Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH:13]=O.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([C:16]1[S:15][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[C:3]=2[CH:13]=1)=[O:18])[CH3:21]
Reactant: O=CC1=C(Cl)CCOc2ccccc21
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)CCOc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2,3-dihydro-benzo[b]oxepine-5-carbaldehyde (605 mg, 5.8 mmol) in dimethyl formamide (8 ml) at 0° C., was added ethyl 2-mercaptoacetate (640 μl, 5.8 mmol) and potassium carbonate (800 mg, 5.8 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then at 70° C. for 2 hours. The reaction mixture was cooled and diluted with water and ethyl acetate, and the organic phase was washed with brine, dried (MgSO4), and concentrated in-vacuo. Purification on silica gave 4,5-dihydro-6-oxa-3-thia-benzo[e]azulene-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([O:21]CC)=[O:20])[C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=[O:20])[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.15 g (6.45 mmol) of ethyl (3R)—N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalinate (diastereomer mixture) were dissolved in a mixture of in each case 8 ml of THF, methanol and water, and 3.87 g (96.8 mmol) of sodium hydroxide were added at 0° C. Ice-cooling was removed and the reaction mixture was stirred at RT for 1 h. The mixture was then added to water, acidified with semiconcentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 1.95 g of the target product which was not purified any further (99% of theory, diastereomer ratio about 2.8:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][C@@H:16]1[C@@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C@H:19]([OH:32])[CH2:18][C@@H:17]1[OH:33].[I:35]I>C(Cl)Cl.C(OCC)C>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH:13]([I:35])[CH:14]1[O:33][C@H:17]2[CH2:18][C@@H:19]([OH:32])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C@H:16]2[CH2:15]1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]1O
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCC(I)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]2O1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
Under an atmosphere of nitrogen, 194 mg of anhydrous potassium carbonate was added to a solution of 140 mg of (5Z,13E)-(9α,11α,15S,16RS)-9,11,15-trihydroxy-16-methyl-20-chloroprosta-5,13-dienoic acid methyl ester [prepared as described in Example 8 of British Patent Application No. 22090/75 and e.g. the equivalent Belgian Specification No. 842,113] in 5 ml of methylene chloride. To the reaction mixture was added 200 mg of iodine in portions during 2 hours with stirring at 0° C. The reaction mixture was diluted with diethyl ether, washed with an aqueous solution of sodium thiosulphate, water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 135 mg of the title compound having the following physical characteristics:
Reaction SMILES: [C@@H:1]1([C:8](Cl)=[O:9])[CH2:4][CH2:3][C@H:2]1[C:5](Cl)=[O:6].[BH4-].[Na+].O.[Cl-].[Na+].O1CCC[CH2:17]1>C(O)C.C(OCC)C>[OH:9][CH2:8][C@@H:1]1[CH2:4][CH2:3][CH2:17][C@H:2]1[CH2:5][OH:6]
Reactant: C1CCOC1
Reactant: O=C(Cl)[C@@H]1CC[C@H]1C(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: OC[C@@H]1CCC[C@H]1CO
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of trans-1,2-cyclobutanedicarboxylic acid dichloride in 40 ml of tetrahydrofuran is carefully instilled at -15° C. in a solution of 8.4 g of sodium borohydride in 280 ml of ethyl alcohol. After completion of the gas generation it is stirred for 30 minutes at -15° C. and then 150 ml of water is slowly instilled. It is stirred for 30 minutes at 22° C. and then diluted with 1.5 liter of diethyl ether. It is shaken twice with water, twice with semiconcentrated sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate, 9.5 g of trans-1,2-dihydroxymethylcyclopentane is obtained as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].CN([Si:30]([CH3:33])([CH3:32])[CH3:31])C(=O)C.[Br:34]N1C(=O)CCC1=O>ClCCl>[Br:34][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N(C)[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 44 %

Procedure:
366 mg (1.05 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were silylated in one hour at room temperature by stirring in 25 ml of dichloromethane with 208 mg (1.43 mmoles) of N-methyl-N-trimethylsilylacetamide. The clear solution obtained was cooled in an ice-bath and bromination was carried out in half an hour using 282 mg (1.58 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 44% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:9]([OH:12])[C:10]#[CH:11]>N1(C2CCCCCCC2)CCCCCCN1>[CH2:1]([NH:6][C:7](=[O:8])[O:12][CH2:9][C:10]#[CH:11])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN=C=O
Reactant: C#CCO
Agent: C1CCCC(N2CCCCCCN2)CCC1
Product: C#CCOC(=O)NCC(C)(C)C
Yield: 94.5 %

