Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloroacetophenone (5.0 g, 32 mmole) was dissolved in methanol (25 mL) and cooled to 0° C. Sodium borohydride (1.2 g, 32 mmole) was added and stirred at 0° C. for 30 minutes. The reaction mixture was neutralized by adding conc. HCI to pH 7.0 and evaporated to dryness. The residue was dissolved in ethanol (30 mL) and filtered, washed with ethanol. The ethanol was evaporated to dryness. The residue was dissolved in methylene chloride (20 mL) and dried over sodium sulfate. The methylene chloride solution was filtered and evaporated to give the desired product as an oil; yield 4.84 g (5.6%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].O1CCOC1.CO[C:17](OC)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:19])[O:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1](=[O:9])[O:8]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)CC(O)C(=O)O
Solvent: C1COCO1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CC(=O)O)O1

Procedure:
Marketed DL-malic acid (with the 4 reference on the above schema) is protected in the dioxolane form in toluene reflux, in the presence of 2,2-dimethoxypropane. The reaction is quantitative. The obtained product (with the 5 reference in the above schema) is directly engaged in the following step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][C:12](=[N:17][NH:18][C:19](N)=O)[C:13]([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>O.C(OCC)C>[C:13]([C:12]1[C:11]([CH:9]=[O:10])=[CH:19][NH:18][N:17]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=NNC(N)=O)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1n[nH]cc1C=O
Temperature: 60 °C
Yield: 6.3 %

Procedure:
Phosphorus oxychloride (18.2 mL, 195 mmol) was added portionwise to DMF (30 mL, 387 mmol) at <5° C. Pinacolone semicarbazone (15.4 g, 97.6 mmol) was added over 1 h maintaining the temperature at <5° C. The reaction mixture became very thick so an additional quantity of DMF (10 mL) was added. The mixture was heated to 60° C. for 3.5 h then allowed to cool and poured into ice. The reaction was neutralised using sodium hydroxide (40 g, 1 mol) in water (130 mL) then heated at 60° C. for 5 min. The mixture was cooled in an ice bath and acidified to pH 6 and the product extracted into EtOAc. The EtOAc was dried over MgSO4 and concentrated onto silica. The crude product was purified by flash chromatography using eluants EtOAc/heptane. Trituration in diethyl ether gave a white solid (1.02 g, 6.1 mmol, 6%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:30])[C@H:12]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:9]>CN(C=O)C>[CH2:8]([O:10][C:11](=[O:30])[CH:12]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1)[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:9]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(NC(=O)c1ccc(Nc2ncccn2)cc1)C(=O)OCC
Temperature: 110 °C
Yield: 69.4 %

