Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([CH2:34][NH:35][C@@H:36]([CH2:40][OH:41])[C:37](O)=[O:38])=O)(C)(C)C>>[OH:41][CH2:40][C@H:36]([NH:35][CH3:34])[C:37]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:38]
Reactant: CC(C)(C)OC(=O)CN[C@@H](CO)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Product: CN[C@@H](CO)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 50 mg (0.12 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 30 mg (0.13 mmol) of (S)-2-(tert-butoxycarbonylmethylamino)-3-hydroxypropionic acid. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[CH:14](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH:14]([N:9]1[C:8]2[CH:13]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2ccc(Br)cc2n1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a cold (0° C.) suspension of sodium hydride (0.589 g of a 60% w/w dispersion in mineral oil, 14.7 mmol) in N,N-dimethylformamide (50 mL) was added in portions 5-bromo-benzo[d]oxazol-2(3H)-one (3.0 g, 14.0 mmol). The reaction mixture was stirred for 1 h at 0° C. and benzhydryl bromide (3.81 g, 15.4 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. Further benzhydryl bromide (1.7 g. 6.9 mmol) was added and the reaction mixture was heated at 70° C. for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was suspended in ethyl acetate (300 mL), washed with water (2 20 mL) and brine (2 20 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-50% gradient of ethyl acetate in hexanes to afford 3-benzhydryl-5-bromobenzo[d]oxazol-2(3H)-one as an orange solid in 71% yield (3.87 g): 1H NMR (300 MHz, CDCl3) δ7.41-7.34 (m, 6H), 7.27-7.21 (m, 4H), 7.19-7.14 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.46 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([F:32])=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[C:21]([F:32])[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c(F)cc1F
Yield: 69.3 %

Procedure:
A mixture of 0.217 g (1.12 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.3 g (1.12 mmol) of N-[5-(3-dimethylamino-acryloyl)-2,4-difluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 320 mg of N-{2,4-difluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 69%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[O:13]([CH3:15])[Na]>CO>[Cl:12][C:4]1[N:3]=[C:2]([O:13][CH3:15])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CO[Na]
Solvent: CO
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A 5-L, four neck round bottom flask equipped with overhead stirrer, positive pressure nitrogen inlet, 500-mL addition funnel with nitrogen outlet and a thermocouple was charged with 2,6-dichloro-3-nitropyridin-4-amine (150.0 g, 0.72 mol) and MeOH (1.50 L) and the resulting brown suspension was stirred at room temperature. NaOCH3 (25% solution in MeOH, 260 mL, 1.155 mol) was charged to the addition funnel and added over 30 min (the temperature did not exceed 32° C.). The resulting red suspension was stirred for 1 h, then transferred to a 3-L round bottom flask (with MeOH) and evaporated to near dryness on a rotary evaporator. The resulting red sludge was diluted with aqueous ammonium chloride (1.75 L) and extracted with EtOAc (2×900 mL). The combined organics were washed with water (150 mL), the water layer was diluted with brine (100 mL) and back-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure at 60° C. to yield 6-chloro-2-methoxy-3-nitropyridin-4-amine as a yellow solid. 1H NMR (CHLOROFORM-d) δ: 6.36 (s, 1H), 6.14 (br. s., 2H), 4.04 (s, 3H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)=[O:9].B.[Na].O>CO>[OH:9][CH:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Agent: B
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)C4CCCCN4C)cc2)CCO3)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
In methanol (40 ml) was dissolved N-(4—(1-methylpiperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) under ice-cooling, and to the mixture was added sodium boron hydride (10 mg). The mixture was stirred for 15 minutes, and to the mixture was added water. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4—(hydroxy(l-methylpiperidin-2-yl)methyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 158) (0.07 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20])([O-:10])=[O:9].[CH2:30](I)[CH2:31][CH3:32]>O>[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][N:16]([CH2:30][CH2:31][CH3:32])[C:15]1=[O:20])([O-:10])=[O:9]
Reactant: CCCI
Reactant: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCC(Cc2ccccc2[N+](=O)[O-])(C(=O)OCC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.59 g) was added to a DMF solution (100 ml) of ethyl 3-(2-nitrobenzyl)-2-oxo-3-piperidinecarboxylate (11.0 g) and propyl iodide (5.79 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with a mixture of ethyl acetate and diethyl ether. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4 to 1/2) to obtain the entitled compound (10.6 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1F.Cl>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]([F:23])([F:24])[F:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[O:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Temperature: 60 °C
Yield: 56 %