Procedure:
4520 g (40 moles) of neopentylisocyanate and 1 g of diazabicyclooctane (Dabco) are heated to 80° C. (10 l flask) and 2240 g (40 moles) of propargyl alcohol are then added in the course of 1.5 hours. When the addition of the alcohol has ended, IR spectra are used to monitor whether the reaction is complete. When the NCO band has disappeared, the mixture is distilled under a high vacuum. 6395 g (95% of theory) of 2-propinyl N-neopentylcarbamate of boiling point: 85° C./40 mbar are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:36])[C:23]([OH:35])([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=2)[C:24]([F:27])([F:26])[F:25])=[C:18]([Cl:37])[CH:17]=1)(C)(C)C>ClCCl.O>[Cl:37][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH:22]([CH3:36])[C:23]([OH:35])([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[C:24]([F:26])([F:27])[F:25])[O:15][CH2:14][C:13]([OH:38])=[O:12]
Reactant: Cc1cc(C(O)(C(C)c2ccc(OCC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(OCC(=O)O)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
Under an atmosphere of nitrogen, trifluoroacetic acid (1.5 ml) was added to a solution of {3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenoxy}-acetic acid tert-butyl ester (Example 78, 98 mg) in dichloromethane (1.5 ml). The reaction mixture was stirred for 1 h at r.t., and then diluted with water, and extracted (ethyl acetate). The combined organic layers were dried (Na2SO4), filtered, and evaporated. Flash chromatography provided the title compound (27 mg, 31%). MS (m/e)=404.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
200 mg (0.68 mmol) of tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate and 159 mg (1.01 mmol) of 4-methoxybenzyl chloride were dissolved in 3 ml of dimethylformamide. 40 mg (1.01 mmol) of a 60% sodium hydride suspension were added and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:3 mixture of ethyl acetate and hexane as the eluent. There were obtained 250 mg (90% of theory) of tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-(4-methoxy-benzyloxy)-piperidine-1-carboxylate as a light yellow oil; MS: 358 (M-C4H9)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([NH:7][CH3:8])[CH3:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([N:7]([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH3:8])[CH3:6]
Reactant: CNC(C)CC(=O)OC
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(C)C(C)CC(=O)OC
Yield: 57.9 %

Procedure:
3-Methylamino-butyric acid methyl ester (7.6 g, 58 mmol, 1.0 equiv) was added neat to methyl acrylate (7.5 g, 87 mmol, 1.5 equiv). The resulting solution was refluxed for 16 h. The reaction was cooled and diluted with hexanes (200 mL) and an insoluble polymer separated out. The hexane solution was decanted and the polymer washed 2×100 mL hexanes with vigorous stirring. The combined hexane solutions were then concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using pure CH2Cl2 as an eluent. The pure product was isolated as a clear colorless oil (7.3 g, 58%); MS, m/z 218=M+1.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:25][CH3:26])CC)C.[CH3:27][OH:28]>ClCCl.C(Cl)(Cl)Cl>[CH3:6][C:5]1[CH:4]=[CH:3][C:2]([C:26]2[CH:25]=[CH:9][CH:10]=[CH:11][C:12]=2[C:27]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([C:6]([N:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)=[O:28])=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-methylphenyl)benzoic acid (140 mg) in dichloromethane (5 ml) were added oxalyl chloride (133 mg) and a few drop of N,N-dimethylformamide and the solution was stirred at ambient temperature for 2 hours. Dichloromethane was evaporated in vacuo to give an acid chloride as an oil and the oil was added to a mixture of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (166 mg) and triethylamine (0.14 ml) in dichloromethane (20 ml). The mixture was stirred at ambient temperature for 2 hours, washed successively with diluted hydrogen chloride, water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was subjected to silica gel column (30 g, 1% methanol in chloroform) to give 1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (202 mg) as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I.CCCCCCC>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:19][CH2:18][Cl:17])[C:9]#[N:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: ClCCCI
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: N#CC(CCCCl)c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-bromo-2-trifluoromethylphenyl)acetonitrile (2.28 g) in tetrahydrofuran (6 mL) was added to a suspension of sodium hydride (containing 60% in mineral oil, 362 mg) in tetrahydrofuran (12 mL) under ice-cooling. The mixture was stirred at the same temperature for 20 minutes. 1-Chloro-3-iodopropane (0.94 mL) was added dropwise to the reaction solution, and then the reaction solution was stirred at room temperature for 40 minutes. Ice water and heptane were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=49:1→19:1) to obtain 2.67 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[C:11]([O:15][CH2:16][CH:17](CC)[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[Na+].[Na+].[C:30](C1C(C(C)(C)C)=C(O)C=CC=1)(C)(C)[CH3:31]>[Pd].CC(N(C)C)=O>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[CH:13]=[CH:12][C:11]([O:15][CH:16]([CH2:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: CC(C)(C)c1cccc(O)c1C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCCC(CC)OC(=O)C=Cc1cc(F)c(F)cc1F

