Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7].[I:20]Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:11]([I:20])=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Reactant: ClI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [O-][n+]1cc2cc(Cl)ncc2c(I)c1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a slurry of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde oxime (850 mg, 2.9 mmol) in acetonitrile (8 mL) was added iodine monochloride (1.4 g, 8.8 mmol). The reaction mixture instantly became homogeneous and was stirred at room temperature. After 15 minutes the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange residue that was used in the next step without further purification (1.2 g, 98%).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:4]2[CH:3]=[C:2]([Br:1])[C:9]([CH3:10])=[CH:8][C:5]=2[C:6]#[N:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(C#N)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(OC2CN(C(=O)OC(C)(C)C)C2)cc1Br
Yield: 75.3 %

Procedure:
Prepared according to Example 28 using 4-bromo-2-fluoro-5-methyl-benzonitrile (1.0 g, 4.7 mmol), 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 6.5 mmol), DMF (20 mL) and NaH (60% in mineral oil, 156 mg, 6.5 mmol) to provide the title compound (1.3 g, 74%). MS (ESI): mass calcd. for C16H19BrN2O3, 366.1; m/z found, 389.1 [M+Na]+. 1H NMR (CDCl3): 7.45 (s, 1H), 6.83 (s, 1H), 4.97-4.88 (m, 1H), 4.35 (ddd, J=9.8, 6.4, 0.9 Hz, 1H), 4.09 (dd, J=10.0, 3.9 Hz, 1H), 2.36 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C[O:12][CH2:11][CH2:10]1.[Li+].CC([N-]C(C)C)C.C1OC1>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][OH:12])[N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CO1
Product: OCCCc1cccc(F)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
To a solution of 2-fluoro-6-methylpyridin (27 mmol) in 65 ml of freshly distilled THF was added via syringe 13.5 ml of 2M LDA, and the resulting mixture was stirred at -78° C. for 20 min. To the above cold solution was added 4 ml of 4M ethylene oxide and the mixture was allowed to warm to room temperature which stirring. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2×) and brine, and dried over sodium sulfate. The organic solution was concentrated, and the residue was purified by flash chromatography (chloroform/ethanol, 10:1) to yield 1.3 g (30.9%) of 2-fluoro-6-(3-hydroxypropyl)pyridine, as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:6][N:5]([CH3:7])[C:3](=[O:4])[CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CN(C)C(=O)CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNS(C)(=O)=O

Procedure:
To a cold (0° C.) solution of 2-amino-N,N-dimethylacetamide (1.62 g, 10 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (50 mL), methanesulfonyl chloride (0.85 mL, 11 mmol) was added over a period of 5 minutes. The resultant mixture was stirred at room temperature for overnight. The product mixture was diluted with dichloromethane and washed with sat. aq. sodium bicarbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title acetamide as white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:15]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])#[N:16]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH2:22][C:21]2[CH:37]=[CH:38][CH:39]=[C:19]([O:18][CH2:17][C:15]#[N:16])[CH:20]=2)[C:24]([CH3:36])=[C:25]3[CH3:35])=[O:33])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 494 [M+H]+.
Reaction SMILES: ON[C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[O:4].C(C1C=C2C(=CC=1)N(S(C)(=O)=[O:47])C=C2C1CCN(S(Cl)(=O)=O)CC1)#N.S(Cl)(Cl)(=O)=O.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.N1CCCC[C@@H]1C(O)=O>>[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=[C:20]2[CH:17]1[CH2:16][CH2:15][N:14]([S:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]2[C:3]([OH:47])=[O:4])(=[O:12])=[O:13])[CH2:19][CH2:18]1)#[N:30]
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)NO)CC2)c2cc(C#N)ccc21
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)Cl)CC2)c2cc(C#N)ccc21
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C(O)[C@H]1CCCCN1
Solvent: O=S(=O)(Cl)Cl
Product: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)O)CC2)c2cc(C#N)ccc21
Yield: 86 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30]([O:38][C@@H:39]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]3[O:41][C:42](=[O:44])[CH3:43])=[N:31][NH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30]([O:38][C@@H:39]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]3[O:41][C:42](=[O:44])[CH3:43])=[N:31][NH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])=[CH:24][CH:23]=1)[CH3:21].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:39]3[O:56][C@H:55]([CH2:57][OH:58])[C@@H:50]([OH:51])[C@H:45]([OH:46])[C@H:40]3[OH:41])=[N:12][NH:13][C:14]=2[C:15]([F:17])([F:18])[F:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Reference Example 28 using 4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 4-[(4-ethyl-phenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[CH2:19]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N-benzyloxycarbonyl-β-alanine (11.16 g, 50.00 mmol) in anhydrous THF (160 mL) and DMF (40 mL) at 0° C. was slowly added NaH (60% in oil, 6.000 g, 150.0 mmol). After stirring at 0° C. for 15 min, benzyl bromide (9.10 mL, 75.00 mmol) was added. The reaction mixture was stirred at rt for 22 h. It was quenched with water (90 mL), followed by 1 N HCl (110 mL), and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash (40-60% EtOAc/hexane) to afford 3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid as a viscous pale yellow oil (14.2 g, 91% in yield). MS (ESI): 312.0 (M−H).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:18]([NH:23][C:8](=[O:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCN
Product: CCCCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=295 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and pentylamine.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)/[C:5]/1=[CH:30]/[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2].C(O)C.[H][H]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[C@@H:5]1[CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc(/C=C2/c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C[C@H]2c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Yield: 92.1 %

