Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:1][C:2]1([CH3:7])[CH2:3][C:4](=[O:5])[C:14]2[C:13](=[CH:12][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:16][CH:15]=2)[O:17]1
Reactant: CC(C)=CC(=O)O
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CC(=O)c2ccc(OC(F)(F)F)cc2O1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
Eaton's reagent (225 mL) was heated to 70° C. and 3-methylbut-2-enoic acid (28.1 g, 281 mmol) and 3-(trifluoromethoxy)phenol (25.0 g, 140 mmol) were added. After 30 min, additional 3-methylbut-2-enoic acid (1 equiv, 14 g) was added and heating was continued. After 30 min, additional Eaton's reagent (150 mL) was added and heating was continued for 35 min. The dark solution was cooled and poured into ice. The aqueous suspension was extracted with Et2O (300 mL), and the organic portion was washed with water (75 mL) and brine (50 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (11.7 g, 45.0 mmol, 32%) as a white solid. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: [N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[SH:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)CCl>CN(C)C=O>[N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([S:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:17])=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:4]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NSC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of Ac-Pro-Leu-Gly-OH (0.7 g, 2.1 mmol), HS-Leu-Leu-Gly-OC2H5 (0.6 g, 1.7 mmol) and HBT (0.26 g, 1.7 mmol) in 15 ml dimethylformamide was added EDC (0.4 g, 2.1 mmol). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between salt water and ethyl acetate. The ethyl acetate layer was washed consecutively with dilute sodium bicarbonate in salt (NaCl) water, dilute hydrochloric acid in salt water, salt water, 1.0 mM cupric sulfate in salt water (to remove any mercapto products) and finally salt water. The ethyl acetate was dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate concentrated in vacuo, yielding 0.8 g (73%) glassy residue of crude thiopeptolide product. A 100 mg sample of this crude product was purified by low pressure C18 column chromatography. The purified thiopeptolide, had an acceptable amino acid analysis, a consistent mass spectrum and a single peak on HPLC analysis. Anal. Calcd. for
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]1=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:23]1([CH:29]([O:36][C:37](=[O:40])[CH2:38]Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([O:21][CH2:38][C:37]([O:36][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:40])[C:17]1=[O:22])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0 61 g, 6.0 mmol was dropped into a solution of (3S-trans)-3-(t-butyloxy-carbonylamino)-1-hydroxy-4-methyl-2-azetidinone (1.08 g. 5.0 mmol) and diphenylmethylchloroacetate (1.43 g. 5.5 mmol) in 10 ml of dry dimethylformamide. The mixture was stirred overnight at room temperature. The precipitate was removed by filtration and the solvent was stripped in vacuo. The residue was taken up in ethyl acetate, filtered, washed with 5% NaHCO3 solution and with water, dried over MgSO4 and evaporated in vacuo to give a colorless oil; yield 2.0 g. By storing in a refrigerator the title compound crystallized, melting point 73°-74° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1.N12CCCN=C1CCCCC2.[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 2 (1.6 g, 5.5 mmol) and N,N-dimethyl formamide (10 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6 mmol) was added followed by 2,4-difluorobenzyl bromide (0.77 mL, 6 mmol). The reaction mixture was stirred at 60 C for 4 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title compound as an orange foam (2.13 g, 93%), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J=2.64 and 11.6 Hz, 1H), 7.82 (td, J=2.7 and 6.8 Hz, 1H), 7.57 (m, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.02 (m, 2H), 6.16 (m, 1H), 6.03 (d, J=3.5 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 6H), 1.93 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.43 (1F), −116.04 (1F) ppm. ES-HRMS m/z 416.1310 (M+H calcd for C22H20F2NO5 requires 416.1304).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[N:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[S:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[N:22][CH:21]=[CH:20][C:19]=2[NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[S:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=2)[N:24]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a slurry of sodium hydride (95%, 0.045 g, 1.8 mmol) in 10 mL anhydrous THF at 0° C. under an atmosphere of N2 was added diethyl malonate (0.32 g, 2.0 mmol) dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product from Example 24a (0.141 g, 0.3 mmol), heated at 110° C. for two hours, cooled and partitioned between EtOAc and water. The ethyl acetate layer washed with saturated brine, dried over sodium sulfate, filtered and concentrated giving the title compound as a yellow glass, (0.14 g, 84% yield).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.N12CCN(CC1)CC2.Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36].O>CS(C)=O>[CH:29]1([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:36])=[C:19]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:5][CH2:6]4)[CH:28]=3)[C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25]2)[CH2:30][CH2:31]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CN(C2CC2)CCN1
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(C4CC4)CC3)c(F)cc2c1=O
Yield: 32.3 %

