Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH3:41])[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](O)=[O:35])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[NH:31][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:41])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)cc1
Yield: 60.8 %

Procedure:
Preparation of example 122 from the title compound of Example 7 (100 mg, 0.362 mmol), 2-(toluene-4-sulfonylamino)-benzoic acid (158 mg, 0.542 mmol), triethylamine (0.201 mL, 1.446 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (206 mg, 0.542 mmol) in N,N-dimethylformamide (4.0 mL) was carried out analogously to Example 11. When the reaction was judged complete, N,N-dimethylformamide was evaporated and methanol was added. The mixture was filtered and the solids collected and washed with methanol, dichloromethane and diethyl ether. After drying under vacuum, the title compound (121 mg, 0.220 mmol) was obtained as a yellow powder in 61% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[N:4]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:26])[F:27])=[CH:18][CH:19]=3)=[O:25])=[CH:9][CH:8]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-morpholinoaniline (270 mg, 1.5 mmol) in dry methylene chloride is added 4-trifluoromethoxy-phenyl isocyanate (229 μl, 1.5 mmol) at room temperature. After stirring at room temperature for 2 hours, the solvent is removed by rotary evaporator. The crude product, 1-(4-Morpholin-4-yl-phenyl)-3-(4-trifluoromethoxy-phenyl)-urea, is recrystallized in methanol to give a white solid (424 mg, 74% yield); 1H NMR (400 MHz, d-DMSO) δ3.00 (dd, J=4.7, 4.8 Hz, 4H), 3.71 (dd, J=4.5, 4.9 Hz, 4H), 6.87 (d, J=9.0 Hz, 2H), 7.24 (d, 2H), 7.29 (d, 2H), 7.5 (m, 2H), 8.44 (s, 1H), 8.75 (s, 1H); MS (ES+) m/e 382.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[C:23]2[C:18]=1[C:19](=[O:39])[C:20]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[CH:21][NH:22]2.[C:40]([CH:43](Cl)[CH2:44][NH-:45])([OH:42])=[O:41]>O.CN(C=O)C>[F:16][C:17]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[C:23]2[C:18]=1[C:19](=[O:39])[C:20]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[CH:21][NH:22]2.[C:40]([CH:43]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH2:44][NH-:45])([OH:42])=[O:41]
Reactant: [NH-]CC(Cl)C(=O)O
Reactant: CN1CCNCC1
Agent: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(C[NH-])C(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-methylpiperazine (276 mg, 2.76 mmol), sodium iodide (440 mg, 2.9 mmol) and potassium carbonate (572 mg, 4.14 mmol) were added to a DMF solution (8 ml) of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide (600 mg, 1.38 mmol) and stirred overnight at 80° C. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction using chloroform. The thus-obtained organic layer was concentrated under reduced pressure, and the residue was then purified using medium pressure liquid chromatography (NH silica gel, dichloromethane:methanol=100:0→10:1). The purified product was concentrated under reduced pressure, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydro-quinoline-2-carboxy-[2-(4-methylpiperazin-1-yl)ethyl]amide (100 mg, yield: 14%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[NH2:20].N1C=CC=CC=1.[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[NH:20][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=1
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: COC(=O)c1cc(OCCCN2CCCCC2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCCCN2CCCCC2)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Amino-5-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (compound A) (1.1 g) produced by the above process was dissolved in anhydrous methylene chloride (12 ml). Pyridine (600 μl) and 3-(chloromethyl)benzoyl chloride (compound B) (600 μl) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for one hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-chloromethyl-benzoylamino)-5-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (1.5 g, yield 93%).
Reaction SMILES: [C:1](O)(C)(C)C.CC(C)([O-])C.[K+].[CH3:12][C:13]1[CH:17]([OH:18])[CH2:16][C:15](=O)[C:14]=1[CH2:20][CH:21]=[CH2:22].P([O-])(O)(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][C:13]1[CH:17]([OH:18])[CH2:16][C:15](=[CH2:1])[C:14]=1[CH2:20][CH:21]=[CH2:22]
Reactant: CC(C)(C)O
Reactant: C=CCC1=C(C)C(O)CC1=O
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])(O)O
Solvent: CCOCC
Product: C=CCC1=C(C)C(O)CC1=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
Ether (125 ml), t-butanol (13.2 ml) and methyltriphenylphosphonium bromide (50 g) were mixed with stirring at room temperature, then potassium t-butoxide (25.7 g) was added portionwise to the mixture and then the resulting solution was stirred for 5 hours at the same temperature. To the solution was added a solution of (RS)-3-methyl-2-(2-propenyl)-4-hydroxy-cyclopent-2-ene-1-one (26.0 g) in ether (25 ml) under ice-water cooling and the resulting reaction mixture was stirred at the same temperature for 2 hours and then for 6 hours at room temperature. The reaction solution was poured into a saturated aqueous solution of sodium dihydrogenphosphate, and the product was extracted with ether. The obtained ether layer was washed with brine and dried over anhydrous magnesium sulfate. Then the filtered solution was evaporated. The obtained oily residue was then subjected to silica gel column chromatography to afford (RS)-2-methyl-4-methylidene3-(2-propenyl)cyclopent-2-ene-1-ol (10.0 g) in a yield of 40%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:3]1=[O:14]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Agent: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
A solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (180 mg, 0.9 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml), under argon at −35° C., was treated with sodium hydride (60% dispersion in oil) (36.0 mg, 0.900 mmol). The mixture was stirred at −35° C. for 15 minutes and then 2,2,2-trifluoroethyl trichloromethanesulfonate (507 mg, 1.800 mmol) was added and the reaction mixture was stirred at −35° C. for 2 hours (the temperature increased slowly to −15° C.). The reaction was quenched with water (5 ml) and allowed to warm to room temperature and the reaction mixture was extracted with ethyl acetate (2×20 ml). The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (10 ml), water (2×10 ml) and brine (20 ml) and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 42%). LC/MS [M+H]+=283. (ii) A solution of 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 0.379 mmol) in TFA/DCM (1:2, 3 ml) was stirred at room temperature for 4 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylic acid (assume ˜0.38 mmol) which was used in the next reaction. LC/MS [M+H]+=227.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6](O)=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1.P(Cl)(Cl)([Cl:23])=O>ClC(Cl)C>[Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6]([Cl:23])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1
Reactant: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1Cl

