Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][C:29]#[CH:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C#CCCCc1ccccc1
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCCCc2ccccc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate (1.60 g, 4.59 mmol) obtained in Example 47 (c) was dissolved in dimethylformamide (16 ml), and 5-phenylpent-1-yne (1.99 g, 13.8 mmol), triethylamine (6.40 ml, 45.9 mmol), copper(I) iodide (175 mg, 0.92 mmol), and dichlorobis(triphenylphosphine)palladium (322 mg, 0.46 mmol) were added thereto followed by stirring for 2 hours at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and after the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-2:3) to give the title compound (1.41 g, 75% yield).
Reaction SMILES: [CH:1]([C:3]1([N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=O.[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16]>ClCCl>[C:9]([O:8][C:7]([N:6]([CH3:14])[C:3]1([CH:1]=[CH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:5][CH2:4]1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CN(C(=O)OC(C)(C)C)C1(C=O)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=CC1(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
1.15 g of the product obtained in Step 1 and 2.01 g of (ethoxycarbonylmethylene)-triphenylphosphorane in 30 ml of dichloromethane are heated at reflux for 20 hours, concentrated under reduced pressure and then chromatographed over silica gel (dichloromethane/tetrahydrofuran: 97/3) allowing the expected product to be isolated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.[Na+].C([O-])=O.[NH4+].C([O-])(=O)C.[K+]>CN(C)C=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>[NH2:1][C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Nc1c(-c2cccc([N+](=O)[O-])c2)cc(Br)cc1S(=O)(=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Product: Nc1c(-c2cccc([N+](=O)[O-])c2)cccc1S(=O)(=O)O
Temperature: 75 °C

Procedure:
A mixture of 8 g (20 mmol) of sodium 2-amino-5-bromo-3'-nitro[1,1'-biphenyl]-3-sulphonate, 7.6 g (120 mmol) of ammonium formate, 2.35 g (24 mmol) of potassium acetate and 1.38 g (1.2 mmol) of tetrakis(triphenylphosphine)palladium (0) in dimethylformamide is heated at 75° C. for 8 hours. The reaction medium is then concentrated under reduced pressure and the residue is purified by chromatography on an RP 18 column, eluting with a water/acetonitrile mixture (8:2). The product is recrystallized from an ethanol/ether mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (249 mg, 0.9 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (350 mg, 1.07 mmol) according to the general procedure M. Obtained as an orange foam (284 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[CH:8]([CH2:10][CH3:11])[S:9][C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.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>[CH2:10]([CH:8]1[C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)=[CH:3][C:4]=2[S:9]1)[CH3:11]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCC1Sc2cc(Br)ccc2NC1=O
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: CCO
Solvent: COCCOC
Solvent: O
Product: CCC1Sc2cc(-c3cccc([N+](=O)[O-])c3)ccc2NC1=O
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of 7-bromo-2-ethyl-4H-benzo[1,4]thiazin-3-one (2 g, 7.3 mmol), 3-nitrophenyl boronic acid (1.22 g, 7.3 mmol), potassium carbonate (3 g, 22 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.84 g, 0.72 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was recrystallized from ethanol to afford the title compound as tan crystals (0.17 g, 7.3%): mp 180° C.; MS (EI) m/z 314 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:27])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=O.[NH3:28].[K+].[Br-]>CO.C(Cl)Cl>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[N:8]2[C:7]([Cl:27])=[N:6][C:5]([C:3]([NH2:28])=[O:2])=[C:9]2[CH2:10][N:11]=1
Reactant: N
