Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C(Cl)Cl>[CH2:16]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-n2cnc3cnccc32)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCc3c(ncn3-c3ccccn3)C2)cc1
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of Intermediate 3 (0.20 g, 1.02 mmol) in DCM (25 mL) was added benzyl bromide (0.12 g, 1.02 mmol). The reaction was let stir for 4 h then concentrated. The resulting solid was dissolved in MeOH (10 mL) and NaBH4 (0.05 g, 1.4 mmol) was added slowly. After 5 h, the reaction was quenched with a small amount of water and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.20 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 8.76-8.66 (m, 1H), 8.55-8.39 (m, 2H), 8.14-8.03 (m, 1H), 7.32 (ddt, J=22.0, 11.6, 7.5 Hz, 6H), 3.89 (s, 1H), 3.78 (d, J=5.4 Hz, 2H), 3.63 (s, 1H), 2.99 (t, J=5.5 Hz, 1H), 2.83 (tt, J=26.6, 5.6 Hz, 3H). MS (ESI): mass calculated for C18H18N4, 290.2. m/z found 291.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[CH:18]=[O:19])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH2:18][OH:19])[CH:20]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.33 g) was added portionwise over 30 minutes to a solution at 0° C. of 5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Aromatic Intermediate 3, step b] (9.9 g) in ethanol (120 mL). The reaction mixture was then stirred at room temperature for 30 minutes before being reduced to half the initial volume by concentration under reduced pressure. The residue was partitioned between ethyl acetate and brine, the organic layer was washed with brine, dried, filtered and the solvent concentrated under reduced pressure. The crude product was purified by flash silica chromatography using 12% ethyl acetate in isohexane as solvent. Fractions containing the product were concentrated to dryness to afford the titled compound. Yield 7.30 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[CH3:36][O:37][Na].CO.O>CO>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][O:37][CH3:36])=[CH:8][CH:7]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: CO[Na]
Solvent: CO
Solvent: O
Product: COCc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.2 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14)(0.000397 mol) and MeONa/MeOH (0.000793 mol) in methanol (2 ml) was stirred at room temperature for 48 hours, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.12 g) was purified by column chromatography over kromasil 10 μm (eluent: CH2Cl2/CH3OH/NH4OH; 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.04 g (20%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(methoxymethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:500, 502 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:4].[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].C(S(O)(=O)=O)(F)(F)F>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:34])=[O:4]
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 mL) was treated with bis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF3SO3H (2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mixture was concentrated, dissolved in EtOAc (100 mL), washed twice with 5% aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO3, (50 mL) once to with brine (50 mL), dried with Na2SO4 and concentrated to give 0.94 g of a clear oil. MS calculated for C10HClF3INO+H: 378, observed: 378.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.Cl>O.CN(C=O)C>[CH3:3][O:4][C:5](=[O:10])[C:6]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20])=[C:7]([OH:8])[CH3:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=C(C)O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 106.7 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.60 g, 65.0 mmol) and DMF (52 mL) is stirred in an ice bath and methylacetoacetate (6.46 mL, 59.9 mmol) is added via a syringe over 10 minutes. The mixture is stirred for an additional 10 minutes and the ice bath is removed. The solution is stirred at ambient temperature for 30 minutes and transferred via cannula into a flask containing 4-chloro-1-fluoro-2-nitrobenzene (5.00 g, 28.5 mmol) cooled to 0° C. via an ice bath. The reaction is allowed to warm slowly and is stirred for two days at room temperature. The black mixture is acidified with 2 N HCl, turning it yellow. The resulting solution is diluted with water and extracted with ether. The combined ether layers are washed with water and brine and dried over MgSO4 to give the crude title compound (8.26 g), which contains a small amount of mineral oil. The material is used without purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-])=O.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]([CH2:16][CH3:17])[CH:8]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)cn1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrol-2-carboxylate (10 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethyl iodide (4.8 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the residue and 10% palladium-carbon (50% containing water, 1.0 g) in tetrahydrofuran (20 mL)-ethanol (20 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl 4- amino-1-ethyl-1H-pyrrole-2-carboxylate (7.1 g, yield 78%) as a brown oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Ic1cc(Nc2ccc3cccnc3c2)ncn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from (6-iodo-pyrimidin-4-yl)-quinolin-7-yl-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester via Suzuki coupling reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN(C(NC3SC(Cl)=CN=3)=O)C2=CC=1.[C:47]([CH2:49][C:50](O)=[O:51])#[N:48]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:50](=[O:51])[CH2:49][C:47]#[N:48])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Agent: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Product: N#CCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 23, with the exceptions that the 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 39 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that cyanoacetic acid was used instead of formic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([Cl:22])=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:22][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]([OH:1])=[C:4]([OH:3])[CH:9]=1)=[C:19]([OH:20])[C:18]2=[O:21]
Reactant: O=c1c(O)c(-c2ccc3c(c2)OCO3)oc2ccc(Cl)cc12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c(O)c(-c2ccc(O)c(O)c2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72704984 %

Procedure:
10 mg (31.6 pmol) of the compound obtained in Example 12 was dissolved in 2 ml of methylenechloride, 3 molar equivalents of boron tribromide (BBr3) was added thereto, and then the mixture was stirred at room temperature for 2 hours. The remained boron tribromide (BBr3) was decomposed with methanol. The residue was concentrated under reduced pressure, and purified by preparative TLC to give 7 mg of the title compound in a yield of 72%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCNCC2)c(F)c1
Yield: 96.4 %

