Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)[C:11]([F:26])=[CH:10][C:9]=1[Cl:27].[C:30](OCC)(=[O:32])C.CCCCCC>CO>[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2[O:32][CH3:30])[C:11]([F:26])=[CH:10][C:9]=1[Cl:27]
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)N(C)OC)c(Cl)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.54 g of sodium methylate in 5 ml of methanol is added dropwise to a suspension of 4.14 g of N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide in 25 ml of methanol and the reaction mixture is stirred for 10 minutes. The mixture is then treated with 30 ml of ethyl acetate as well as 50 ml of n-hexane, filtered and the filtrate is evaporated. The resulting colourless, viscous crude product crystallizes from diethyl ether/n-hexane. There is obtained N-methoxy-N-methyl-2-chloro-4-fluoro-5-[2-methoxy-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-benzamide, m.p. 119° C.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])[CH3:8])CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:19]=3[CH:18]=2)[C:14]([Cl:29])=[CH:13][N:12]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[CH:7]1([NH:4][C:26]([C:25]2[C:19]3[CH:18]=[C:17]([C:15]4[C:14]([Cl:29])=[CH:13][N:12]=[C:11]([Cl:10])[N:16]=4)[S:21][C:20]=3[CH:22]=[CH:23][CH:24]=2)=[O:28])[CH2:9][CH2:8]1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.42 mL) is added to a stirred suspension of 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (2.55 g, 7.84 mmol) in anhydrous dichloromethane (40 mL) at 0° C. under nitrogen to form a solution, followed by sequentially addition of cyclopropylamine (0.570 mL, 8.23 mmol) and powdered 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.64 g, 8.23 mmol). The resultant mixture is allowed to stir at 0° C. for 2 hours, then at ambient temperature for 3 hours. Diethyl ether (35 mL) is added in small portions to the mixture, the mixture is stirred for another 20 minutes before filtration. After drying, the crude title compound (2.45 g) is obtained as a tan solid. It is used without further purification.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].O>CCOCC>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[CH:7][C:8]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CCOc1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Bromine (18.2 g) was slowly added dropwise to Compound (b) (19.3 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. Water and ether were added for liquid separation, and the aqueous layer was extracted three times with ether. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 21.0 g of Compound (c).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:40][CH:39]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCN(CCOc2ccc(-c3cccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)c3)cc2)CC1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (7.9 g) and 1-methyl-4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-piperazine (9.0 g) are dissolved in DME (300 mL). Under an inert gas atmosphere there are added (Ph3P)3PdCl2 (2.4 g) and 2M Na2CO3-solution (50 mL) and the mixture is heated to 100° C. for 2 h. The mixture is filtered, evaporated and the residue is treated with ethyl acetate and 5% solution of NaHCO3. The organic phase is dried and evaporated and the crude product is purified by silica gel flash chromatography. 5.7 g of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15].C(=O)([O-])[O-].[K+].[K+].[CH:22](B)=[CH2:23]>COCCOC.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>[CH:22]([C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15])=[CH2:23]
Reactant: BC=C
Reactant: COc1cc(F)c2ncc(F)c(Br)c2c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(F)cnc2c(F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
4-Bromo-3,8-difluoro-6-(methoxy)quinoline (0.63 g, 2.3 mmol) in DME (26 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL), and vinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture was heated at 100° C. for 2 hr. It was cooled, diluted with water and extracted with ether, dried over magnesium sulfate and evaporated to dryness. After work-up the product was chromatographed on silica gel, eluting with 10% methanol in DCM to afford a white solid (0.46 g, 90%). MS (+ve ion electrospray) m/z 221 (MH+).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[ClH:7].Cl.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:24])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:9].[ClH:7].[CH:1]([NH:4][C:5](=[SH:24][CH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:26][CH:25]=2)[CH2:16][CH2:17]1)[OH:6])([CH3:3])[CH3:2]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 56.3 %

Procedure:
The procedure described in Example 2 was followed, using 0.5 g of isopropyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.7 g (28% of theory) of N-isopropyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 247°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1cccc(Oc2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)c1
Yield: 16.3 %

Procedure:
5-Bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (37 mg, 0.09 mmol) was reacted with 3-isopropylphenol (23 mg, 0.18 mmol) to give the title compound (7 mg, 14%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18](O)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([N:46]1[C:42](=[O:52])[C:43]2[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:45]1=[O:47])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol (0.6 mmol), Ph3P, (1 mmol), phthalimide (1.8 mmol) in 5 mL of dry THF at 0° C., was added DIAD (1 mmol) drop wise. The mixture was warmed up to room temperature gradually and stirred overnight. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (10% EtOAc:hexane) to yield 170 mg of title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>C(O)C>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: CN
Reactant: OCc1ccnc(Cl)c1
Solvent: CCO
Product: CNc1cc(CO)ccn1
Temperature: 200 °C
Yield: 46 %

Procedure:
A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and methylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200° C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-hydroxymethyl-2-(methylamino)pyridine (440 mg, 46%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1

