Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(OCC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(OCCNc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(4-methoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1.Cl.CC[O:30]C(C)=O>CCO.[OH-].[Na+].OO>[NH2:1][C:2]1[C:6]([C:7]([NH2:8])=[O:30])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(N)c3C#N)cc2)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(N)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a mixture of 1-[4-(3-amino-4-cyanoisothiazol-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea (10.2 mg, 0.028 mmol) in 0.8 mL EtOH at rt was added 15 drops 1.0M aqueous NaOH, 7 drops 30% hydrogen peroxide and the reaction stirred at rt for 30 min, then heated at 60° C. After 2.5 hours an aqueous HCl (dilute) and EtOAc workup was done to give a light yellow solid. To this material was added an impure lot from another reaction, and the combined lots triturated with EtOAc to give the title compound as a pale yellow solid (26 mg, 93% combined yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(C)cc(I)cc1F
Reactant: COc1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2cc(C)c(C(C)=O)c(F)c2)cc1
Temperature: 100 °C
Yield: 42.5 %

Procedure:
To a solution of 1-(2-fluoro-4-iodo-6-methylphenyl)ethanone (30-4, 1.1 g, 4.0 mmol), K3PO4 (1.7 g, 8.0 mmol), 4-methoxy-phenol (0.60 g, 4.8 mmol) in toluene (20 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (51 mg, 0.12 mmol), Pd(OAc)2 (38 mg, 0.08 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)ethanone (0.47 g, 1.7 mmol) as yellow oil in 43% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (m, 2 H), 6.90 (m, 2 H), 6.54 (s, 1 H), 6.42 (m, 1 H), 3.80 (s, 3 H), 2.50 (d, J=4.1 Hz, 3 H), 2.30 (s, 3 H). ESI-MS: m/z 275.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[O:18]1[C:20]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19]1>CCO.O>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][CH2:10]/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][C:20]2([OH:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: C1CCC2(CC1)CO2
Reactant: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=C(NC/C=C/c1cccc(NCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O(9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH:3]1[C:12]([O:14][CH3:15])=[O:13].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH:3]([C:12]([O:14][CH3:15])=[O:13])[C:2]1=[O:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)C1CC2(CCC1=O)OCCO2
Product: COC(=O)C1CC2(CC(=CN(C)C)C1=O)OCCO2

Procedure:
Methyl 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylate (64 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (80 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 270.3 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[NH:15][C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]3=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.[CH2:19](N1C2C(=CC=C(C3C=CC=CN=3)C=2)C(=O)C(C(O)=O)=C1)[CH3:20].C(Br)C>>[CH2:19]([N:15]1[C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]2=[CH:17][CH:18]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]12)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Reactant: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1
Solvent: CCBr
Product: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21

Procedure:
It was found that the 4-(4-pyridinyl)isatoic anhydride prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) alkylating it with ethyl bromide, as in Ranken et al., to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (b) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (c) hydrolyzing that ester.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:17])[CH2:15]Br)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:15][C:14]([C:13]1[CH:18]=[CH:19][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1)=[O:17])(=[O:22])[CH3:21]
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)O
Product: CCCCCCCCOc1ccc(C(=O)COC(C)=O)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-n-octyloxyphenacyl bromide are reacted with 5 grams of acetic acid to obtain 4-n-octyloxyphenacyl acetate, m.p. 44°-45° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH2:9][OH:10])=[C:6]([Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:12][C:6]1[C:7]([CH:8]([CH3:11])[CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CC(CO)c1c(Cl)ncnc1Cl
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-propan-1-ol (0.40 g, 1.93 mmol) in DCM (40 mL) were added MsCl (0.50 g, 4.36 mmol), TEA (1 mL) and catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-propyl ester (0.54 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 4.74 (m, 1H), 4.55 (m, 1H), 4.14 (m, 1H), 2.99 (s, 3H), 1.49 (dd, J=7.2 Hz, J=1.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][C@@H:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([N:28](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[O:13])[O:9][N:8]=2)[CH:2]=1.C(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:28][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]([CH:10]2[O:9][N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:11]2)=[O:13])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.8 %

