile was added dropwise to 1.6 g (5.8 mmol) of 2-(4methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole dissolved in 50 of acetonitrile. The mixture was then stirred at 70° C. for 15 minutes. The solution was concentrated in vacuo, washed with water and saturated aqueous NaCl solution and dried over MgSO4. The residue obtained after evaporation resulted, after treatment with diisopropyl ether, in a semicrystalline crude product which crystallized from ethyl acetate. Melting point 125°-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH:26]=[C:5]2[CH2:6][CH2:7][N:8]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1.NN>C(O)C.[Pd]>[CH3:1][N:2]1[CH:26]=[C:5]2[CH2:6][CH2:7][N:8]([C:15](=[O:25])[C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1
Reactant: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Yield: 90.5 %

Procedure:
A mixture of 0.520 g of 2,4,5,6-tetrahydro-2-methyl-6-(4-nitrobenzoyl)pyrazolo[4,3-d][1]benzazepine, 118 μl of anhydrous hydrazine and 52 mg of 10% palladium-on-carbon in 30 ml of absolute ethyl alcohol is heated at reflux for 1 hour. The reaction mixture is filtered through diatomaceous earth and the cake washed with 100 ml of methyl alcohol and 1:1 chloroform-methyl alcohol to give 430 mg of the desired product as off-white crystals. CIMS(CH4)MH+ =319.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[O:7])=[C:4](F)[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CO.CN1C(=O)CCC1>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[C:4]([O:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][C:26]=2[O:31][CH3:32])[CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cc1
Reactant: COc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1cc(Cl)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
A mixture of methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (34.21 mg, 0.1 mmol), 4-chloro-2-methoxyphenol (12.16 μl, 0.1 mmol), potassium carbonate 13.82 mg, 0.1 mmol) and N-methyl pyrrolidinone (1 mL) were heated at 80° C. for 2.5 hours. Methanol (100 μL) and sodium hydroxide (3M, 100 μL, 0.3 mmol) were added and the reaction was stirred at 50° C. for 2 hours. An additional 100 μL of MeOH and 100 μL of 3M NaOH were added and the reactions were heated for another hour. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) (11.78 mg, 25%). ESI-MS m/z calc. 464.99. found 466.3 (M+1)+; Retention time: 2.20 minutes (3 minutes run).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:3]=1[C:4](OC(C)(C)C)=[O:5].COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:46])[CH3:44])[CH:12]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-({2-[(tert-butoxycarbonyl)-amino]ethyl}amino)-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-nicotinate (0.113 g, 0.178 mmol) in THF (5 mL) was added a solution of Vitride® (3.4 M, 1.0 mL, 3.4 mmol). The mixture was stirred at 0° C. for 0.5 hrs, quenched with saturated aqueous potassium sodium tartaric acid solution, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a solid, which was triturated with ethyl acetate and diisopropyl ether to give tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethylcarbamate as a pink solid (0.078 g, yield; 78%).
Reaction SMILES: Br[C:2]([F:17])([F:16])[S:3][C:4]1[N:8]=[CH:7][N:6]([C:9](=[O:15])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[N:5]=1.C([O-])=O.[NH4+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>CN(C)C=O.O>[CH2:13]([N:10]([CH2:11][CH3:12])[C:9]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH:2]([F:16])[F:17])=[N:5]1)=[O:15])[CH3:14]
Reactant: CCN(CC)C(=O)n1cnc(SC(F)(F)Br)n1
Agent: O=C[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)n1cnc(SC(F)F)n1
Temperature: 50 °C
Yield: 87.2 %

Procedure:
To a stirred solution of 10.7 g (0.033 mol) 3-(bromodifluoromethylthio)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as in Example 1, step (c), in 25 ml N,N-dimethylformamide, was added 4.11 g (0.065 mol) ammonium formate and 2.24 g (0.01 mol) ammonium persulfate and the mixture was heated at 50° C. for 2.5 h. The reaction mixture was then diluted with 100 ml water and extracted with ether (3×100 ml). The combined resulting organic layers were washed with water, dried over MgSO4 and evaporated to give 7.2 g (88% yield) of the desired 1-(N,N-diethylcarbamoyl)-3-(difluoromethylthio)-1,2,4-triazole as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Product: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1
Yield: 30 %