Procedure:
To a solution of 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (5.0 g) in dimethylformamide (DMF) (25 ml) was portionwise added sodium hydride (60% in oil) (1.29 g) with stirring under ice-cooling. The mixture was successively stirred at ambient temperature for 30 minutes, stirred at 60° C. for 1 hour and cooled with an ice bath. To the reaction mixture was added 1,5-dibromopentane (6.72 ml), and the mixture was stirred at ambient temperature for 3 hours. The reaction solution was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate (80 ml) and n-hexane (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-bromopentyloxy)-1-N-t-butoxycarbonylpiperidine (2.44 g).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chlofororm (100 ml×3). The chloroform layer was washed with water (150 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.36 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:24])(=O)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH2:42])=[O:41])(=[O:34])=[O:33].[H-].[Na+]>C1COCC1.O>[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH:42][C:13](=[O:24])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1)=[O:41])(=[O:34])=[O:33]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NC(=O)c2ccc3c(c2)OCO3)c1Br
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
Carbonyldiimidazole (21 3 mg. 1.31 mmol) was added to a solution of piperonylic acid (181.5 mg., 1.09 mmol) in dry THF (10 ml). The resulting mixture was stirred for 15 minutes. N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide (Example 89) (400 mg, 1.09 mmol) and NaH (175 mg, 60% in mineral oil, 4.37 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours. Water was added to destroy the excess NaH. The solvent was then evaporated and the residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4), the solid filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]aminocarbonyl}thiophene-3-sulfonamide (20 mg, 3.6% yield) as a yellowish powder (m.p. 90°-93° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:10]=[CH:11][C:3]=12
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(F)cnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (Adesis, 4.60 g, 27.0 mmol) in N,N-dimethylformamide (70 mL) was added 60% sodium hydride in mineral oil (1.186 g, 29.7 mmol) at 0° C. and the mixture was warmed to room temperature and stirred for 30 minutes. Benzenesulfonyl chloride (3.79 mL, 29.7 mmol) was added and after stirring 3 hours, the mixture was quenched with water and aqueous sodium bicarbonate. The suspension was filtered, washed with aqueous sodium bicarbonate, water, and heptanes, and vacuum oven-dried to give the title compound. MS (ESI+) m/z 311.0 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:33][C:34]1([CH3:41])[CH2:39][C:38](=[O:40])[O:37][C:35]1=[O:36]>C(Cl)Cl>[ClH:1].[CH3:33][C:34]([CH3:41])([CH2:39][C:38](=[O:40])[N:5]1[CH2:6][CH2:7][CH2:8][N:2]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:24])[F:25])=[O:17])=[CH:11][CH:10]=2)[CH2:3][CH2:4]1)[C:35]([OH:37])=[O:36]
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1)C(=O)O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (35 mg, 0.075 mmol), methylene chloride (5 mL), and TEA (40 mg, 0.39 mmol) was stirred at room temperature. 2,2-Dimethylsuccinic anhydride (20 mg, 0.15 mmol) was added slowly. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in ethyl acetate (50 mL) and washed with saturated ammonium chloride (50 mL), water (50 mL), and brine (20 mL). The solvent was removed and the residue was treated with hydrogen chloride in ether (1 N, 4 mL). The solid was filtered and washed with dry ether to afford 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-yl)-butyric acid hydrochloride salt (35 mg, 85% yield). LCMS calcd for C28H29F3N4O5 (m/e) 558, observed 559 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Yield: 83.5 %

Procedure:
To a solution of Example 180A (39 mg, 0.11 mmol) in benzene (1 mL) was added celite (39 mg), pyridinium dichromate (0.17 g, 0.45 mmol), and a solution of 70% t-butyl peroxide in water (58 μL, 0.45 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (3 mL), washed with 5% Na2S2O5 (3 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10%-20% ethyl acetate/hexane) afforded product as a white solid (33 mg, 83%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1H), 0.75 (m, 7H), 0.93 (d, J=5.88 Hz, 3H), 1.03 (d, J=5.88 Hz, 3H), 1.34 (m, 1H), 1.79 (m, 1H), 2.08 (m, 1H), 3.84 (s, 3H), 4.13 (m, 1H), 4.41 (d, J=10.30 Hz, 2H), 4.57 (m, 1H), 5.96 (s, 1H), 7.43 (m, 2H), 7.59 (m, 1H), 8.19 (d, J=7.72 Hz, 1H).
Reaction SMILES: ClC1C=CC2OC(NC[C@@H]3[C@H](C)CCCN3C(OCC=C)=O)=NC=2C=1.[NH2:26][CH2:27][C@@H:28]1[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:36].Cl[C:51]1[O:52][C:53]2[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:54]=2[N:55]=1>>[F:60][C:58]1[CH:57]=[CH:56][C:54]2[N:55]=[C:51]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:36])[O:52][C:53]=2[CH:59]=1
Reactant: Fc1ccc2nc(Cl)oc2c1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccc(F)cc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-6-fluorobenzo[d]oxazole. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(C(C)C)C(C)C.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[S:30]([O:1][C:2]1[CH2:3][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:5][CH2:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:31])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.0 g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf2O (1.36 mL, 8.11 mmol) at −78° C., then the temperature was warmed up to room temperature and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate, which was used for next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.323 g. of caproic acid chloride as in Example 1. The 0.613 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.555 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl hexanoate obtained melts at 56.1° and has a clearing point of 70.7° UV (EtOH): ε 273 = 26400.