Procedure:
) (50 ml) was added dropwise to a solution of 1,1-dimethylethyl (5S)-[[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl][(1,1-dimethylethoxy)carbonyl]carbamate (0.0233 mol) in CH2Cl2 (500 ml), stirred at RT (CO2 gas evolution). The reaction mixture was stirred for 48 hours at RT. The reaction mixture was added dropwise to a saturated aqueous NaHCO3 solution, and this mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 97.5/2.5). The desired fractions were collected and the solvent was evaporated under reduced pressure. The resultant oil was stirred in EtOAc, filtered off, washed with EtOAc and DIPE, then dried, yielding 2.5 g (30%) of (±)-N-[4-(aminophenylmethyl) phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 502).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a suspension of phthalimide, potassium derivative (11.5 g, 0.062 mol) in dry dimethylformamide (60 mL) was added 1-bromo4-methyl-3-pentene (10.0 g, 0.061 mol) and the suspension was stirred under N2 at 90° C. for 4 h. The reaction mixture was poured into water (300 mL) and the precipitated solid was filtered and washed with water and the solid was dried under vacuum. Yield: 12.8 g (91%). mp 95-97° C. MS: (M+H)+=229.9.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[I:23]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:23])[C:3]=12
Reactant: Oc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1I
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc[nH]c2ncc(I)c1-2
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 1.0 g of 4-hydroxypyrrolo [2,3-d]pyrimidine in 20 ml of DMF, 3.3 g (2.2 eq) of bis(trimethylsilyl)acetamide was added, and the resulting solution was stirred at 40° C. in an oil bath for about 2 h. Completeness of silylation was indicated by NMR analysis of an aliquot showing disappearance of the N-3 proton signal. The reaction was cooled to ambient temperature and 1.6 g (1.2 eq) of N-iodosuccinimide (NIS), was added in one portion. The reaction mixture was protected from light and stirred at ambient temperature until completion was indicated by NMR analysis (disappearance of pyrrole C-H doublets and emergence of a single, finely split doublet at δ7.17, about 2 h). The mixture was poured into 50 mL of water with stirring. After 1-2 hours, the product was collected by filtration, washed with water, dried, and reslurried in 10 volumes of 10% methanol in chloroform. Filtration and drying gave 1.7 g of 4-hydroxy- 5-iodopyrrolo[2,3-d]pyrimidine (88% yield), mp 248°-253° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ7.17 (d, J=2.4 Hz, 1 H), 7.80 (d, J=2.3 Hz, 1 H), 11.82 (s, 1 H), 12.14 (s, 1 H). 13C NMR (75.5 MHz, DMSO-d6) δ53.8, 107.3, 125.5, 143.6, 147.9, 157.8. Anal. Calcd for C6H4IN3O: C, 27.61; H, 1.54; N, 16.10. Found: C, 27.71; H, 1.48; N, 15.85.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6].[CH2:16]([OH:21])[CH:17]([OH:20])[CH2:18]Cl>CO>[CH3:3][N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:18][CH:17]([OH:20])[CH2:16][OH:21])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6]
Reactant: OCC(O)CCl
Reactant: CN1C(=O)CCc2c(O)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 22 %

Procedure:
2.0 g of potassium hydroxide was dissolved in 80 ml of methanol, and 4.8 g of 1-methyl-5-hydroxy-3,4-dihydrocarbostyril and 4.0 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 4 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 120 ml of chloroform, and the extract was washed with a 5% aqueous potassium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethyl acetate to give 1.5 g of 1-methyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 120° - 121° C.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[CH2:3][C@H:4]([NH:37]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].N1CCCCC1>C(Cl)Cl>[NH2:37][C@@H:4]([CH2:3][C:2]([F:55])([F:56])[F:1])[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate (10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 30-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm) 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12 (2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s), 6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91 (1H, d, J=13.14 Hz), 3.71 (1H, d, J=13.39 Hz), 2.66 (2H, m). (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was prepared in the same method here and isolated as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m), 6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07 Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H, m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) and (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyebutanamide (Example 323B) was assigned arbitrarily.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added (2-bromoethyl)benzene (2.22 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.72 g, 55%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20].[Na]>C(#N)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH2:1])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Na]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
Under nitrogen, 17.7 g (128 mmol) of 4-fluoroacetophenone (Aldrich) and 20.7 mL (192 mmol) of triethylamine at ambient temperature was treated with 24.4 mL (192.3 mmol) of chlorotrimethylsilane and allowed to stir of 20 minutes prior to the slow addition of a suspension of 30 g (200 mmol) of sodium iodode in 200 mL of acetonitrile. The extracts were combined, dried (K2CO3), and concentrated in vacuo to give 27 g of crude 1-fluoro-4-[1[(trimethylsilyl)oxy]ethenyl]benzene as an oil: NMR (CDCl3) δ 0.28 (s, 9H), 4.41 (d, J=2 Hz, 1H), 4.84 (d, J=2 Hz, 1H), 7.00 (d, J=8 Hz, 2H), 7.53 -7.60 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=O.O.[NH2:20][NH2:21]>C(O)COCCO>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=[N:20][NH2:21])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13]
Reactant: NN
Reactant: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc(Cl)ccc1N)c1c(F)cccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2',6'-difluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2',6'-difluorobenzophenone hydrazone.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]2[N:11]=[C:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:9]2=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O>CO>[NH2:5][C:6]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]2[N:11]=[C:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:9]2=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1nc1n2CCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1nc1n2CCC1
Yield: 66.2 %

Procedure:
A solution of methyl 6-(2,2-dimethylpropionylamino)-2,3-dihydro-1Hbenzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (Intermediate 56, 0.61 g) and concentrated sulfuric acid (1.5 mL) in methanol (30 mL) was stirred and heated at reflux for 44 hours. After cooling, the solution was concentrated in vacuo and the residue was dissolved in water and ethyl acetate and basified with 5M sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (×8) and the combined extracts were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether and filtered to give methyl 6-amino-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (0.296 g) as an off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-t-butoxycarbonylamino-5-trifluoromethyl-benzoate (3.80 g; prepared in Reference Example 27.) in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added. The mixture was stirred for 8 hours at room temperature. The solvent was distilled off azeotropically with toluene three times. To the reaction mixture, an aqueous sodium hydrogencarbonate solution was added to neutralize. The mixture was extracted with ethyl acetate, washed, dried, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=5:1) to give the title compound (2.35 g) having the following physical data.