Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=1.O1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C>[C:15]([O:14][C:12]([NH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][CH2:3][CH:2]=[O:1])[N:10]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCC(O)CO)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCC=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of N-[6-(3,4-dihydroxybutyl)(2-pyridyl)](tert-butoxy)carboxamide in tetrahydrofuran/water (1 eq/1 eq, 0.1M) was added sodium metaperiodate (1.3 eq) at 0° C. and stirred for 1 hr. The reaction was warmed to room temperature and diluted with ethyl acetate. The reaction was extracted with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated in vacuo to yield the product. EI-MS m/z 251(M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1.[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]([OH:26])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1cccc(COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cccc(COC2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 55.1 %

Procedure:
A solution of 3-(tetrahydropyranyloxymethyl)bromobenzene (11.8 g, 43.5 mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of 1.6M n-butyl lithium-hexane solution (30 ml, 48 mmol) in tetrahydrofuran (100 ml) at -78° C. in a nitrogen stream over 15 minutes. This reaction solution was stirred at -78° C. for 40 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (7.2 g, 21.9 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. The reaction solution was stirred at -78° C. for 30 minutes and then allowed to gradually warm and saturated aqueous ammonium chloride was added thereto. This solution was poured into a liquid mixture of ethyl acetate with water and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=6:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[α-hydroxy-3-(tetrahydropyranyloxymethyl)benzyl]pyrrolidine (6.3 g, yield: 55.0%) as a yellow oily substance.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22](Br)[CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:7]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:9]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)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>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:7]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:9]=1
Reactant: O=C(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Reactant: OB(O)c1ccccc1
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: CC#N
Solvent: O
Product: O=C(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(-c3ccccc3)cc12
Yield: 32.6 %

Procedure:
To (3,5-Bis-difluoromethoxy-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-1519, 29.0 mg, 0.067 mmol) in acetonitrile (4.0 mL) were added phenylboronic acid (12.2 mg, 0.10 mmol), Tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 8.65E-6 mol) and 1.0 M potassium carbonate in water (1.5 mL). The reaction was microwaved (300 watts) at 160° C. for 7 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated, and purified with silica gel column chromatography to give the compound as a white solid (P-1521, 9.4 mg, 33%). MS (ESI) [M+H+]+=431.2.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[C:10]([O:14]Cl)(C)(C)[CH3:11].CC[C:18](OCC)=[S:19].C(N(CC)CC)C.Cl>ClCCl.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][C:10](=[O:14])[CH:11]2[S:19][CH3:18])#[N:2]
Reactant: CC(C)(C)OCl
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=S)CC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Following the procedure described in PCT Published Patent Application, WO 99/10325, a solution of 4-cyanoaniline (10 g, 84 mmol) in dry dichloromethane (200 mL) under nitrogen was cooled to −78° C. To this stirred solution was added a solution of t-butylhypochlorite (10.9 mL, 84 mmol) in dry dichloromethane (20 mL). The resulting solution was stirred for 10 minutes. A solution of ethyl methylthioacetate (10.9 mL, 84 mmol) in dichloromethane (20 mL) was added dropwise. After 1 hour, triethylamine (12 mL, 86 mmol) was added dropwise to the solution and the resulting reaction mixture was allowed to warm to ambient temperature over 1 hour. The reaction mixture was washed with water, brine, dried (Na2SO4) and concentrated to afford an orange oil. This oil was dissolved in ether (200 mL) and treated with 2N HCl (15 mL). The reaction mixture was stirred vigorously at room temperature for 18 hours. The resulting solid was collected by filtration, washed with ether, and dried in vacuo to afford 5-cyano-3-methylthioindolin-2-one as a solid (11 g).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[N:30]=[CH:29][C:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:33][CH:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCCCC4)cn3)ncc12
Temperature: 25 °C