Procedure:
2-Chloropyrimidine (0.72 g, 6.3 mmol) and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.04 g, 6.3 mmol, 1 equiv.) were dissolved in DMF (4 mL) and the resulting mixture was heated to 110° C. for 3 hrs. Reaction was complete as determined by TLC. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and concentrated by rotavap. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane) to afford 1.75 g of desired product 2-[4-(pyrimidin-2-ylamino)-benzoylamino]-pentanedioic acid diethyl ester in 69% yield. MS (ESI) m/z 399.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH:3]1[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].ClC(Cl)(Cl)C[O:45][C:46](=O)[NH:47][C:48]1[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:53]([C:51]1[CH:52]=[C:48]([NH:47][C:46]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:4]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:45])[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 56e (87.0 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 66.8 mg, 0.17 mmol), DIPEA (39.2 μL, 0.23 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo and the residue purified by FCC, using 0-10% MeOH in DCM, to provide the title compound as a pale yellow foam (64 mg, 51%). LCMS (Method 3): Rt 3.63 min, m/z 834 [M+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:27][NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N>C(Cl)Cl.CO>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:13])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2ccccc2n1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
97 mg (0.56 mmol) of quinoline-2-carboxylic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =582.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:26]1([S:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.9726 g, 4.00 mmol), triethylamine (0.56 mL, 4.02 mmol), and benzenesulfonyl chloride (0.51 mL, 4.00 mmol) in ethyl acetate (70 mL) was heated briefly to obtain a solution. The reaction was stirred overnight at room temperature under nitrogen. An additional equivalent of triethylamine and ½ equivalent of benzenesulfonyl chloride was added and the mixture heated to 50-60° C. After 7 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and washed with 1N HCl followed by saturated NaHCO3. The organic layer was filtered, dried with MgSO4, and stripped of solvent by rotary evaporator. Trituration of the residue in hexane/ethyl acetate (4:1) afforded the product (0.268 g); m.p. 190-194° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:15])([F:14])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(F)(F)F>>[F:5][C:6]([F:14])([F:15])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)Oc1ccccc1
Agent: FB(F)F
Product: CC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
Into a 250 ml stainless steel reactor equipped with a magnetic stirrer system, 100 ml of anhydrous HF, 23.6 g (0.3 mole) of acetyl chloride, and 32.4 g (0.2 mole) of trifluoromethoxybenzene were introduced at around 0° C. The reactor was closed and gaseous boron trifluoride (BF3) introduced until a constant pressure of 6 bars was achieved. The reaction was then allowed to proceed with stirring at ambient temperature for 3 hours. Following reaction, the reactor was decompressed to atmospheric pressure, then the reaction mixture poured over 200 g of crushed ice. The resultant heterogeneous mixture was extracted three times with 200 ml of methylene chloride. The organic phases were washed three times with 200 ml of water, once with 200 ml of 3% aqueous potassium hydroxide solution, and twice with 200 ml of water. The organic phase was dried over magnesium sulfate and the solvent eliminated by distillation under reduced pressure. 37.2 g (yield: 91%) of p-trifluoromethoxyacetophenone having a purity of 96.3% was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(Br)c1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
3-Bromophenol (2.84 g, 16.4 mmol) was dissolved in dimethylformamide (50 ml) in a dry 100 ml flask under nitrogen. Sodium hydride (0.7 g of a 60% suspension in mineral oil, washed with hexane, 16.7 mmol) was added in portions and the mixture was stirred for one hour at room temperature. Ethyl bromoacetate (1.85 ml, 16.7 mmol) was added drop-wise and the reaction was stirred overnight at room temperature. Approximately two-thirds of the solvent was removed under reduced pressure and the residue was mixed with water (150 ml) and extracted with methylene chloride (3×20 ml). The extracts were combined, washed with water (50 ml), saturated sodium chloride solution (50 ml), then dried (MgSO4). The solution was filtered and concentrated which gave 4.18 g (98%) of ethyl 3-bromophenyloxyacetate.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:3]=1[O:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)=[N:13][CH:12]=[CH:11]2)(=[O:7])=[O:6].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:14]1[C:15]2[C:10](=[CH:9][C:8]([S:5]([O:4][C:3]3[C:2]([F:1])=[C:33]([F:34])[C:32]([F:35])=[C:31]([F:36])[C:30]=3[F:37])(=[O:6])=[O:7])=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)nccc2c1
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)isoquinolin-1-yl)pyrrolidine-1-carboxylate (1.02 g, 1.873 mmol) and DCM (5.0 mL) to give a light yellow solution. TFA (1.443 ml, 18.73 mmol) was added in one portion to give a yellow solution. The reaction was stirred for two hours. The reaction was concentrated, dissolved in diethyl ether, and sonicated until a fine white solid triturated out of solution. The solids were filtered, washed with diethyl ether, and vacuum dried overnight to afford perfluorophenyl 1-(pyrrolidin-2-yl)isoquinoline-6-sulfonate 2,2,2-trifluoroacetate as a white solid. (ESI) 445.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([OH:36])[CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)[O:36][C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: CNC(=O)c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
5-Fluoro-N-methylpyridine-2-carboxamide (150 mg, 0.97 mmol) synthesized in Example (123a) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (438 mg, 1.27 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (269 mg, 1.95 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (281 mg, yield 60%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCc1ccccc1)OCC
Yield: 93.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with (2-bromoethyl)benzene (2.70 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (chloroform only) to obtain the title compound (4.45 g, 94%).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:7].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CCOCC>[CH2:6]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([O:15][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:7]
Reactant: CCOC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
12.2 Under an argon atmosphere, 120 ml of DMF are added to 28.01 g of 1-tert-butyloxycarbonyl-(2R,4S)-4-hydroxyproline ethyl ester, 30.28 g of tert-butyldimethylchlorosilane and 16.41 g of imidazole. The mixture is stirred for a further 2 hours. MTB ether is added, and the mixture is subjected to conventional work-up. The residue is chromatographed on silica gel, giving 40.4 g of 1-tert-butyloxycarbonyl-(2R,4S)-4-(tert-butyldimethylsilyl-oxy)proline ethyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:23][C:24]#[N:25])=CC=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][N:2]([CH3:16])[C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:23][C:24]#[N:25])[CH:8]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 1 h
Yield: 9.9 %