Procedure:
Beginning with 0.189 gm (0.90 mMol) 1-(4-indolyloxy)-3-chloropropane and 0.300 gm (0.90 mMol) 4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 0.137 gm (30%) of the title compound was recovered as a white solid by the procedure described in Example 1.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][O:12][C@@H:11]([CH3:25])[O:10]1>ClCCl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([C@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][O:12][C@@H:11]([CH3:25])[O:10]1)=[O:7]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of pyridine (1.64 ml) in dichloromethane (45 ml) was added chromium trioxide (1.07 g) at 10° C. and the solution was stirred at room temperature for 1 hour. The solution was cooled in an ice bath and was added (2R,4R,5S)-4-hydroxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (500 mg) in dichloromethane (3 ml). After being stirred at room temperature for 2 hours, the solution was diluted with ether (100 ml) and passed through a silica gel column. The eluate was evaporated in vacuo and the residue was chromatographed on a silica gel column (20 g) with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (336 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[CH3:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Br:1][C:2]1[S:3][C:4]([N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH3:8])=[CH:5][CH:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Brc1ccc(Br)s1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Br)s1
Yield: 31.3 %

Procedure:
To the solution of 2,5-dibromothiophene (20 g, 82.6 mmol) and 2-methyl-1H-imidazole (4.1 g, 50 mmol) in DMSO (100 mL) was added CuI (3.14 g, 16.5 mmol), L-proline (0.95 g, 8.3 mmol), K2CO3 (22.9 g, 0.165 mol), the resultant mixture was heated to 100° C. under N2 balloon protection overnight. The reaction mixture was filtrated and the filtrate was poured into water, extracted with EtOAc (300 mL×5). The combined organic layers were washed with brine, dried over Na2SO4, and then filtrated, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give desired 1-(5-bromothiophen-2-yl)-2-methyl-1H-imidazole (3.8 g, yield 31.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[F:9][C:10](I)([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>CS(C)=O.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]([F:27])([F:9])[C:11]([F:25])([F:26])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Fc1cccc(I)c1
Agent: [Cu]
Solvent: CS(C)=O
Product: Fc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1

Procedure:
1-Fluoro-3-(perfluorohexyl) benzene was prepared by heating 6.02 g 1-fluoro-3-iodobenzene and 13.3 g perfluorohexyl iodide with excess copper in dimethyl sulfoxide (DMSO) at approximately 125° C. for 24 hours. The product, 1 -fluoro-3-perfluorohexyl benzene, was obtained in good yield (10.0 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:30])[C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:21][OH:22])[CH3:17])=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:36]([F:38])[F:37]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:30])[C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:21][O:22][CH:36]([F:38])[F:37])[CH3:17])=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CC(C)NC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc(CC(C)NC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
1.90 g (4.41 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide, 0.99 g (17.6 mmol) of 10% aqueous potassium hydroxide solution, 716 mg (2.20 mmol) of tetrabutylammonium bromide and 20 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature to 50° C. After a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatograph analysis, the reaction mixture was cooled. Then, 5% hydrochrolic acid was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give 1.80 g of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-3-difluoromethoxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 8-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (290 mg, 0.66 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (210 mg, 93.2%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:14]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:36](=[CH2:47])[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:36](=[CH2:47])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[CH:15][C:14]=1[F:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(Br)C(=O)OCc1ccccc1
Reactant: CC1(C)OB(c2ccc(COCCOCc3ccccc3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C(=O)OCc1ccccc1)c1ccc(COCCOCc2ccccc2)c(F)c1
Reaction time: 0.17 h
Yield: 16.1 %