Yield: 27.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). 1H NMR δ (400 MHz, CDCl3) 8.79 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.38 (d, J=6.8 Hz, 1H), 5.98 (m, 1H), 3.1 (m, 4H), 2.60 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.57-1.75 (m, 8H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)C(C)C)(C)C>O1CCCC1.Cl>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:16]([CH3:17])[CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
To a solution of 40.44 g (0.20 mol) of 3-acetylbenzenesulfonyl fluoride in 200 ml of dry tetrahydrofuran is added 20.4 g (0.25 mol) of dimethylamine hydrochloride and 43.6 ml (0.25 mol) of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 48 hours, diluted with 250 ml of 1N HCl and extracted with CH2Cl2. The extract is dried (MgSO4) and the solvent removed. The residue is chromatographed (silica gel column) with CH2Cl2 -hexane (1:1). The fractions containing product are combined, the solvent removed and the residue crystallized from CH2Cl2 -hexane to give 28 g (62%) of white crystals, m.p. 73°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][N:31]([CH3:35])[C:32]([Cl:34])=[O:33]>C(#N)C.ClCCl.C(OCC)(=O)C>[ClH:34].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH:6]=[CH:5][C:4]=1[O:23][C:32](=[O:33])[N:31]([CH3:35])[CH3:30]
Reactant: COc1cc(CCN2CCN(c3ccccn3)CC2)ccc1O
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(CCN2CCN(c3ccccn3)CC2)ccc1OC(=O)N(C)C
Product: Cl
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 2-methoxy-4-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl)phenol (1.0 g) and cesium carbonate (1.0 g) in 25% acetonitrile/dichloromethane was added dimethylcarbamyl chloride (0.7 g), and the reaction mixture was stirred for 18 hrs, under nitrogen. The reaction mixture was diluted with ethyl acetate, and washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was flash chromatographed (silica) eluting with 2% methanol/dichloromethane. The appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and ethereal hydrogen chloride was added. The precipitate was collected to give product 0.9 g (73%), mp 192-193° C.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncnc2ccncc12
Reactant: NCc1ccccc1
Solvent: CCO
Product: c1ccc(CNc2ncnc3ccncc23)cc1
Yield: 16.9 %

Procedure:
4-Methylthiopyrido[4,3-d]pyrimidine (160.4 mg, 0.902 mmol), and benzylamine (106.3 mg, 0.992 mmol) in EtOH (2 mL) are heated at 80° C. for 12 h, and then the solvent is removed under reduced pressure. The resulting solid is suspended in CH2Cl2, filtered, and the resulting solid is purified by preparative tlc on silica, eluting with 5% MeOH in CHCl3. Removal of the solvent under reduced pressure yields 4-benzylaminopyrido[4,3-d]pyrimidine (36 mg, 17%). 1H NMR (DMSO) δ 9.60 (1H, s), 9.37 (1H, t, J=5.8 Hz), 8.72 (1H, d, J=5.8 Hz), 8.57 (1H, s), 7.54 (1H, d, J=5.8 Hz), 7.37 (2H, d, J=7.0 Hz), 7.33 (2H, t, J=7.3 Hz), 7.25 (1H, t, J=7.2 Hz), 4.81 (2H, d, J=5.8 Hz).
Reaction SMILES: [SH:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([S:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(S)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC(C)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 31.3 %

Procedure:
3-[(3-Mercapto-2-benzylbutanoyl)amino]benzoic acid (compound of Example 194) (1.7 g) is suspended in dichloromethane (17 ml), and thereto is added triethylamine (0.52 g)with stirring under ice cooling. To the mixture are further added dropwise acetyl chloride (0.51 g) and triethylamine (0.52 g) simultaneously, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then dichloromethane is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17](Br)[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[CH3:27][Sn](C)(C)C>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>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([CH3:27])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 103(b) from 1-bromo-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, tetramethyl tin, and bis(triphenylphosphine)-palladium(II) dichloride (Pd(PPh3)2Cl2). The title compound, ESI MS (m/z): 347 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[OH:18].CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Br:1][C:2]1[C:3]([O:18][CH3:21])=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1Br
Temperature: 40 °C
Yield: 100.3 %

Procedure:
To a solution of 2-bromo-4-nitro-3-phenylaminophenol (450 mg, 1.45 mmol) in acetone was added methyl iodide (0.34 mL, 5.44 mmol) and potassium carbonate (751 mg, 5.44 mmol) and the reaction mixture heated at 40° C. for 16 h. The mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo to give the title compound as a yellow oil (470 mg, 100%). 1H NMR 400 MHz δ (CDCl3): 8.36 (1H, br s), 8.19 (1H, d, J=9.6 Hz), 7.28-7.22 (2H, m), 7.05-7.00 (1H, m), 6.89-6.84 (2H, m), 6.69 (1H, d, J=9.7 Hz), 4.01 (3H, s).
