Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH:16]([F:18])[F:17])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:15][CH:16]([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(F)F)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown oil (0.726 g; 89%). MS (ESI): m/z=369.12 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.277 g, 1.07 mmol), hydrazine monohydrate (0.5 mL) and DMSO (2.0 mL) were stirred at room temperature overnight. Then the reaction was heated to 50° C. and stirred for 7 hours. Purified by RP-HPLC to provide 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as an orange solid (0.118 g, 43%). LCMS: (M+H)+=255.3.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH:11]3[C:24]([O:26][CH3:27])=[O:25])=[CH:4][C:3]=2[O:2]1>C1(C)C=CC=CC=1>[CH3:27][O:26][C:24]([C:11]1[C:12](=[O:23])[C:13]2[C:18]([C:10]=1[C:5]1[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=1)=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)=[O:25]
Reactant: CCCOc1ccc2c(c1)C(=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(c1)C(=O)C(C(=O)OC)=C2c1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 43.4 %

Procedure:
Methyl(1RS,2SR)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-3-oxo-indane-2-carboxylate (26.2 g, 71 mmol) was dissolved in toluene (250 mL) and DDQ (dichlorodicyano-quinone) (16.5 g, 71 mmol) was added. The mixture was heated at 80° C. for 2 h. then cooled, filtered and the solvent removed in vacuo. The product was purified by flash column chromatography on silica gel (eluant: EtOAc/hexane, 20:80) to give the title compound as an orange solid (11.3 g, 44 %); m.p. 125°-126° C. Anal. Calc. for C21H18O6 : C, 68.85; H, 4.95. Found: C, 68.45; H, 4.97.
Reaction SMILES: [C:1](OC(=O)CC)(=O)CC.[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH:31](F)F)[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>N1C=CC=CC=1.ClCCl>[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH2:31][CH3:1])[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Propionic anhydride (0.136 ml, 1.06 mmol) is added dropwise to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.88 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is stirred for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.28 g, 80%). M.p. 144-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 41 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.7 g) was obtained, melting point: 230° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10]Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14]S>C(O)=O>[N+:1]([C:4]1[C:5]([S:10][CH2:14][CH2:13][NH2:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCCS
Reactant: O=[N+]([O-])c1cccnc1SCl
Solvent: O=CO
Product: NCCSc1ncccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
The 3-nitro-2-pyridinesulfenyl chloride was added to a solution of 2-aminoethanethiol (4.1 grams, 36.19 mmol) in 230 mL of 90% formic acid. The solution was vigorously stirred for one hour. The resulting precipitate was removed by filtration, and a large volume of diethylether was added to the supernatant. The precipitate was collected, dissolved in warm methanol, and reprecipitated with diethyl ether. 3-Nitro-2-pyridinesulfenyl-ethylamine was obtained in 68% overall yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])[CH3:2].[CH3:19][NH:20][CH3:21].Cl>C(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7]([N:20]([CH3:21])[CH3:19])(=[O:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N(C)C
Reaction time: 0.25 h

Procedure:
A solution of 359 mg of 2-benzyl-3-chlorosulphonylpropionic acid ethyl ester in 2 ml of methylene chloride is cooled to -10° and 0.464 ml of a 5.6M solution of dimethylamine in ethanol is added thereto. The solution is stirred for 15 minutes at -15°, mixed with 2N HCl and extracted with methylene chloride. The extracts are washed with water, dried with magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with eluant C. Rf (A)=0.43.
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.94 ml (134.8 mmol) of bromine in 25 ml of acetic acid is slowly added dropwise over a period of 40 min to a solution of 20 g (122.5 mmol) of N-phenylmorpholine in 170 ml of acetic acid at room temperature. After stirring at room temperature for 30 min, the reaction mixture is stirred into 750 ml of water and adjusted to pH 11 with 45% strength sodium hydroxide solution. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. Recrystallization from ethanol results in 18.6 g (62.9% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](N3C(=O)CCC3=O)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:35]([O:34][CH2:33][CH:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:32]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:36])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (19 g) synthesized in Example 7 in tetrahydrofuran (60 mL) was added N-(9H-fluorene-9-ylmethyloxycarbonyl)succinimide (23 g), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The precipitate was filtered and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (33 g) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:28][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCCN)cc1
Product: COC(=O)c1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenylglyoxal (1.99 g) and 3-(4-carbomethoxyphenyl) propylamine (1.9 g) and crystallised from hexane m.p. 86°-96°. τ(CDCl3) 7.9-8.35 (2H,m), 7.55 (2H, broad, replaceable by D2O), 7.0-7.5 (6H,m), 6.15 (3H,s), 5.3 (1H,m), 2.85 (2H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.05 (2H,d,J=8 Hz).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[CH:42][N:41]=5)=[C:34]([CH3:49])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[CH:42][N:41]=5)=[O:59])=[C:34]([CH3:49])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cc(OCC)ccn4)c(C)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cc(OCC)ccn4)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.17 g) in methylene chloride (5.1 ml) was added dropwise a solution of m-chloroperbenzoic acid (55 mg) in methylene chloride (3.4 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 226) (32 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3]1=[O:14]
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2S,5R)-2-methyl-5-phenylmorpholin-3-one from Step E (90 mg, 0.47 mmol) in DMF (2 mL) at 0° C. was added NaH (20 mg of a 60% dispersion in oil, 0.50 mmol). After 10 min, ethyl bromoacetate (79 mg, 0.47 mmol) was added and the mixture was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (3 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-90:10 to 60:40, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[NH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[C:1]([CH3:2])=[O:3]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C