Procedure:
Sodium hydride (60% in oil, 0.44 g, 11.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.98 g, 10.0 mmol) and 3-chloro-4-fluoro-5-nitrobenzotrifluoride (1.5 g, 10.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 60° C. for 7 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (80 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/3), to give a yellowish solid of 3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole (1.8 g, yield: 56.6%). mp: 120-123° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.29 (s, 3H), 5.79 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.65-9.30 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18](Br)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41]#[CH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:42]#[C:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Reactant: C#CCc1ccccc1
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: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Temperature: 65 °C

Procedure:
A solution of 4-(7-bromo-3-oxo-2H-isoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (1.50 g, 3.62 mmol) in dimethylformamide (10 mL) is degassed with nitrogen, then treated with triethyl-amine (2.07 mL, 14.8 mmol), CuI (0.050 g, 0.26 mmol), Pd(Ph3P)4 (0.173 g, 0.15 mmol), and 3-phenyl-1-propyne (1.13 mL, 9.05 mmol). The reaction mixture is heated in an oil bath at 65° C. for 5 hours, cooled to room temperature, the DMF is evaporated, and the residue is dissolved in ethyl acetate. The solution is washed with 1N HCl, brine, dried over MgSO4 and evaporated onto silica gel. Purification on a 3.5×18 cm silica gel column eluted with hexane/ethyl acetate 4:1, followed by drying, will afford the desired product.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](#[N:11])[CH:9]=[CH2:10].C[O-].[Na+]>>[CH2:1]([S:7][CH2:10][CH2:9][C:8]#[N:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CC#N
Reactant: CCCCCCS
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCSCCC#N

Procedure:
β-n-Hexylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-hexanethiol (25.0 g; 0.21 moles), acrylonitrile (11.2 g; 0.21 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)CNCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reaction time: 1 h

Procedure:
To a stirred, precooled solution (-40° C.) of 0.41 mL of sulfuryl chloride in 10 mL of chloroform was added a mixture of 1.0 g of 7-methoxy-1,2,3,4-tetrahydro-isoquinoline-hydrochloride and 2.1 mL of triethylamine in 25 mL of chloroform at −40° C. Stirring was continued at −30° C. for one hour and additionally at 5° C. for one hour. The mixture was poured on ice, the organic layer extracted with cold water, dried (sodium sulfate) and concentrated. The residue was redissolved in diethyl ether and chromatographed on silica gel (isohexane/ethyl acetate=8/2 v/v) yielding 0.62 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride as an oil. EI-MS: 261 (M+).
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:30]=[CH:29][C:28]4[N:27]=[CH:26][C:25](=[O:31])[N:24]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:23]=4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:32]1([N:24]2[C:23]3[N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[N:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]2=[O:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of 0.14 g (0.28 mmol) of 2-[[4-[3-(tert-butoxycarbonyl amino)pyrrolidin-1-yl]phenyl]amino]-8-cyclopentyl-8H-pteridin-7-one (from example 23) in 10 mL CH2Cl2 is treated with 1 mL of trifluoroacetic acid, and the resulting mixture is stirred at room temperature for 3 hours. After removal of the solvent, the residue is triturated with aqueous ammonia to give 0.11 g (100%) of the title compound (Compound 17): mp (MeOH(aq)) 197–200° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reaction time: 0.07 h
Yield: 82.8 %