Reaction SMILES: [I-:1].[K+].N([O-])=O.[Na+].N[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O>C(#N)C>[I:1][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: [I-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium iodide (5.6 g, 34 mmol) and sodium nitrite (2.4 g, 35 mmol) were added to a solution of 2-amino-4-trifluoromethyl-benzonitrile (2.58 g, 14 mmol) in acetonitrile (60 mL). The resultant mixture was cooled to 0° C. in an ice-water bath with magnetic stirring. Ice-cold concentrated HCl (14 mL) was added slowly drop-wise to the reaction mixture, causing the reaction mixture to become cloudy and deep red in color. The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature. Stirring at room temperature proceeded for 3 hours. The reaction mixture was poured into water, and the resulting suspension was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated to give a purple liquid. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a silica gel column. Manual flash chromatography using 5% ethyl acetate in hexanes afforded 2-iodo-4-trifluoromethyl-benzonitrile as 3.58 g (87%) of a purple, crystalline solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:17]=[CH:16][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:5][O:4][C:2]([N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([Br:6])[CH:17]=[CH:16][C:10]=2[CH2:11][CH2:12]1)=[O:3]
Reactant: Brc1ccc2c(c1)CCNCC2
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccc(Br)cc2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Methyl chloroformate (444 mg, 4.70 mmol) was added to a 0° C. mixture of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine (950 mg, 3.82 mmol) and triethylamine (915 mg, 9.04 mmol) in 19 mL of dichloromethane. The resulting solution was stirred at 0° C. for 2 h. Water was added, the layers were separated and the aqueous phase was washed with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave 1.07 g of an oil. This material was combined with 52 mg from an earlier experiment and purified by column chromatography on silica gel (24 g SiO2, Analogix column) eluting @ 30 mL/min with 1:1 ethyl acetate/heptane. 763 mg of product was obtained.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=O)=[N:4][C:3]=1[CH3:10].[CH3:11][N:12](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:13].F[P-](F)(F)(F)(F)F.Cl.CNC.C(N(CC)CC)C>CN(C)C=O.CCOC(C)=O>[I:1][C:2]1[NH:6][C:5]([C:7]([N:12]([CH3:13])[CH3:11])=[O:9])=[N:4][C:3]=1[CH3:10]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(C(=O)O)[nH]c1I
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N(C)C)[nH]c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-iodo-4-methyl-1H-imidazole-2-carboxylic acid (compound 239.3, 200 mg, 0.79 mmol) in N,N-dimethylformamide (4 mL). HBTU (602 mg, 1.59 mmol), dimethylamine hydrochloride (96 mg, 1.18 mmol) and triethylamine (552 μL, 3.96 mmol) were added to the reaction. The reaction mixture was stirred for 3 h at room temperature, then diluted with 50 mL of EtOAc. The organic layer was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 150 mg (68%) of the title compound as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:22]=1[NH2:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=1[CH3:20])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(O)C(=O)O