Procedure:
A mixture of 3.0 g of ethyl 2-chloro-9-hydroxythiazolo- [5,4-f]quinoline-8-carboxylate, 20 ml of phosphorus oxychloride and 300 ml of dichloroethane was refluxed for 8 hours.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:17][C:18]1[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: FC1(CNc2cccc(Br)n2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc(-c2cccc(NCC3(F)CCOCC3)n2)c(Cl)cn1
Temperature: 100 °C
Reaction time: 0.3 h

Procedure:
A mixture of 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (1 g, 3.46 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.092 g, 6.23 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.282 g, 0.346 mmol) in DME (13 mL) and 2M aqueous Na2CO3 (5.19 mL, 10.38 mmol) in a sealed tube was heated at 100° C. for 2 hr. The mixture was cooled to ambient temperature and was diluted with EtOAc (˜50 mL) and saturated aqueous NaHCO3. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=5/95 for 4 min, then EtOAc/heptane=5/95 to 50/50 over 18 min, then EtOAc/heptane=50/50] providing 5′-chloro-2′-fluoro-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine as a colorless oil. Yield: 1.00 g. LCMS (m/z): 340.1 [M+H]+; Retention time=0.67 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1])=[O:26]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)Nc1cc([N+](=O)[O-])ccc1F
Reaction time: 2 h