Procedure:
Add trimethylsilylacetylene (3.4 mL, 24.0 mmol) to a mixture of bis(triphenylphosphine)palladium (II) dichloride (766 mg, 1.1 mmol), copper (I) iodide (418 mg, 2.2 mmol) and 3-iodobenzonitrile (5 g, 21.8 mmol) in triethylamine (20 mL). Upon addition of the trimethylsilylacetylene an exothermic reaction occurs and after about 4 min the reaction mixture solidifies. Cool the reaction mixture for about 15 min, dilute with ethyl acetate (100 mL), filter through fluted filter paper using ethyl acetate and concentrate. Dissolve the residue in ethyl acetate (200 mL) and wash sequentially with an aqueous solution of 0.1 N hydrochloric acid and a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes, to give the title compound as a tan solid (3.6 g, 83%).
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].N.CO>C(OCC)(=O)C>[NH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:9]=[C:8]([C:2]([OH:1])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C)(O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(C)(O)c1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate gradient), gave Example 120 a colorless oil. Yield (0.157 g, 90%): 1H NMR (400 MHz, CDCl3) δ 7.20-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.73 (t, J=7.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.70-1.84 (m, 4H), 1.53 (s, 3H), 1.42 (brs, 3H), 1.18-1.30 (m, 3H), 1.06-1.16 (m, 1H), 0.84 (t, J=7.2 Hz, 3H). ESI MS m/z 236.2 [m+H]+, 218.2 [m+H—H2O].
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ncc[nH]1)C12CC3CC(CC(C3)C1)C2

Procedure:
A solution of 5 g. of 1-adamantyl bromomethyl ketone in 10 ml. of dimethylformamide is added dropwise with stirring and ice-cooling to 7 g. imidazole in 10 ml. dimethylformamide. The resulting solution is stirred overnight at room temperature and then poured into 250 ml. water. The precipitate which forms is filtered off, washed with water and air dried. Thereafter the resulting residue is chromatographed on silica gel to effect purification. Elution with 10% acetone in dichloromethane yields 1-adamantyl 1-imidazolylmethyl ketone, M.P. 128.5°-129.5° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:32][C:30]1[CH:29]=[C:16]([CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:31]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(COc2cc(N)cc(Cl)c2)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1ccc(COc2cc(Cl)cc(Nc3ccnc4nc(C)ccc34)c2)cc1

Procedure:
The product from Example 1d (70 mg, 0.39 mmol) was reacted with the product from Example 197d (110 mg, 0.39 mmol) for 23 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the title compound (140 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (s, 2H), 6.90 (d, J=7.0 Hz, 1H), 7.12 (br-s, 1H), 7.17 (br-s, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.9 Hz, 1H), 8.50 (d, J=7.0 Hz, 1H), 9.12 (d, J=8.9 Hz, 1H), 10.06 (s, 1H), 11.17 (br-s, 1H); MS (ESI+) m/z 433, 435 (M+H)+, (ESI−) m/z 431, 433 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH2:11][C:12](=[O:14])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:10][CH:11]=1)(=[O:25])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(C2=NC(=O)CO2)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)co2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Compound 16 (516 mg, 1 eq) was dissolved in CH2Cl2. To the resulting solution, at 0° C., was added 501 μL (1.6 eq) of 2,6-lutidine, followed by the dropwise addition of Tf2O (681 ml, 1.5 eq). The resulting mixture was stirred for 4 h at RT, then an additional 501 μL (1.6 eq) of 2,6-lutidine and 681 ml (1.5 eq) of Tf2O were added. After 1 h, the mixture was evaporated and the residue purified by flash chromatography (SiO2, CH2Cl2/hexane, 9/1) giving 17 as a red oil in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)[CH2:19][N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (170 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (256 mg, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (387 mg, 0.83 mmol) in chloroform (7 mL). DIEA (600 μL, 3.44 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (311 mg, 0.55 mmol, 80%): LC-MS (ES) m/z=567 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CC1NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-methylimidazolidine-2,4-dione (2.00 g), 4-methoxybenzyl chloride (2.85 mL) and potassium carbonate (3.15 g) were added N,N-dimethylformamide (20 mL) and potassium iodide (0.29 g), and the mixture was stirred at 90° C. for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (2.82 g).