Reactant: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 0.5 g (0.0012 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 20 ml of a 20% solution of ammonia in methanol was heated at 120°-125° in a steel bomb for 18 hrs. Evaporation of the solvent at reduced pressure gave an amorphous solid. The solid was dissolved in methylene chloride, washed with water, dried and evaporated at reduced pressure to give a tan, amorphous solid which crystallized when stirred with a small amount of boiling ether. Recrystallization from a solution of methanol and methylene chloride gave white crystals with mp 285°-288°. Uv λ 214 mμ (ε=44,300) sh 245 (26,500) sh 260 (16,400) sh 300 (600); ir (KBr) 3470, 3335 cm-1 (NH2) 1670 (CON).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[CH:18]=[CH:19][C:20]=2[OH:21])=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.COC(=O)[C@@H:39]([NH:53]C(C1C=C(C2C=CC(F)=C(Cl)C=2)C=CC=1O)=O)CC1C=CC(C2C=CC=CC=2)=CC=1.CN.C1COCC1.C[Si](Br)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[CH:18]=[CH:19][C:20]=2[OH:21])=[O:14])[C:9](=[O:11])[NH:53][CH3:39])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reactant: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Agent: CN
Agent: C[Si](C)(C)Br
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O

Procedure:
Resin bound 3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid (30 mg, 0.09 mmol) prepared from resin bound 3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl3-carbonyl)-amino]-propionic acid methyl ester following general procedure C, was reacted with methyl amine in THF(0.45 mmol) as described in general procedure A, then cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography to give the title compound. (36 mg). LC/MS (m/z): 503 (M+1)+.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[CH3:13]
Reactant: CCO
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: CCOC(=O)CCC1CCC(=O)N1

Procedure:
Twenty-eight grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 100 g of ethyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at reflux for 104 hours. The mixture is cooled and excess ethyl alcohol is distilled at reduced pressure. The oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from carbon tetrachloride-petroleum ether yields 5-oxo-2-pyrrolidinepropanoic acid ethyl ester with a melting point of 60°-61° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>[OH-].[K+]>[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCl
Reactant: Oc1cccc2ncccc12
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCOc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-hydroxyquinoline (4.91 g, 0.0340 mole) (Aldrich) in 17 ml 2 N potassium hydroxide was refluxed while an ice cold solution of 3-chloropropionic acid (4.05 g, 0.0373 mole) (Aldrich) in 18.6 ml 2 N potassium hydroxide was added during 1 minute. The pH was maintained at pH 9.5 by addition of 2 N potassium hydroxide. After 10 minutes, the mixture was allowed to come to room temperature and stirred for 16 hours. The pH of the solution was adjusted to pH 3.8 and the mixture evaporated in vacuo to a residue which was column chromatographed on silica gel by elution with 4:1 ethyl acetate:methanol. Material of Rf =0.45 (thin layer chromatography using 1:1 ethyl acetate:methanol) was obtained and recrystallized from water; m.p. 217°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1/[CH:4]=[CH:5]/[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1/[CH:4]=[CH:5]/[C:6]([Cl:16])=[O:7]
Reactant: O=C(O)/C=C/c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1c(F)cccc1F

Procedure:
To a solution of (E)-2,6-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,6-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,6-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[S:32][C:6]2[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:8](=[O:16])[N:9]([CH:12]([CH3:15])[CH:13]=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([Mg]Br)=[CH:37][CH:36]=1>O1CCCC1>[CH2:1]([C:3]1[S:32][C:6]2[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:8](=[O:16])[N:9]([CH:12]([CH3:15])[CH:13]([OH:14])[C:38]3[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCc1cc2c(=O)n(C(C)C=O)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(C(C)C(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To a mixture of 4′-{[6-ethyl-3-(1-methyl-2-oxoethyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.7 g) and tetrahydrofuran (100 mL) was added 4-methoxyphenyl-magnesium bromide (12.6 mL), and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.68 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]([NH:37][C:33]1[CH:32]=[C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])[CH:36]=[CH:35][CH:34]=1)(=[O:40])[CH3:39]