Procedure:
A solution of piperazine (24 g, 0.28 mol) and 3,4,5-trifluoronitrobenzene (13 mL, 0.11 mol) in acetonitrile (200 mL) was stirred at 60° C. The progress of reaction was monitored by TLC. On completion, acetonitrile was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and resulting solution was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:9 methanol:chloroform) to provide title compound (25.8 g, 92%) as orange solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C(#N)C.Cl>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])([O-:14])=[O:13]
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)COc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 73.9 %

Procedure:
A solution of 1,5-dichloro-2,4-dinitrobenzene (2.0 g), ethyl glycolate (1.32 g) and anhydrous potassium carbonate (0.88 g) and TDA-1 (0.27 g) in acetonitrile (10 g) was refluxed for 5 hours. After cooling, the reaction mixture was diluted with 3% hydrochloric acid (200 ml) and extracted with ethyl acetate. The organic layer was washed with 5% sodium carbonate solution, water and saturate sodium chloride solution in order, dried over magnesium sulfate, filtered and concentrated. The precipitated crystals were collected by filtration and recrystallized from methanol to give ethyl 2,4-dinitro-5-chlorophenoxyacetate (1.9 g; yield, 73.9%). M.P., 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([S:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([S:32]([C:35]2[CH:36]=[C:37]([NH:41][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:24])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][CH2:27]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CN1CCN(S(=O)(=O)c2cccc(NC(=O)c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)c2)CC1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 613.3 [(M+H)+]; mp 181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[CH2:12][CH2:13][CH2:14][CH2:15][Br:16]>>[Br:16][C:15]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[CH:13]=[CH:12][N:7]2[CH2:8][CH2:9][CH2:10][CH2:2][Br:1]
Reactant: BrCCCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Product: BrCCCCn1ccc2c(Br)cccc21

Procedure:
The procedure is as for Example 39 using as substrate 5-bromo-1H-indole and 1,4-dibromobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14]C)=[CH:12][CH:11]=[CH:10][C:9]=2[F:16])=[C:4]([CH3:17])[CH:3]=1>Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: COc1cccc(F)c1-c1ccc(Cl)cc1C
Agent: Br
Product: Cc1cc(Cl)ccc1-c1c(O)cccc1F
Yield: 86.1 %

Procedure:
Treatment of 4-chloro-2′-fluoro-6′-methoxy-2-methylbiphenyl (2.7 g, 10.8 mmol) with hydrogen bromide (33% in acetic acid, 50 mL) according to the procedure described for Example 69, Step 2 provided 2.2 g (86%) of 4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(=[CH:35][CH:36]=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:35]/[CH:36]=[O:37])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cccc(F)c2)cn1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
584 mg of 5-(3-fluorophenyl)pyridine-2-carbaldehyde and 883 mg of (triphenylphosphoranylidene)acetaldehyde are stirred at RT overnight. The solvent is evaporated and the residue is purified by column chromatography (silica gel, MeOH:DCM=99.5:0.5).
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].Cl.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[OH:16].C(OC(=O)C)C>C(O)C.C(O)(=O)C.O.CO>[ClH:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH2:1][CH3:2])=[O:12])=[CH:9][C:8]=1[OH:16]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N)c(O)c1
Temperature: 0 °C

Procedure:
To a dry 100 mL round-bottom flask was added absolute ethanol (50 mL) and the solution cooled to 0° C. (ice-bath) under dry N2(g). Acetyl chloride (5.0 mL) was added slowly with stirring and this solution allowed to stir under anhydrous conditions for 2 hours to prepare anhydrous 1.40 M HCl in ethanol. To this solution was added 4-amino-3-hydroxybenzoic acid (2.50 g, 16.32 mmole) and the mixture allowed to stir as above at room temperature overnight. TLC (irrigant=7:1:1:1 ethylacetate:methanol:water:acetic acid, Rf=0.85) indicated complete conversion to the ethyl ester. Yield 3.5 g (99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:40](=[O:41])[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)Cc1ccccc1
Yield: 67.4 %

Procedure:
In a manner analogous to that described in Example 21, from 223 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 77 mg of phenylacetyl chloride and 65 mg of diisopropylethylamine there were obtained 190 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(phenylacetyl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid (from ethyl acetate/n-hexane); MS: m/e 567 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3ON=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[S:30]1C=CC=[C:31]1C1C=CC(N)=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[S:30][CH:31]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1ccc(-c2cccs2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cccs2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(thiophen-2-yl)aniline in step 1. MS: 410.0 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[C:16]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[C:16]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 202.7 %

Procedure:
To a solution of Compound 17b (1.5 g; 3.6 mmol) in CH2Cl2 (30 mL) was adde TFA (10 mL). The solution was stirred at room temperature for 1.5 h, and the solvent was evaporated in vacuo. The residue was triturated with Et2O, collected the solid and dried to afford the title Compound 17c (2.25 g; 96% yield based on tri-TFA salt). MS: m/z 309.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COC(=O)C(C)CN
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CNc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 15 h
Yield: 60.7 %

Procedure:
To a solution of 1,4-difluoro-2-nitrobenzene (14.3 g, 90 mmol) in tetrahydrofuran (250 mL) was added methyl 3-amino-2-methylpropanoate (10.5 g, 90 mmol) and potassium carbonate (24.8 g, 180 mmol). The reaction mixture was heated to reflux and stirred for 15 hours. Then the mixture was concentrated in vacuo, and the residue was dissolved in water (250 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers was separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford methyl 3-(4-fluoro-2-nitrophenylamino)-2-methylpropanoate as a red solid (14.0 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:12]=[C:13](I)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]2[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:11]([C:10]([F:9])([F:23])[F:22])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 3,5-bis(trifluoromethyl)iodobenzene (0.89 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-3,5-bis(trifluoromethyl)benzene (0.44 g). MS calcd. for C14H8BrF6S [(M+H)+] 402, obsd. 402.