Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:14]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccccc1Oc1ccccc1
Yield: 34.5 %

Procedure:
In a similar manner to Example 8, 500 mg (2.80 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 700 mg (3.00 mmol) of 2-phenoxybenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 360 mg (yield: 32.8%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[C:7]([C:14]([NH:16][CH3:17])=[O:15])[C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.[C:36](O)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:13][NH:12][C:10]([C:8]1[O:9][C:5]2[CH:4]=[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:21])=[O:22])[C:2]([Br:1])=[CH:18][C:6]=2[C:7]=1[C:14]([NH:16][CH3:17])=[O:15])=[O:11])(=[O:38])[CH3:37]
Reactant: CNC(=O)c1c(C(=O)NN)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(=O)NNC(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of compound 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (210 mg, 0.50 mmol), EDCI (384 mg, 2.0 mmol) and acetic acid (60 mg, 1.0 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue diluted with water, and the resulting solid was filtered to give the product 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.25 (br s, 1H), 10.22 (s, 1H), 9.68 (br s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 3.20 (s, 3H), 3.17 (s, 3H), 2.83 (d, J=4.4 Hz, 3H), 1.92 (s, 2H). MS (M+H)+: 461/463.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:25])([F:24])[CH2:20][N:21]=[N+]=[N-])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:24])([F:25])[CH2:20][NH2:21])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN
Reaction time: 0.17 h
Yield: 53.8 %

Procedure:
To a mixture of (S)-5-azido-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.35 g, 0.6 mmol) in MeOH (2 mL), was added 10% Pd/C (0.1 g). The mixture was transferred to an autoclave reactor, charged with 10 psi of hydrogen, and stirred for 10 min. The catalyst was filtered off and the filtrate was concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The elute was washed with saturated NaHCO3. The organic layer was concentrated to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.18 g, 54%) as a white solid. LRMS (M+H+) m/z 558.1.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[Br:18])(=O)C>CO.O>[Br:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1ccc2ccccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Potassium hydroxide (25.3 g, 0.45 mol) was added to a solution of 1-bromo-2-naphthalenemethanol acetate (105 g, 0.38 mol) in methanol (300 mL) at room temperature. The resulting yellow solution was stirred at room temperature for 3 hours, then diluted with water and a precipitate was formed. The mixture was extracted with ether (2×300 mL), and the combined organic layers were washed with water (250 mL), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The pure product was obtained as a light yellow solid (86.8 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([Cl:19])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)o1
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)o1

Procedure:
A solution of 28.28 g (0.11 moles) of 5-(2,4-dichlorophenyl)-2-furancarboxylic acid in 43 ml of thionyl chloride is heated at reflux for 3 hours. The solvent is removed and the residue is treated with 100 ml of toluene. The solvent is removed and the residue is carried on directly to the next step of the reaction.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21](Cl)=[N:22][CH:23]=1>CO.C(O)CCC>[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][CH2:4][CH:3]([OH:2])[CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccc3c(c2)CCC3)n1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccc4c(c3)CCC4)n2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 89, 156 mg, 0.56 mmol) in methanol (2 ml) was added to a solution of 5-bromo-2-chloro-4-(indan-5-ylamino)pyrimidine (Method 15, 200 mg, 0.62 mmol) in n-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica.(1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (117 mg, 42%). NMR: 2.03 (m, 2H), 2.18 (s, 6H), 2.32 (m, 2H), 2.83 (m, 4H), 3.80 (m, 3H), 4.76 (d, 1H), 6.70 (d, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.41 (m, 3H), 8.10 (s, 1H), 8.35 (s, 1H), 9.03 (s, 1H); MS (MH+): 498.4, 500.4.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:5][C:6]1[CH:11]=[C:10]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -10 °C