Procedure:
In 1.5 ml of methylene chloride was dissolved 100.8 mg (0.178 mmol) of (Z)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethylene)-1,2,3,4-tetrahydroisoquinoline, and 7.5 ml of ethanol was further added thereto. A separately prepared solution of 2.9 mg (1.7×10-3 mmol) of Ru2Cl4 ((S)-(-)-BINAP)2N(C2H5)3 in 1.5 ml of methylene chloride was added to the above prepared solution, and the mixture was transferred to an autoclave. The mixture was subjected to hydrogenation at 23° C. for 62 hours at a hydrogen pressure of 4 kg/cm2 while stirring. After completion of the reaction, the solvent was removed by distillation, and the residue was purified by silica gel column chromatography (silica gel: 15 g, eluent: ethyl acetate/hexane=3:1 by volume) to give 92.8 mg (0.164 mmol) of (S)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethyl)-1,2,3,4-tetrahydroisoquinoline in a yield of 92%. The optical rotation [α]D24 of this product was +62.8° (c=0.92, CHCl3).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[Cl:33]>>[Cl:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Nc1ccncc1Cl
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3ccncc3Cl)cnc(OC)c2o1
Yield: 72.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 4-amino-3-chloropyridine (0.15 g). Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (0.14 g) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Reactant: OC1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN1CCN(CCNC(=O)c2nn(C3CCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71 %

Procedure:
To a solution of N-[2-(4-n-butyl-1-piperazinyl)-ethyl]-1H-indazole-3-carboxamide (0.42 g) obtained in Example 10 in THF (10 ml) were successively added cyclopentanol (0.16 g), triphenylphosphine (0.41 g) and diethyl azodicarboxylate (0.36 g) under ice-cooling, and then the mixture was stirred at room temperature for 22 hours. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:1-chloroform:methanol:aqueous ammonia=10:1:0.05) to give a fraction (0.47 g) containing the title compound. This fraction was separated by thin-layer chromatography on silica gel (chloroform:methanol:aqueous ammonia=10:1:0.1) to give the title compound (0.36 g) as a pale yellow oily substance. Yield=71%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[C:6]=1[CH3:16])=[O:4].[Cl-].[OH:18][C@H:19]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])[CH2:20][NH+:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1COCC1>[OH:18][C@H:19]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([C:5]2[C:14]([CH3:15])=[CH:13][C:8]3[C:9](=[O:12])[O:10][CH2:11][C:7]=3[C:6]=2[CH3:16])=[O:4])[CH2:23][CH2:22]1
Reactant: Cc1c([C@@H](O)C[NH+]2CCNCC2)ccc2c1COC2=O
Reactant: Cc1cc2c(c(C)c1C(=O)CBr)COC2=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)c1C(=O)CN1CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC1)COC2=O
Temperature: 50 °C