Reactant: Cc1ccc(N)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 287 mg (1 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxyvaleric acid, 363 mg (3 mmol) of 2,4-dimethylaniline, 288 mg (1.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 150 mg (1.1 mmol) of 1-hydroxybenzotriazole in 10 ml of dichloromethane was stirred at room temperature for 2 hours. The solution was diluted with diethyl ether, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulphate, filtered and evaporated to give 363 mg of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxy-2′,4′ dimethylvaleranilide as a white solid, 1H NMR (250 MHz, CDC3) δ: 1.4 (s,4H), 1.45 (s,5H), 2.1 (s,1.5H), 2.15 (s, 1.5H), 2.3 (s,3H), 2.2-2.6 (m,1H), 2.7-3(m,1H), 4.2-4.6 (m,2H), 5.3 (d,0.5H), 5.6 (d,0.5H), 5.9 (d,0.5H), 6.2 (d,0.5H), 7.0 (m,2H), 7.6 (d,0.5H), 7.7 (d,0.5H), 8.6 (s,1H).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:63])[CH2:20][O:21][CH2:22][C:23](=[O:62])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:51][C:52]([CH:54]2[CH2:59][CH2:58][C:57]([F:61])([F:60])[CH2:56][CH2:55]2)=[O:53])[CH2:32][CH2:33][N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][CH:37]([N:42]2[C:46]([CH3:47])=[N:45][N:44]=[C:43]2[CH:48]([CH3:50])[CH3:49])[CH2:38]3)=[CH:27][CH:26]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:20][O:21][CH2:22][C:23]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:51][C:52]([CH:54]2[CH2:55][CH2:56][C:57]([F:61])([F:60])[CH2:58][CH2:59]2)=[O:53])[CH2:32][CH2:33][N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][CH:37]([N:42]2[C:46]([CH3:47])=[N:45][N:44]=[C:43]2[CH:48]([CH3:50])[CH3:49])[CH2:38]3)=[CH:27][CH:26]=1)=[O:62])=[O:63]
Reactant: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCN)cc1
Yield: 51 %

Procedure:
A solution of 27 (260 mg, 0.291 mmol) in methanol (15 mL) was hydrogenated in the presence of 5% Pd/C (26 mg) under a H2 atmosphere (60 psi) at room temperature for 48 h. The mixture was filtered, and the filtrate was concentrated to give 28 as white foaming (113 mg, 51% yield). 1H NMR (400 MHz, CDCl3): (δ8.80 (s, 1H), 7.58 (d, J=8.48 Hz, 2H), 7.25 (d, J=8.48 Hz, 2H), 6.61 (d, J=7.48 Hz, 1H), 6.47 (m, 1H), 5.10 (q, J=7.00 Hz, 1H), 4.30 (m, 1H), 4.17 (s, 2H), 4.12 (s, 2H), 3.40-3.30 (m, 4H), 2.98 (seq, J=6.90 Hz, 1H), 2.68 (t, J=6.84 Hz, 2H), 2.48 (s, 3H), 2.43 (t, J=6.62 Hz, 2H), 2.26-2.12 (m, 5H), 2.08-1.53 (m, 16H), 1.44 (qu, J=6.72 Hz, 2H), 1.383 (d, J=6.76 Hz, 3H), 1.382 (d, J=6.80 Hz, 3H); 1.34-1.30 (m, 6H); 1H NMR (400 MHz, CD3OD): δ 7.60 (d, J=8.52 Hz, 2H), 7.33 (d, J=8.56 Hz, 2H), 5.03 (t, J=7.34 Hz, 1H), 4.39 (m, 1H), 4.20 (s, 2H), 4.12 (s, 2H), 3.41 (m, 2H), 3.30-3.21 (m, 3H), 2.69 (t, J=7.32 Hz, 2H), 2.50 (s, 3H), 2.46-2.41 (m, 2H), 2.40-2.30 (m, 1H), 2.30-2.05 (m, 2H), 2.05-2.03 (m, 4H), 2.02-1.96 (m, 2H), 1.89-1.65 (m, 10H), 1.60-1.45 (m, 4H), 1.36-1.34 (m, 12H); 13C NMR (100 MHz, CDCl3): δ 176.59, 171.68, 170.07, 161.41, 152.60, 140.39, 138.07, 128.21, 123.91 (J 13C-19F 239 Hz), 121.88, 71.95, 71.75, 60.69, 60.19, 52.41, 43.69, 42.03, 40.07, 36.77, 36.16, 33.90 (J 13C-19F 24 Hz), 33.87 (J 13C-19F 24 Hz), 32.28, 30.38, 30.11, 27.86, 27.78, 27.20 (J 13C-19F 9 Hz), 27.05 (J 13C-19F 9 Hz), 26.76, 22.07, 12.45. mp 100-102° C. IR v (Diamond, cm−1): 3256, 1651, 1538, 1515, 1261, 1103, 743. MS (ESI) m/z found 757.9 (M+H)+.