Procedure:
To a stirring suspension consisting of aluminum trichloride (15.9 g) in dichloromethane (200 mL) cooled to an internal temperature of −10° C. under a nitrogen atmosphere is added 2-fluoroanisole (10 g) over one minute. Phenylacetyl chloride (11.6 mL) is subsequently added to the mixture at a rate that maintained the internal temperature below 0° C. The reaction mixture is allowed to warm to room temperature overnight. Water (100 mL) is cautiously added to the stirring mixture. The layers are subsequently separated and the dichloromethane layer is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate and washed with water, 1 M sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 1-(3-fluoro-4-methoxy-phenyl)-2-phenyl-ethanone (14.1 g.)
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1>[C:1]1([CH:17]([OH:18])[C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Phenyllithium (1.8M solution in cyclohexane/diethyl ether, 25.5 milliliters, 46 mmol) was added dropwise over 15 minutes to a stirred solution of 3-cyclopentyloxy-4-methoxybenz-aldehyde (6 grams, 27 mmol) in dry tetrahydrofuran (20 milliliters) at -78° C. The resulting solution was stirred at -78° C. for 30 minutes and quenched at -78° C. by the rapid addition of aqueous saturated NH4Cl (70 milliliters). After warming to room temperature, water was added to dissolve the solids and volatiles were removed in vacuo. The residue was partitioned between water (250 milliliters) and ethyl acetate (250 milliliters), the aqueous phase was extracted with ethyl acetate (3×250 milliliters) and the combined organic layers washed with water (200 milliliters). The organics were dried over Na2SO4 and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 :hexane/ethyl acetate (4:1)) to afford the title compound as a pale yellow oil (7.4 grams) .
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.ClC[C:36]1[NH:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[N:37]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCCC(N)C2)cc(=O)n(Cc2nc3ccccc3[nH]2)c1=O