Procedure:
To a 5 ml microwave tube were added 5-(bromoacetyl)-4,6-dimethyl-2-benzofuran-1(3H)-one (0.220 g, 0.777 mmol), 1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-ium chloride (0.215 g, 0.777 mmol), and a stir bar; the mixture was dissolved in THF (2 mL). The tube was capped, degassed and purged with N2. The tube was then placed in an oil bath and heated at 50° C. for 12 h; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.6 mL), filtered and was then subjected to purification by mass-directed HPLC to give 5-({4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4,6-dimethyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 479 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 4-(4-fluorophenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g,. 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCL and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:33])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40](N1C=CN=C1)=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:33])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:41]
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
The amine from above (131 mg, 0.28 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (168 mg, 0.56 mmol) were combined in DMF (4.0 mL) and treated with DIPEA (0.29 mL, 1.7 mmol). The solution was stirred at 75° C. for 2 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (25:1:0.1 CH2Cl2:MeOH:NH4OH), COMPOUND 307 (72 mg, 45%). 1H NMR (CDCl3): δ 1.30 (q, 2H, J=11.1 Hz), 1.59 (s, 6H), 1.66 (d, 2H, J=12.3 Hz), 2.26 (s, 3H), 2.61 (br t, 3H, J=11.7 Hz), 3.35 (s, 2H), 3.65 (s, 2H), 4.14 (d, 2H, J=13.2 Hz), 6.68 (s, 2H), 6.86 (m, 4H), 7.19 (br, 2H), 7.37 (s, 1H), 7.82 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H). 13C NMR (CDCl3) δ 18.40, 18.81, 28.08 (2C), 31.12 (2C), 42.14, 44.20 (2C), 54.06, 54.67, 58.01, 115.13 (d, 2C, J=84 Hz), 121.44, 127.07 (d, 2C, J=30 Hz), 130.07, 133.81, 134.84, 137.31, 142.96, 144.59 (2C), 145.07, 145.36, 146.61 (2C), 155.31, 155.96, 157.96, 161.91 (d, 1C, 975 Hz). ES-MS m/z 577 (M+H). Anal. Calcd. for C31H35N7OClF.0.2CH2Cl2O.0.2H2O: C, 62.46; H, 6.02; N, 16.32; Cl, 8.85; F, 3.16. Found: C, 62.60; H, 6.02; N, 16.09; Cl, 8.79; F, 2.94.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]1([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]3[CH2:35][O:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[ClH:1].[C:8]1([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[CH2:35][O:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1cccc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-phenylpicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (143 mg, 0.231 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 102.1 mg (99%) of the title compound. LC-MS: RT=4.36 min, [M+H]+=375.6.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28](C)[C:27]1=[O:36].CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:23][CH2:24][CH2:25][N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]3=[O:36])[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21]
Reactant: Cn1c(=O)n(CCN)c2ccccc21
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCn3c(=O)[nH]c4ccccc43)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.308 mmol), 1-(2-amino-ethyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one (140 mg, crude), and DIEA (85 mg, 0.66 mmol) in THF (3 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by preparative standard methods to afford the title compound (36.7 mg, 0.084 mmol, 24% yield over 2 steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.08-7.94 (m, 1H), 7.11-7.08 (m, 4H), 4.26-4.10 (m, 3H), 3.89-3.66 (m, 2H), 3.40-3.35 (m, 4H), 1.96-1.51 (m, 6H), 1.05-0.99 (m, 6H). MS (ESI) m/z 436.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:14]([O:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OCc1ccoc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-hydroxymethylfuran (1.01 g., 10.3 mmol) and pyridine (0.87 g., 10.3 mmol) in 30 ml dry tetrahydrofuran at 0° under argon was added lauroyl chloride (2.36 g., 10.8 mmol). This solution was allowed to warm to room temperature, during which time a white precipitate formed. After one hour, the mixture was filtered and the solution partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, three times with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This material was further purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.