Procedure:
To a solution of dimethyl-(4-nitro-2-trifluoromethylphenyl)amine (0.95 g) in N,N-dimethylformamide (20 mL) were added (4-chlorophenoxy)acetonitrile (0.75 g) and 1 mol/L potassium tert-butoxide (4.5 mL, in tetrahydrofuran solution) under ice cooling, and this mixture was stirred at the same temperature for 1 hour. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.11 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.Cl.[NH2:42][C:43]1[CH:48]=[C:47]([NH2:49])[C:46]([F:50])=[CH:45][N:44]=1.CN1CCCC1>C(Cl)(Cl)Cl>[NH2:42][C:43]1[CH:48]=[C:47]([NH:49][CH:4]=[C:5]([C:11](=[O:22])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=2[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:46]([F:50])=[CH:45][N:44]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: Nc1cc(N)c(F)cn1
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CN1CCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CNc1cc(N)ncc1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 1.2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.34 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.25 g of 2,4-diamino-5-fluoropyridine hydrochloride together with 0.28 g of N-methylpyrrolidine. The solution was concentrated under reduced pressure, and to the residue were added 0.52 g of anhydrous potassium carbonate and 0.8 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 14 g; eluent: chloroform:methanol, 1:0, and then, 100:1), and the fraction containing the main product was concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 1.06 g of the title mixture (1:1 in NMR) as a pale brown powder.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:31])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[C:49]([NH:56][C:57]1[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][C:58]=1[C:59]([OH:61])=O)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:52]([O:51][C:49](=[O:50])[NH:56][C:57]1[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][C:58]=1[C:59](=[O:61])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:31])([CH3:53])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of {(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (0.097 mg, 0.22 mmol, see procedure 1b above) was dissolved in CH2Cl2 (4 mL) and treated with TFA (2 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. The product amine was dissolved in 1:1 DMF/CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol), N-Boc-2-amino-5-(trifluoromethyl)-benzoic acid (S. Takagishi, et al., Synlett 1992, 360; 73 mg, 0.24 mmol), and HATU (97 mg, 0.26 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography afforded (2-{(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(87 mg, 64% yield). MS found: (M+Na)+=655.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[OH-].[K+]>ClCCl.C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 47.5 °C
Reaction time: 3 h

Procedure:
A solution of 86.2 g (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mL triethylsilane in 75 mL dichloromethane and 150 mL acetonitrile is cooled to 10° C. Then with stirring 50.8 mL of boron trifluoride etherate are added so that the temperature does not exceed 20° C. The solution is stirred for 14 h at ambient temperature, before another 9 mL triethylsilane and 4.4 mL boron trifluoride etherate are added. The solution is stirred for a further 3 h at 45-50° C. and then cooled to ambient temperature. A solution of 28 g potassium hydroxide in 70 mL of water is added and the resultant mixture is stirred for 2 h. Then the organic phase is separated and the aqueous phase is extracted another three times with diisopropylether. The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After the solvent has been eliminated the residue is stirred in ethanol, separated off again and dried at 60° C.