Procedure:
1.3 g of 1-cyclopropylpiperazine and 2.2 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 25 ml of dimethyl sulphoxide, and the mixture is heated at 140° for 5 hours. 40 ml of water are added to the suspension and the precipitate is filtered off with suction, washed with water and boiled up with 20 ml of methanol. 1.2 g of 1-cyclopropyl-7-(4-cyclopropyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 226°-229° (with decomposition) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH3:31])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 83.8 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H-Boc)+.
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10](Cl)(=[O:12])=[O:11]>C(OCC)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10]([O:3][CH2:2][C:1]#[N:4])(=[O:12])=[O:11]
Reactant: N#CCO
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCOCC
Product: N#CCOS(=O)(=O)c1cccs1
Reaction time: 3 h

Procedure:
Method of preparation: Glycolonitrile is reacted with 2-thiophenesulfonyl chloride using the procedure as described in the previous example, with 2 hours of reaction at 0° C., followed by three hours at room temperature. The reaction mixture separates into two layers; the bottom dark layer is isolated and dissolved in diethyl ether, the solution washed with weak caustic solution and cold water, and the solvent is stripped off under reduced pressure to give the product (in 79% conversion), a green oily liquid, nD24.5 1.535.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[OH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](O)[CH:10]=[CH:9][N:8]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([OH:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1c(Cl)ccnc1O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Phosphorous oxychloride (63.4 mL, 0.68 mol) was added dropwise to a stirred mixture of 2,4-dihydroxy-3-nitropyridine (28.92 g, 0.17 mol) and benzyl triethylammonium chloride (155 g, 0.68 mol) in acetonitrile (560 mL). The reaction mixture was warmed to 60° C. for 1 h then was heated to reflux for 1 h. The reaction was cooled and the volatiles were evaporated in vacuo. An ice/water slurry (500 mL) was added to the residual oil and the mixture was stirred for 3 h at 0° C. The solids were collected by filtration, washing with water and hexanes to give the title compound as a solid;
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:18][CH:17]=[CH2:16])[C:9]=1[OH:14]
Reactant: Cc1ccccc1Sc1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cccc(Sc2ccccc2C)c1O
Yield: 62.7 %

Procedure:
A mixture of 2-(o-tolylthio)phenol (32.7 g), allyl bromide (27.5 g) and dried potassium carbonate (42 g) in methyl isobutyl ketone (400 ml) was refluxed under heating for 4 hours. The reaction mixture was treated in the same manner as Example 21-(1) to give oily 2-(o-tolylthio)-6-allylphenol (24.3 g), bp. 150°-162° C./0.7-0.8 mmHg.
Reaction SMILES: C(OC(=O)[CH:5]([C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)C(OCC)=O)C>CS(C)=O.O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11](=[O:22])[CH3:5])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)C(C(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
2-[2-(4-Nitro-phenyl)-acetyl]-malonic acid diethyl ester (1.4 g) was taken up in a mixture of DMSO (8 ml) and water (4 ml) and heated at 150° C. with stirring for 10 hr. The product was extracted with ethyl acetate (50 ml). The organic layer was washed with water, aqueous sodium bicarbonate solution and brine. The organic layer was then dried over sodium sulphate, filtered and evaporated. Purification by column chromatography over silica gel using ethyl acetate and hexane (6:94) as eluent yielded 1-(4-nitro-phenyl)-propan-2-one (160 mg, 24%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccccc1COC(=O)Cl
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1ccccc1COC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(C#N)cc2)C1

Procedure:
2-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 2-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 25 mg (27.8%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.7 Hz, 2H), 7.26 (d, J=7.3 Hz, 1H), 7.19 (m, 1H), 7.14 (m, 2H), 6.98 (m, 2H), 5.05 (m, 2H), 3.7 (m, 1H), 3.55 (m, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.74 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.91 (m, 2H), 1.78 (m, 3H), 1.61 (m, 1H), 1.33 (m, 5H), 1.21 (m, 1H).
Reaction SMILES: O=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][NH3+:15].[Cl-].N1C=CC=CC=1>C(O)C>[CH3:13][O:14][N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CO[NH3+]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(=O)OCC
Yield: 93221.8 %