Procedure:
Title compound 20 was prepared by the methods used in the preparation of compound 17, except that 2-chloromethyl benzimidazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.67 (d, J=3.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.47 (d, J=3.3 Hz, 2H), 7.46 (d, J=3.3 Hz, 1H), 7.37-7.40 (m, 2H), 5.52 (s, 3H), 5.23 (s, 2H), 3.51 (d, J=9.6 Hz, 1H), 3.36 (m, 1H), 2.87-2.92 (m, 2H), 2.64-2.72 (m, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.52-1.64 (m, 2H). MS (ES) [m+H] calc'd for C25H26N7O2, 456.2; found 456.2.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>>[CH2:31]([NH:38][C:11](=[O:13])[C@@H:10]([OH:14])[CH:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCC(N)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.29 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethyl (4 mL) was added in one portion. The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield (S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([CH:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnn(C2CCOCC2)c1
Product: C[C@@H](c1ccc(-c2cnn(C3CCOCC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 18 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-(tetrahydro-pyran-4-yl)-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 3): tR=2.98 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=O)=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C@@H:9]2[NH:8][C:21](=[O:23])[CH2:20][NH:19][C:17]2=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNC(=O)[C@H](CC2CCOCC2)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A 250-mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH2Cl2, and 5 mL of TFA. After 10 min at room temperature, the mixture was concentrated then dissolved in 2N NH3 in MeOH (20 mL) and stirred at room temperature for 4 h. The reaction was then concentrated and triturated with ether to give (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
1-(4-Hydroxyphenyl)ethanone (15.0 g, 110 mmol) was dissolved in acetone (125 mL). The resultant mixture was sequentially added with potassium carbonate (30.4 g, 220 mmol) and 1-methylethyl iodide (16.5 mL, 165 mmol) and then stirred at 70° C. for 8 hours. The reaction solution was filtered, washed with acetone, and concentrated in vacuo. The obtained residue was added with water and ethyl acetate, and then extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-[4-(1-Methylethoxy)phenyl]ethanone (18.2 g, yield 93%) was obtained as a white crystal.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[H][H].C(OCC)(=O)C>C(O)C.[C].[Pd]>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
441 mg (1 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-trifluoromethylbenzoyl)piperidine are hydrogenated (ambient temperature, 30 minutes, hydrogen pressure 50 psi) in 10 ml of anhydrous ethanol and 2.5 ml of ethyl acetate in the presence of 0.5 g of palladium-carbon (10%). The catalyst is then suction-filtered, the filtrate is evaporated under reduced pressure at a bath temperature of 50° C. and the residue is purified by column chromatography (Silica gel; ethyl acetate). 200 mg (48% of theory) of the title compound of melting point 115° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:7]=1)[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][N:25]([C:29](=[O:31])[CH3:30])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C:19]([Li])(C)(C)C.IC>>[CH3:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: [Li]C(C)(C)C
Solvent: CI
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
To a solution of tert-butyl 4-(trifluoromethyl)phenylcarbamate (13.2 g, 50.5 mmol) at −78° C. was added tert-butyllithium (1.7 in pentane, 62.4 mL, 106 mmol). The reaction was allowed to gradually warm to −20° C. in the ice bath (ca. 1 h). The reaction was recooled to −78° C. and treated with iodomethane (3.79 mL, 61 mmol). The reaction was allowed to gradually warm to 0° C. and held there for 15 min. The reaction was quenched by addition of saturated ammonium chloride. The mixture was poured onto diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. The solid was triturated with pentane and filtered to collect a first crop (10.4 g, 75%). The mother liquor gave a second crop of solid (2.15 g, 15%) which was again collected by filtration. 1H-NMR (CDCl3, 500 MHz) δ 8.06 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.40 (bs, 1H), 2.28 (s, 3H), 1.53 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 152.5, 139.8, 127.2 (q, J=3.8 Hz), 126.2, 125.0 (q, J=33 Hz), 124.4 (q, J=272 Hz), 124.2 (q, J=3.8 Hz), 119.5, 81.3, 28.4, 17.7. Mass spec.: 298.00 (MNa)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:8]([NH:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.52 mL of triethylamine and 0.16 mL of benzoyl chloride were added to 3.8 mL of methylene chloride suspension containing 0.39 g of methyl 2-amino-4-((phenylthio)methyl)benzoate hydrochloride while ice-cooled and stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent vas evaporated under reduced pressure, Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate as white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:24]=[CH:23][N:13]([C@@H:14]2[O:22][C@H:19]([CH2:20]O)[C@@H:17]([OH:18])[C@H:15]2[OH:16])[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:45]=[N+:46]=[N-:47].[Li+].C(Br)(Br)(Br)Br>CC(N(C)C)=O.C(OCC)(=O)C>[N:45]([CH2:20][C@H:19]1[O:22][C@@H:14]([N:13]2[CH:23]=[CH:24][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:25])[C@H:15]([OH:16])[C@@H:17]1[OH:18])=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A suspension of cytidine (9.72 g, 40.0 mmol) in pyridine (200 ml) was added to trimethylchlorosilane (25.6 ml, 200 mmol). After 15 minutes of stirring, benzoyl chloride (23.2 ml, 200 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then cooled on an ice bath, and water (40 ml) was added. Five minutes later, 28% aqueous ammonia (40 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Then, the solvent was distilled off under reduced pressure, and acetone was added to precipitate a white solid. The precipitate was filtered off and recrystallized from water to give N4-benzoylcytidine (13.3 g, 96%). The N4-benzoylcytidine (13.0 g, 37.4 mmol), triphenylphosphine (28.0 g, 107 mmol) and lithium azide (13.0 g, 266 mmol) were suspended in dried DMA, and carbon tetrabromide (35.5 g, 107 mmol) was added to the suspension. After 3 hours of stirring at room temperature, ethyl acetate (1500 ml) was added, and the mixture was washed with water and a saturated aqueous solution of sodium chloride (1000 ml each). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give 5′-azido-5′-deoxy-N-benzoylcytidine (12.4 g, yield 89%). A solution of 5′-azido-5′-deoxy-N4-benzoylcytidine (10.0 g, 26.9 mmol) in methanol-DMF (1:1 v/v, 100 ml) was vigorously stirred with 10% palladium-on-carbon (about 1.0 g) in a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 5′-amino-5′-deoxy-N4-benzoylcyridine (9.04 g, yield 97%).