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1cccc(NC(C)=O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 43.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), N-{3-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (Preparation 45) (79 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was concentrated under high vacuum. The oil residue was purified with a silica gel chromatotron plate to give the title compound (62 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:24])[NH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Si:27]([O:34][CH:35]([C:45]([F:48])([F:47])[F:46])[CH:36]([NH:40][C:41](=[O:44])[CH2:42]I)[CH:37]([CH3:39])[CH3:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:24])[N:14]([CH2:42][C:41]([NH:40][CH:36]([CH:37]([CH3:39])[CH3:38])[CH:35]([O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:45]([F:46])([F:48])[F:47])=[O:44])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(-c2ccccc2)[nH]c1=O)OCc1ccccc1
Reactant: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
3-Benzyloxycarbonylamino-6-phenylpyrid-2-one (1.7 g) was added to a suspension of NaH (0.14 g) in dry dimethylformamide (50 mL). After 15 min stirring, the turbid, orange solution was treated with N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (2.65 g) and the mixture was stirred overnight. The mixture was diluted with 10% hydrochloric acid (125 mL) and extracted with ethyl acetate (2 times 150 mL). The combined extracts were washed with 10% hydrochloric acid and water (twice), dried and evaporated to an orange-brown glass. Purification by flash chromatography (gradient elution, 1%-4% ethyl acetate in dichloromethane) and overnight drying under vacuum yielded the N-alkylated product 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.97 g, 28%); TLC: Rf =0.35, dichloromethane:ethyl acetate (97:3); 300 MHz NMR: 0.08 (s,3), 0.10 (s, 3), 0.81 (d,3, J=6.6), 0.86 (s,9), 0.93 (d,3, J=6.6), 1.67-1.78 (m,1), 3.81 (t,1, J=10), 4.22-4.40 (m,2), 4.64 (broad d,1, J=15), 5.19 (s,2), 6.22 (d,1, J=7.6), 7.33-7.48 (m,10), 7.63 (d,1, J=9.9), 7.92 (d,1, J=7.6), 8.53 (s,1). Also obtained was the O-alkylated product 2-(3-benzyloxycarbonylamino-6-phenylpyrid-2-yloxy)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (2.11 g, 62%); TLC: Rf =0.61, dichloromethane:ethyl acetate (97:3), 300 MHz NMR: 0.01 (s,3), 0.07 (s,3), 0.75 (s,9), 0.77 (d, 3, J=6.6), 0.89 (d,3, J=6.6), 1.67-1.81 (m,1), 3.84 (t,1, J=10), 4.26 (m,1), 4.81 (d,1, J=15), 5.14 (d,1, J=15), 5.20 (s,2), 7.35-7.48 (m,9), 7.62 (d,1, J=8), 7.99 (dd,2, J=1.6, J=8.4), 8.12 (d,1, J=8), 9.31 (s,1); MS: m/z=646(M+1). (A mixed fraction (0.25 g, 7%) was also obtained).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:30]([N:33](CC)C(C)C)(C)C.[C-]#N.[K+]>C(#N)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:30]#[N:33])=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 336 h
Yield: 46.3 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropane-carboxamide (1.08 g, 2.78 mmol), methanesulfonyl chloride (0.24 mL, 3.1 mmol), and N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) were dissolved in acetonitrile (27 mL) at 25° C. After complete dissolution, KCN (450 mg, 6.95 mmol) was added and the reaction was stirred for 14 d. The reaction was diluted with dichloromethane (25 mL) and washed with water (25 mL). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropane carboxamide (514 mg, 46%). ESI-MS m/z calc. 398.0. found 399.1 (M+1)+; retention time 3.24 minutes.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37](CO)[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37]([CH2:20][Cl:24])[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CCl)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of triphenylphosphine (1.10 g, 4.19 mmol), carbon tetrachloride (1.62 mL, 16.8 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 10 minutes. A mixture of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol (780 mg, 2.09 mmol) in tetrahydrofuran (2.5 mL) was added, and the reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate. The resulting mixture was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of the crude product in dichloromethane was evaporated over silica gel, and the silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (10%-30% ethyl acetate in hexanes) afforded 450 mg (55%) of 1-(4-ethanesulfonyl-benzyl)-3-chloromethyl-7-fluoro-2-methyl-naphthalene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 7.96-8.04 (m, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.68-7.75 (m, 1 H), 7.41 (td, J=8.6, 2.1 Hz, 1 H), 7.30 (d, J=8.2 Hz, 2 H), 5.01 (s, 2 H), 4.63 (s, 2 H), 3.22 (q, J=7.2 Hz, 2 H), 2.47 (s, 3 H), 1.06 (t, J=7.2 Hz, 3 H). MS (ES+) cald. for C21H20CIFO2S [(M−Cl)+] 355, obsd. 355.