Procedure:
2-Fluoro-5-nitroaniline (500 mg, 3.2 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) were stirred in dry dichloromethane (10 ml) under nitrogen. 4-Chlorobutyryl chloride was added drop-wise over 1 minute and the reaction was stirred for a further 2 hrs. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The organics were collected, dried (magnesium sulphate), concentrated in vacuo and the residue purified by flash column chromatography (SiO2) eluting with dichloromethane to give 537 mg of 4-chloro-N-(2-fluoro-5-nitro-phenyl)-butyramide as a white solid. This material was re-dissolved in dry tetrahydrofuran and cooled over an ice-bath. Sodium hydride (83 mg, 2 mmol) was added and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 ml). The organics were washed with water (50 ml), dried (magnesium sulphate) and concentrated in vacuo to give 430 mg of crude 1-(2-fluoro-5-nitro-phenyl)-pyrrolidin-2-one as a yellow solid. This material was suspended in diethyl ether (20 ml) and ethanol (2 ml). A solution of tin (II) chloride dihydrate in concentrated HCl (20 ml) was added drop-wise over 5 minutes and the reaction stirred at room temperature for 3 hrs. The reaction mixture was neutralised to pH 7 by addition of 2M sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford crude 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (424 mg, 68%) as a yellow solid. HPLC retention time 3.3 min. Mass spectrum (ES+) m/z 195 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([N:13]([C:15]1([C:23]#N)[CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]1)[CH3:14])=[O:12].S(=O)(=O)(O)[OH:26].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:12])[N:13]([CH3:14])[C:15]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[C:23]=1[OH:26]
Reactant: O=S(=O)(O)O
Reactant: CON1CCC(C#N)(N(C)C(=O)Cc2cc(C)c(C)cc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON1CCC2(CC1)C(O)=C(c1cc(C)c(C)cc1Cl)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a solution of 2-(2-chloro-4,5-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-acetamide (compound P4.27) (1.15 g, 3.29 mmol) in methanol (˜3 ml) at 10° C. was added concentrated sulfuric acid (0.876 ml, 16.43 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. After further treatment with concentrated sulfuric acid (0.876 ml, 16.43 mmol) and stirring at 80° C. overnight, additional concentrated sulfuric acid (0.876 ml, 16.43 mmol) was added and stirring continued at 90° C. over another night. The mixture was poured on ice, neutralised carefully with 30% aqueous sodium hydroxide to pH 5-6, the resulting precipitate filtered and dried to afford a first crop of product as a beige solid (225 mg). The mother liquor was concentrated, and the residue purified by chromatography on silica gel (ethyl acetate) to further deliver 462 mg of product as a yellowish solid. Yield: 687 mg of 3-(2-chloro-4,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.26) as a solid, mp 191-192° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O>C1COCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12]2=[O:16])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCN(C(=O)CCC1CCNC1=O)c1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)CCC1CCN(CC(F)(F)F)C1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Yield: 24.8 %

Procedure:
N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(2-oxopyrrolidin-3-yl)propanamide (0.037 g, 0.10 mmol) was added to a vial with stir bar, followed sodium hydride (60% in mineral oil, 0.010 g, 0.26 mmol). The vial was placed under N2 and chilled to 0° C. THF (1 mL) was then added and the reaction was allowed to stir for 30 minutes 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.037 mL, 0.26 mmol) was added neat, dropwise. The reaction stirred overnight. The reaction was adsorbed onto CELITE®. Purification by flash column chromatography using MeOH/CH2Cl2 as eluent provided the title compound as a colorless oil (0.011 g, 24%).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>C(#N)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:19]([N:17]2[CH2:18][C@H:14]([O:13][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:15][C@H:16]2[C:32]([OH:34])=[O:33])=[O:20])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
608 μl of chlorotrimethylsilane and 670 μl of triethylamine, whilst ice-cooling, were added to a solution of 620 mg of trans-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 20 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium chloride. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 648 mg of trans-1-(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline as a powder. The whole of this was dissolved in 14 ml of dry acetonitrile, and then 330 mg of N,N'-carbonyldiimidazole were added. The mixture thus obtained was stirred at room temperature for 1 hour. At the end of this time, a solution of 630 mg of 1-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]piperazine in 2 ml of dry acetonitrile was added to the reaction mixture, and the resulting mixture was stirred overnight an room temperature and then at 40° C. for a further 1 hour. The reaction mixture was then mixed with 14 ml of 1N aqueous hydrochloric acid and stirred at room temperature for 1 hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was made slightly alkaline by the addition of an aqueous solution of sodium hydrogencarbonate; it was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 589 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(i) above.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][CH2:6][OH:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[O:7]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
A 20-L reactor equipped with a mechanical stirrer was charged with (S)-tert-butyl 1,5-dihydroxypentan-2-ylcarbamate (950 g, 4.33 mol), Ph3P (2272 g, 8.66 mol) and DCM (10 L). Then DIAD (1751 g, 8.66 mol) was added dropwise to the reaction solution. The solution was stirred for 48 h at room temperature until the reaction was complete. After filtration and concentration in vacuo, the residue was purified by column chromatography with petroleum ether as eluent to give 550 g of (S)-tert-butyl tetrahydro-2H-pyran-3-ylcarbamate as white solid. 1H NMR (400 MHz, CDCl3) δ 4.77 (m, 1H), 3.78 (d, J=11.1 Hz, 1H), 3.63 (d, J=8.8 Hz, 3H), 3.38 (m, 1H), 1.88 (td, J=8.4, 3.8 Hz, 1H), 1.74 (ddd, J=10.4, 9.1, 4.9 Hz, 1H), 1.65-1.51 (m, 2H), 1.45 (s, 9H).