Procedure:
A solution of diethyl ketomalonate 1 (51.0 g, 0.293 mmol), o-methylhydroxylamine hydrochloride (24.46 g, 0.293 mmol) and pyridine (23.2 g, 0.293 mmol) in ethanol (250 ml) is heated to reflux for 3 hr. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dilute hydrogen chloride, aqueous sodium hydrogencarbonate solution, and water successively. After drying over sodium sulfate, the solvent is removed under reduced pressure. The resultant residue is distilled under reduced pressure at 80°-85° C./0.5 mmHg to obtain Compound 2 (55.5 g, 93.2%). NNMR (CDCl3)δ: 1.35 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 4.11 (3H, s), 4.36 (2H, q, J=7.1 Hz), 4.37 (2H, q, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[C:11]=1[C:12]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2c(Oc3ccc(F)cc3)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
4-Fluorophenol (12.05 mg, 0.1075 mmol), methyl 4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate (40 mg, 0.09774 mmol), and K2CO3 (40.52 mg, 0.29 mmol) were combined in DMF (0.5 mL) and heated at 90° C. for 10 min resulting in complete conversion to methyl 4-[[2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate. NaOH (97.73 μL of 3 M, 0.29 mmol) was added and the reaction heated at 90° C. for 2 hours, then at 50° C. for overnight. Additional NaOH was added [2×NaOH (97.73 μL of 3 M, 0.29 mmol), 6 eq] and the reaction heated at 90° C. for 5 hours. HPLC purification using a gradient of acetonitrile in water (10-99%) with 5 mM HCl as a modifier provided 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid (11) as a white solid. ESI-MS m/z calc. 487.06, found 488.3 (M+1)+; Retention time: 1.84 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 11.14 (s, 1H), 7.99 (s, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.48 (s, 1H), 7.36-7.22 (m, 4H) ppm.
Reaction SMILES: CN1CCCCC1C(O)=O.C1C=NC2[N:17](O)[N:18]=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C([O:55][C@@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80](=[O:83])[NH:81][CH3:82])[N:79]=1)[CH2:57][C@@H:58]([N:62]([CH2:71][CH2:72][O:73][CH3:74])[C:63](=[O:70])[C@@H:64]([NH2:69])[C@@H:65]([CH3:68])[CH2:66][CH3:67])[CH:59]([CH3:61])[CH3:60])(=O)C>ClCCl>[N:69]([C@@H:64]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C:63]([N:62]([C@@H:58]([CH:59]([CH3:61])[CH3:60])[CH2:57][C@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80]([NH:81][CH3:82])=[O:83])[N:79]=1)[OH:55])[CH2:71][CH2:72][O:73][CH3:74])=[O:70])=[N+:17]=[N-:18]
Reactant: On1nnc2cccnc21
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CCOC)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCCCC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N=[N+]=[N-])C(=O)N(CCOC)[C@H](C[C@@H](O)c1nc(C(=O)NC)cs1)C(C)C
Reaction time: 0.08 h
Yield: 127.6 %

Procedure:
To a suspension of N-methyl pipecolinic acid (0.15 mmole, 21 mg) in dichlbromethane (5 mL) were subsequently added, in the order, HOAt (0.11 mmole, 15 mg), HATU (0.11 mmole, 42 mg) and Et3N (0.21 mmole, 29 μL). After stirring for 5 minutes, a solution in dichloromethane (1 mL) of the compound obtained in example 15.3 (0.1 mmole, 46 mg) was added. The reaction mixture was stirred for 4 hours, At the end dichloromethane was removed under vacuum. The crude product was dissolved in ethyl acetate (10 mL) and washed, in the order, with a NaHCO3 saturated aqueous solution (1×10 mL) and with brine (1×10 mL). The organic phase were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by flash chromatography (eluent chloroform:methanol 97:3 volume/volume). 58 mg (99% yield) of pure 2-((1R,3R)-3-((2S,3S)-2-azido-N-(2-methoxyethyl)-3-methylpentanamido)-1-hydroxy-4-methylpentyl)-N-methylthiazole-4-carboxamide were isolated. Rf=0.37 (chloroform/methanol 97:3 volume/volume). 1HNMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.62 (m, 1H), 7.57 (m, 1H), 5.75 (dd, 1H), 4.61 (dd, 1H), 4.11 (m, 1H), 3.70-3.48 (m, 4H), 3.22 (s, 3H), 3, 20-3.08 (m, 1H), 2.92 (m, 3H), 2.88-2.78 (m, 1H), 2.40 (m, 1H), 2.2-2.09 (m, 6H), 2.09-1.81 (m, 5H), 1.69-1.48 (m, 5H), 1.39-1.30 (m, 1H), 1.26-1.09 (m, 1H), 1.08-0.86 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Li+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([CH2:13][CH:12]=[CH2:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(F)c(C#N)c1

Procedure:
A mixture of compound 5-bromo-2-fluorobenzonitrile (2.5 g, 12.5 mmol), allyl-tributyl-stannane (4.97 g, 12.5 mmol), LiCl (1.6 g, 37.5 mmol) and Pd(PPh3)4 (0.2 g) in anhydrous toluene was refluxed under N2 overnight. Distilled the solution under reduce pressure and the residue was purified with silica gel cloumn chromatography to give the product 2-fluoro-5-(prop-2-en-1-yl)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([OH:11])[C:5]=1[OH:12].Br[CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)C>[Cl:10][C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:13])[C:5]2[O:12][CH2:17][CH2:16][CH2:15][O:11][C:6]=2[CH:7]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1cc(Cl)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1OCCCO2
Yield: 94.8 %

Procedure:
A mixture of 5-chloro-2,3-dihydroxy-benzoic acid methyl ester (0.3 mol), 1,3-dibromopropane (0.42 mol) and K2CO3 (0.66 mol) in 2-propanone (500 ml) was stirred and refluxed for 20 hours, then filtered hot and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding 69 g of methyl 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylate (intermediate 5).