Procedure:
3.0 g (14.2 mmol) of 1-bromo-2,4,5-trifluorobenzene are refluxed under protecting gas with 30.0 mmol of 2-ethylhexyl acrylate, 140 mg of palladium on activated charcoal (5% strength), 0.82 g of sodium carbonate and 10 mg of di-tert-butylphenol in 10 ml of dimethylacetamide for 18 hours at 170° C. The catalyst is filtered off, the mixture is diluted with dichloromethane and extracted with water. The crude product is chromatographed.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[C:40](=[N:41][O:42][CH3:43])[CH2:39][CH2:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:44][O:45]C(=O)C)[CH2:7][O:8]2)(=O)C.C1COCC1.O.O[Li].O>CO>[CH3:43][O:42][N:41]=[C:40]1[CH2:39][CH2:38][CH:37]=[C:36]1[O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@@:9]34[O:20][C@@:6]([CH2:44][OH:45])([CH2:7][O:8]3)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]4[OH:16])[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:30][CH:31]=1
Reactant: CON=C1CCC=C1Oc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CON=C1CCC=C1Oc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of compound (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-((5-(methoxyimino)cyclopent-1-en-1-yl)oxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (110 mg, 0.16 mmol) in MeOH:THF:H2O (0.48 mL, 0.36 mL, 0.12 mL), LiOH.H2O (10.3 mg, 0.24 mmol) was added at 0° C. The reaction mixture was stirred for 1 h at r.t. After completion of the reaction as confirmed by TLC, the solvent was evaporated in vacuo. The crude compound obtained was purified by column chromatography (silica gel, 0.4:9.6 MeOH:DCM) to provide title compound (75 mg, 90.5%) as off-white solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nn1cccc1C(=O)c1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 143.4 %

Procedure:
1-Amino-2-(2-chlorobenzoyl)pyrrole (24.3 g, 0.12 mol) and t-butoxycarbonyl glycine (22.7 g, 0.13 mol) were dissolved in 300 ml of dichloromethane. Dicyclohexylcarbodiimide (26.8 g, 0.13 mol) was added over 3 minutes and the reaction mixture stirred at ambient temperature for 4 hours. The resultant slurry was filtered, and the the filtrate evaporated to give 65 g of oil. This oil was purified by flash chromatography (silica, 2:1 hexane-ethyl acetate) to give 21.9 g (48%) of cystals, m.p. 156°-158°.
Reaction SMILES: C(OC([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][O:14][C:13]=2[C:12]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][N:32]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:33](=[O:52])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH2:50][CH3:51])[CH:49]=3)[CH:40]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60]>C(Cl)Cl>[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60].[CH:53]1([N:32]([CH2:31][CH2:30][NH:22][CH2:21][CH2:20][C:12]2[C:13]3[O:14][CH2:15][C:16](=[O:19])[NH:17][C:18]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[C:33](=[O:52])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH2:50][CH3:51])[CH:49]=3)[CH:40]=2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl(2-(N-cyclohexyl-3-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanamido)ethyl)carbamate [Example 4, Step vi)] (245 mg), DCM (5 mL) and TFA (2.5 mL) was stirred at 25° C. for 30 min. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (62.3 mg). MS [M+H]+=605.3 (calc=605.3451) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.70 (s, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 4.46 (q, J=7.3 Hz, 2H), 3.76-3.62 (m, 5H), 3.48 (t, J=5.7 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.92-2.83 (m, 4H), 2.62 (t, J=6.0 Hz, 2H), 1.80-1.56 (m, 4H), 1.55 (t, J=7.3 Hz, 3H), 1.44-1.24 (m, 5H), 1.17-1.02 (m, 1H).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Cl:25][C:26]1[C:27]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31](O)=[O:32].COC[CH2:54][S:55]([NH2:58])(=[O:57])=[O:56].CS(N)(=O)=O>>[Cl:25][C:26]1[C:27]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:32]
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 150 step 5 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide, the title compound was obtained as a colorless solid (0.035 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.20 (d, J=12.28 Hz, 1H), 4.00 (s, 2H), 3.22 (s, 3H), 2.26-2.15 (m, 3H), 2.07-1.97 (m, 3H), 1.82-1.74 (m, 6H); MS (ES−) m/z 468.21, 470.20 (M−1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4]([CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH3:6])[CH3:5].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(#N)C>[N:13]1([CH2:2][C:3](=[O:12])[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)([CH3:6])[CH3:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Solvent: CC#N
Product: CC(C)(C(=O)Cn1ccnc1)C1OCCO1
Yield: 58.1 %

Procedure:
106.8 g (0.55 mol) of 1-chloro-3-(dioxolan-2-yl)-3-methyl-butan-2-one and 74.8 g (1.1 mols) of imidazole in 500 ml of acetonitrile are stirred for 15 hours at 65° C. The solvent is distilled off, the residue is taken up in 800 ml of methylene chloride and the solution is extracted with twice 1 liter of water. The methylene chloride phase is dried over sodium sulphate, and the solvent is distilled off. 71.7 g (57.7% of theory) of 1-(imidazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are obtained (purity according to gas chromatography 95.4%).
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CC1C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N1CC1C
Yield: 88.7 %

Procedure:
A mixture of 2.5 g (0.0059 mol) of product of Example 81, 0.6 g (0.0059 mol) of triethylamine and 0.25 g of 5% Pd/C (50% water coated) in 100 ml of ethanol was hydrogenated (446 kPa for 18 hours at 50° C. The mixture was then filtered through celite and concentrated in vacuo to remove the ethyl alcohol. The residue was poured into water, and extracted with diethyl ether. The ether extract was washed with water, then dried over MgSO4. The dry ether phase was then concentrated in vacuo to yield 2.00 g of a yellow solid. This solid was then recrystallized in hexane to yield 1.28 g (56%) of product as a tan solid; mp 61° C.