Procedure:
A suspension of 2-(4-((2-(benzyloxy)ethoxy)methyl)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16 g, 41.45 mmol), Cs2CO3 (40.5 g, 124.35 mmol) in DMF (150 ml) was deoxygenated by purging argon for 30 min at RT and Pd(dppf)Cl2 (1.69 g, 2.072 mmol) was added and purging continued. After 10 min, benzyl 2-bromoacrylate (15.7 g, 62.17 mmol) was added and stirred at 100° C. for 1 h until complete consumption of 2-(4-((2-(benzyloxy)ethoxy)methyl)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, as evidenced by TLC analysis. The reaction mixture was diluted with ethyl acetate (300 mL), filtered through a Celite and washed with ethyl acetate (2×50 mL). The combined filtrate was washed with water (3×200 mL), brine (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 10% ethyl acetate in PE as eluent to afford benzyl 2-(4-((2-(benzyloxy)ethoxy)methyl)-3-fluorophenyl)acrylate (2.8 g, 16%) as pale brown oil (TLC solvent system: 10% EtOAc in PE; Rf: 0.3).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:12]1[C:11](=[O:22])[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13]1
Reactant: CN1CN(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CN(c2ccccc2)C2(CCCNC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-oxo-1-phenyl-1,3,7-triaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (70 mg, 0.2 mmol) in DCM (5 ml) was added TFA (0.5 ml, 6.5 mmol). The reaction mixture was stirred at RT for 1 hour before applying the reaction mixture to a 1 g SCX-2 cartridge. Impurities were eluted with 1:1 DCM:MeOH, followed by 0.05 M ammonia in 1:1 DCM:MeOH. Product was eluted with 1M ammonia in 1:1 DCM:MeOH. The clean fractions were concentrated in vacuo to afford the title compound. No further purification was performed on the title compound.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(OC(C)(C)C)=O)CC1.[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]1>>[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([OH:40])=[O:39])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 4, and making variations as required to replace tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoate with tert-butyl 5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluorobenzoate, the title compound was obtained as a colorless solid (2.29 g, 50%): MS (ES+) m/z 329.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>C(COC)OC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Yield: 61.1 %

Procedure:
To a solution of 0.66 g (2 mmol) of 1-t-butoxycarbonyl-4-trifluoromethylsulfonyloxy-1,2,3,6-tetrahydropyridine and 0.57 g (6 mmol) of 4-trifluoromethylphenylboronic acid in 6 mL of DME (dimethoxyethane) was added 2.5 mL (5 mmol) of a 2M solution of Na2CO3, 0.24 g (6 mmol) of LiCl and 0.115 g (0.1 mmol) of Pd(PPh3)4 and the reaction mixture was heated at reflux for 4 h. The reaction mixture was concentrated and dissolved in 10 mL of CH2Cl2. The solution was washed with sat'd NaHCO3 solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, hexanes: ethyl acetate, 10:1) to give 0.4 g of the title compound. 1H NMR (CDCl3) δ1.51 (s, 9H), 2.54 (m, 2H), 3.67 (t, 2H, J=6 Hz), 4.12 (br, 2H), 6.14 (br, 1H), 7.47 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>S(Cl)(Cl)=O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:12]([C:10]2[S:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=2)=[O:14])=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(-c3ccccn3)s2)cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 66.6 %

Procedure:
5-(pyrid-2-yl)thiophene-2-carboxylic acid (0.279 g; 1.36 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.19 ml; 1.36 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.3 g;1.36 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as a orange gum (0.37 g;67%), which was converted to the oxalate salt, mp=131° C.(dec).
Reaction SMILES: [Na].[CH:2]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH2:15][C:16]#[N:17])=[CH:14][C:9]=3[N:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3]1.[CH2:20]([OH:22])[CH3:21]>>[CH:2]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH:15]([C:20](=[O:22])[C:21]4[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=4)[C:16]#[N:17])=[CH:14][C:9]=3[N:8]([CH3:18])[C:7]2=[O:19])[CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CC#N)cc21
Reactant: CCO
Agent: [Na]
Product: Cc1cccc(C(=O)C(C#N)c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Temperature: 75 °C

Procedure:
Sodium metal (1.2 g) was diluted with ethanol (12 mL). After dissolution (1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetonitrile (2.0 g, 8.29 mmol) was added followed by ethyl 3-methyl benzoate (2.0 mL). The reaction was heated to 75° C. for 2.5 hours then cooled and extracted into ethyl acetate from saturated sodium bicarbonate. Chromatography on silica gel gave the desired 2-(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile.