Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]CC2C=CC=CC=2)=O)[C@@H:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)(=[O:3])[CH3:2].[H][H].[CH3:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([CH3:39])[CH:38]=1)C(Cl)=O>C(O)C.Cl.[Pd]>[C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:13])[C:32]2[CH:36]=[C:37]([CH3:39])[CH:38]=[C:30]([CH3:29])[CH:31]=2)[C@@H:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@H]1CCN(C(=O)c2cc(C)cc(C)c2)[C@@H](c2ccccc2)C1

Procedure:
A solution of 496 mg (1.41 mmol) of (2R*,4S*)-N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine in 30 ml of ethanol and 8 ml of 1N hydrochloric acid is mixed with 50 mg of 10% Pd/C catalyst and stirred under a hydrogen atmosphere until no more hydrogen is taken up. The catalyst is removed by filtration through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in 5 ml of dichloromethane and 5 ml of 10% strength aqueous sodium bicarbonate solution and, while stirring at 0°, 285 mg (1.69 mmol) of 3,5-dimethylbenzoyl chloride are added slowly over the course of 1 hour. The reaction mixture is extracted with dichloromethane. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The title compound crystallises from ethyl acetate; melting point 201°-203°; CI-MS: (M+H)+=351.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:14]([CH:19]=[O:20])[CH:13]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 5-bromopentanoate (28.6 g) was added to a suspension of 4-bromo-2-formylphenol (25.0 g) and potassium carbonate (18.9 g) in DMF (100 ml), and the resulting solution was stirred at 50° C. overnight under a nitrogen atmosphere. The solution was allowed to cool. Water was added and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain yellow oil of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (40.9 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[H][H].[Cl:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:15]>CS(C)=O.O>[C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:14]2([C:13]3[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=3[Cl:11])[CH2:4][O:15]2)=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccccc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccccc1C1(c2ccc(-c3ccccc3)cc2)CO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
90 ml of dimethylsulphoxides are added to 2.7 g (0.09 mol) of 80% strength sodium hydride and 19.8 g (0.09 mol) of trimethyloxosulphonium iodide in the course of 20 minutes. When the evolution of hydrogen has ended, a solution of 22 g (0.075 mol) of 2-chloro-4'-phenyl-benzophenone in 60 ml of dimethylsulphoxide is added dropwise and the mixture is subsequently stirred at 50° C. for 1 hour. 200 ml of water are added to the cooled reaction mixture and the mixture is extracted by shaking with ether. The ether solution is washed with water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue is recrystallised from diisopropyl ether. 15 g (65% of theory) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane of melting point 70° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=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: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(-c3ccccc3)ccc2n(C)c1=O
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (200 mg, 465 μmol), phenylboronic acid (85 mg, 697 μmol), 2M Sodium carbonate (0.7 ml, 1395 μmol), Tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 μmol) and N,N-Dimethylformamide (10 ml) was stirred at 100° C. After 8 hrs, an additional equivalent of the phenyl boronic acid was added, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated on a roto-evaporator and extracted with EtOAc. This product was then washed with water and brine, then dried with MgSO4 and concentrated on a roto-evaporator to give the crude product as a red-orange oil. The crude product was purified by silica flash chromatography (10-75% EtOAc:Hex step gradient) to give the desired product as a white solid. Yield=120 mg. In some cases, ester hydrolysis was observed and the carboxylic acid was isolated.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][I:18]>CC(C)=O>[I-:18].[CH3:17][N+:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: c1ccc(N2CCc3ccccc3C2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(c2ccccc2)CCc2ccccc2C1
Product: [I-]
Reaction time: 48 h

Procedure:
2-phenyl-1,2,3,4-tetrahydroisoquinoline (1.01 g,) was dissolved in acetone (10 ml) and methyl iodide (0.794 g,) was added. The clear solution stood at -20° for 48 hr when t.l.c. indicated the presence of unchanged starting material. A further quantity of methyl iodide (0.3 ml) was added and the reaction mixture was heated at reflux for 3 hrs. The solvent was removed in vacuo and the residue triturated with ether. The resulting solid 1,2,3,4-tetrahydro-2-methyl-2-phenylisoquinolinium iodide was filtered off and dried (1 g). m.pt. softens 190°, melts 195° (decomp.)
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[OH:30][N:29]=[CH:1][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(C=NO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Yield: 96 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g), hydroxylamine hydrochloride (580 mg) and sodium acetate (1.6 g) are dissolved in ethanol (20 ml) and water (10 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue. The mixture is extracted with chloroform, dried with sodium carbonate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:2) and recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxyiminomethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) as white powder, m.p.: 222°-224° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:44][CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Reactant: NC1CCCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(NC5CCCC5)cc4)cc3n2Cc2ccccc2)cc1OC

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (151 mg) and cyclopentylamine (118 μl) in N-methylpyrrolidinone (1.5 ml) was heated at 110° C. in a sealed tube for 3 hours. The reaction mixture was allowed to cool then poured into water (30 ml) and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-cyclopentylamino-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (122 mg) as a brown solid. Mass spectrum: 599 [M+H]+, retention time=4.0 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C>C(O)C>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:20][CH3:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCCNCCC
Solvent: CCO
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 79.6 %

Procedure:
A heavy walled glass reaction tube of approximately 50 ml. capacity was charged with 7.0 grams (0.023 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride, 4.64 grams (0.0458 mole) of di-n-propylamine and 40 ml. of absolute ethanol. The tube was sealed and heated in an oil bath at 94°-99° C. for 98 hours. The cooled reaction mixture was then evaporated to dryness to give an oily residue which was extracted with boiling diethyl ether. The insoluble di-n-propylamine hydrochloride was removed by filtration and washed with additional ether. The combined ether filtrates were evaporated to give an oily orange residue which was dissolved in 100 ml. of absolute ethanol and decolorized with activated charcoal. The ethanol and volatiles were removed by evaporation under reduced pressure to give the product (6.77 grams) as a viscous reddish oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=2)=[N:10]1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2ccncc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Reaction time: 24 h
Yield: 33.1 %

Procedure:
To a solution of 4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g, 1.73 mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL) was added cesium carbonate (0.676 g, 2.07 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc and washed successively with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and partially purified by running through a plug of silica gel (5% acetone/CH2Cl2) to afford 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH2Cl2): Rf=0.39. MS (electrospray): exact mass calculated for C18H14F3N3O, 346.1 [M+H]+, m/z found, 346.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11]N1C(=O)CCC1=O.[Na+].[Cl-]>CN(C=O)C>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(C)c1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1N
Yield: 100.6 %

Procedure:
To a solution of 2-ethyl-6-methylaniline (2.03 g, 15 mmol) in DMF (50 mL) at 0° C. was added N-bromosuccinimide (2.66 g, 14.9 mmol). The mixture was stirred at room temperature for 10 minutes before addition to saturated aqueous NaCl. The mixture was extracted with EtOAc, the organic phase was washed with sat aqueous NaCl (2×), concentrated and the crude material was purified by Biotage chromatography (40M, 15% EtOAc/heptane) to provide 4-bromo-2-ethyl-6-methylbenzenamine as a red brown liquid (3.21 g, 100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:13][NH:12][C:11]=1[NH2:20].NC1NN=C(CCCCO)C=1[C:32]1SC2C=CC=C[C:35]=2[N:36]=1.CNC.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:36]([CH3:35])[CH3:32])=[N:13][NH:12][C:11]=1[NH2:20]
Reactant: Nc1[nH]nc(CCCCO)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCCBr)c1-c1nc2ccccc2s1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)CCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (41 mg) was prepared using 185 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(4-bromobutyl)-2H-pyrazol-3-ylamine, which was derived from 4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-butan-1-ol, and 5 mL of a 2 M solution of dimethylamine in THF (10 mmol). MS (m/z, ES+): 316.4 (M+1, 100%).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1.O.CO.C(OCC)C.[BrH:30]>>[BrH:30].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CCCN(CCC)[C@H]1CCc2ccc(OC)cc2[C@H]1C
Agent: Br
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCCN(CCC)[C@H]1CCc2ccc(O)cc2[C@H]1C
Yield: 84 %

Procedure:
cis-7-Methoxy-1-methyl-2-(di-n-propylamino) tetralin hydrochloride (500 mg, 1.60 mmol) was heated in 48% aqueous HBr (5 ml) for 3 h at 140° C. under N2. Water (20 ml) was added and the volatiles were evaporated in vacuo. The faint orange-coloured residue was treated with abs. ethanol twice (with intervening evaporation). The dry residue was dissolved in methanol and the solution was treated with active charcoal. After filtration the solvent was evaporated, whereupon the residue was dissolved in methanol and ethyl ether was added. The obtained white crystals were recrystallized from MeOH-ethyl ether yielding the desired product (450 mg, 84% yield), m.p. 195°-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])OC(C)(C)C)[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2.[C:43]([N:50]([CH3:56])[C@H:51](C(O)=O)[CH3:52])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])[C@@H:51]([N:50]([CH3:56])[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH3:52])[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
A rt solution of tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (75 mg, 114 μmol) in 4 M HCl in 1,4-dioxane (568 μl) was stirred for 1.5 h then concentrated. This material was taken up in DMF (380 μl) and Boc-N-methyl-L-alanine (25.5 mg, 125 μmol), N,N-diisopropylethylamine (78.9 μl, 456 μmol), and HBTU (47.6 mg, 125 μmol) were added. The reaction was stirred at rt for 20 min, then diluted with EtOAc, washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (81 mg, 95%) as a white solid. MS m/z 767/769 (M+Na)+
Reaction SMILES: C12(C3C=C[C:14]([O:15]CC(O)=O)=[CH:13]C=3)CC3CC(CC(C3)C1)C2.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:14](=[O:15])[CH3:13])[CH:28]=[CH:27][CH:26]=1)(=[O:30])(=[O:31])[NH2:32]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(S(N)(=O)=O)c1
Reaction time: 8 h
Yield: 38.5 %

Procedure:
The mixture of [4-(1-adamantyl)-phenoxy]acetic acid (80.7 mg, 0.28 mmol), 3-amino-benzenesulfonamide (72.3 mg, 0.42 mmol), N,N-diisopropylethylamine, redistilled (DIPEA) (0.1 ml, 0.56 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (291.4 mg, 0.56 mmol) in DMF (5 mL) was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 244-Adamantyl-1-yl-phenoxyl)-N-(3-sulfamoyl-phenyl)-acetamide as a white solid (23.1 mg, 18.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:19][C:20]1[N:24]([CH3:25])[C:23]2[CH:26]=[C:27]([O:33][CH3:34])[C:28]([C:30]([OH:32])=O)=[CH:29][C:22]=2[N:21]=1.[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1>>[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:30]([C:28]2[C:27]([O:33][CH3:34])=[CH:26][C:23]3[N:24]([CH3:25])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]5([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]5)=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:21][C:22]=3[CH:29]=2)=[O:32])=[CH:38][CH:37]=1
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C
Reactant: Nc1ccc(Br)cc1
Product: COc1cc2c(cc1C(=O)Nc1ccc(Br)cc1)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C

Procedure:
The title compound was prepared from 2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-methoxy-1-methyl-1H-benzimidazole-5-carboxylic acid (92 mg; 0.19 mmol) and 4-bromoaniline (33 mg; 0.19 mmol) in accordance with Example 59, step (a). Yield: 73 mg (59%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.16 (1H, s) 8.40 (1H, t, J=6.0 Hz) 8.25 (1H, s) 7.85-7.81 (1H, m) 7.76-7.68 (3H, m) 7.51-7.46 (2H, m) 7.40 (1H, d, J=8.2 Hz) 7.22-7.17 (1H, m) 6.92-6.86 (1H, m) 4.25 (2H, d, J=6.0 Hz) 3.97 (3H, s) 3.71 (3H, s) 1.37-1.32 (2H, m) 1.23-1.18 (2H, m). MS m/z: 650, 652, 654 [M+H]+.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7]12[C:15](=[O:16])[CH2:14][CH2:13][CH:12]1[CH:11]([O:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][C:23]1([CH3:28])[O:27][CH2:26][CH2:25][O:24]1)[C:10](=O)[CH2:9][CH2:8]2>C1(C)C=CC=CC=1>[CH3:6][C:7]12[C:15](=[O:16])[CH2:14][CH2:13][CH:12]1[CH:11]1[C:10]([CH2:9][CH2:8]2)=[C:20]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[C:19](=[O:29])[CH2:18][O:17]1
Reactant: CC1(CCCC(=O)COC2C(=O)CCC3(C)C(=O)CCC23)OCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 25% (w/w) solution of sodium methoxide in methanol (2.71 mL, 12.8 mmol, 1 eq) was added to the stirred solution of 7a-Methyl-4-[5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-pentyloxy]-hexahydro-indene-1,5-dione (4.5 g, 12.8 mmol, 1 eq) in toluene (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then the reaction was quenched with a 10:1 (v/v) of ammonium chloride/potassium bisulfate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried with magnesium sulfate. The resulting solution was then filtered and concentrated to yield the title compound as an oil, which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C1C(=O)c2ccc(-c3cccnc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccc(-c3cccnc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 65 was synthesized using 9-pyridin-3-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.: 240-242° C.; 400 MHz 1H NMR (DMSO-d6) δ 9.04 (d, J=2.0 Hz, 1H), 8.69 (dd, J=1.6, 4.8 Hz, 1H), 8.24 (dt, J=1.6, 8.8 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.93 (dd, J=1.6, 8.4 Hz, 1H), 7.59 (dd, J=4.8, 8.0 Hz, 1H), 7.55-7.47 (m, 3H), 7.41 (d, J=7.6 Hz, 1H), 4.32 (br, 1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.03 (m, 1H), 1.90 (m, 2H); LC MS: 519 [M+H].