Procedure:
81.3 g of acetanilide are suspended in 600 ml of carbon disulphide and 76.7 g of butyryl chloride and, in portions, 198 g of aluminium trichloride are added while stirring. The mixture is stirred for some time at 30°-35° and heated at the boil for 18 hours. It is then allowed to cool, stirred into 200 ml of ice-water and extracted twice with 500 ml of ethyl acetate each time. The organic phases are combined, washed with 500 ml of additional acid and twice with 500 ml of 15% strength sodium carbonate solution each time, dried over magnesium sulphate and concentrated to 150 ml under reduced pressure. The residue obtained by concentration is allowed to cool, filtered with suction, washed twice with diethyl ether and dried under reduced pressure. p-Acetaminobutyrophenone having a melting point of 141°-143° is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(I)cc(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)cc(I)cc1C(C)(C)C

Procedure:
A solution of 2-bromo-6-tert-butyl-4-iodophenol (5.0 g, 14.08 mmol) in acetone (50 mL) was treated with potassium carbonate (2.92 g, 21.13 mmol) and dimethylsulfate (1.95 g, 15.49 mmol) at reflux for 16 hours, cooled and concentrated. The residue was dissolved in ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with 2% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [C:1]([O-])(=O)CC.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].IC>CN(C=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([C:30]2[N:34]([CH3:1])[N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Reactant: CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnnn2C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a stirring mixture of 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (18.9 g, 40.7 mmol) and DMF (120 ml), NaH (2.4 g,m 100 mmol) was added. The mixture was stirred at room temperature for 30 minutes. To the resulting brown solution, iodomethane (15 g, 106 mmol) was added slowly. It was stirred for 30 minutes and poured onto H2O (400 ml). The mixture was extracted with CH2Cl2 (2×250 ml). The CH2Cl2 solution was washed with H2O (4×400 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, 1% MeOH/CH2Cl2) to give 1-benzyl-4-(1-methyl-1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidine (4.58 g, 11.3 mmol) as a colorless viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHZ, CDCl3) δ 0.834, (t, 3H, CH3CH2CO), 1.789 (q, 2H, CH3CH2), 3.334 (s, 2H, phCH2), 4.435 (s, 3H, tetrazolyl CH3), 7.15 to 7.47 (m's, 10H, phenyl H's), and 1-benzyl-4-(2-methyl-2H-tetrazol-5-yl)-4-(N-phenyl)propionamido)piperidine (2.75 g, 6.8 mmol) as a viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHz, CDCl3) δ 0.830 (t, 3H, CH3CH2CO), 1.810 (q, 2H, CH3CH2), 3.402 (s, 2H, phCH2), 4.369 (s, 3H, tetrazolyl CH3), 7.20 to 7.54 (3m's, 10H, phenyl H's). ##STR31##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27](Br)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:53])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]#[CH:52])=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27]([C:52]#[C:51][C:48]4[NH:47][C:46]([CH:42]5[CH2:43][CH2:44][CH2:45][N:41]5[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:53])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=4)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#CC2=CC3SC(c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)=CC3S2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 17.8 %

Procedure:
(1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (140 mg, 0.440 mmol), {1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (130 mg, 0.254 mmol), Pd(PPh3)4 (29 mg, 0.0254 mmol), CuI (10 mg, 0.0508 mmol) and triethylamine (0.354 mmol, 2.54 mmol) were combined in DMF (2.5 mL) and degassed with N2 for 17 min. The reaction was heated to 85° C. for 4 h then cooled to RT, diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC chromatography to afford the title compound (34 mg, 18%). MS (ESI) m/z 749 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12.CCOC(S)=[S:19]>>[SH:19][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12
Reactant: Cc1ncc(CCl)c2c1OC(=O)OC2
Reactant: CCOC(=S)S
Product: Cc1ncc(CS)c2c1OC(=O)OC2

Procedure:
5-Chloromethyl-8-methyl-2-oxo-4H-m-dioxino-[4,5-c]pyridine is converted to the corresponding ethyl xanthogenate and reduced in accordance with the procedure of Example 19, Step B, to give 5-mercaptomethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([O:35]C)=[O:34])[C:30]([O:37][CH3:38])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([OH:35])=[O:34])[C:30]([O:37][CH3:38])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)OC)n3)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)O)n3)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a stirring solution of methyl 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinate (400 mg, 0.74 mmol) in dioxane/H2O (10 mL/1 mL) was added LiOH.H2O (93 mg, 2.22 mmol) under N2 protection. The mixture was stirred at 70° C. for 3 h. The mixture was concentrated in vacuo and then extracted with EtOAc. After the organic layer was washed with HCl (a.q.), brine, dried over Na2SO4, filtered and evaporated, the crude product was purified by prep-TLC (PE:EtOAc=1:3) to give the product of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinic acid (300 mg, yield: 77%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.86˜7.90 (m, 2H), 7.80 (s, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.55˜7.57 (m, 1H), 7.14 (t, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.04 (s, 3H), 2.86 (s, 3H), 2.82 (s, 3H). MS (M+H)+: 528.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:17]=2[N:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:25][C:23]1[C:22]([F:26])=[CH:21][C:18]2[N:19]([CH3:20])[C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:16][C:17]=2[CH:24]=1
Reactant: Cn1c(CC2CCCCN2C(=O)OC(C)(C)C)nc2cc(F)c(F)cc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CC2CCCCN2)nc2cc(F)c(F)cc21

Procedure:
(RS)-2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester, D60 (0.5 g) was treated with trifluoroacetic acid (5 ml) as described for Description 6 to afford the title compound (0.363 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:23](=[O:24])[C:22]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:20]([CH3:19])[CH:21]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(Cc2coc3ccccc23)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cc2c(C(=O)c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Acylation of 3-p-methoxybenzylbenzofuran with 3,5-dimethylbenzoyl chloride and stannic chloride in methylene chloride according to the procedure described in Example 1 gives 3-p-methoxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran.