Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.O=[C:14]1[CH2:19][CH2:18][CH2:17][S:16][CH:15]1[C:20](OCC)=[O:21]>C(O)(=O)C.O>[N:7]1([C:4]2[N:3]=[C:2]3[NH:1][C:14]4[CH2:19][CH2:18][CH2:17][S:16][C:15]=4[C:20](=[O:21])[N:6]3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: Nc1nc(N2CCCCC2)n[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c([nH]c3nc(N4CCCCC4)nn13)CCCS2
Reaction time: 0.17 h
Yield: 80 %

Procedure:
16.7 g (0.1 mole) of 5-amino-3-piperidino-1H-1,2,4-triazole are dissolved in 10 ml of acetic acid and 18.8 g (0.1 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added, then the reaction mixture is boiled for 10 minutes. The thick crystal mass thus obtained is diluted with 100 ml of water, the precipitated product is filtered off, washed with i-propanol and recrystallized from dimethylformamide. Thus 23.3 g (82.2%) of 2-piperidino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained with a melting point above 350° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5].[OH-:11].[Na+].Cl.[Cl-].[Na+]>CCCCCC.C(OCC)(=O)C>[OH:11][CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5]
Reactant: CC1=C(CBr)C(=O)OC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=C(CO)C(=O)OC1=O
Reaction time: 12 h
Yield: 26 %

Procedure:
To 2-bromomethyl-3-methylmaleic anhydride (1.25 g, 6.10 mmol) was added 5 M aqueous sodium hydroxide solution (4 mL) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was adjusted to pH 1 with 5 M hydrochloric acid (5 mL), added with sodium chloride and extracted three times with ethyl acetate. The combined organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 227 mg of the title compound as oil (yield: 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[N:17]=[C:16]3[C:19]([F:25])=[C:20](F)[C:21]([F:23])=[CH:22][C:15]3=[CH:14][C:13]=2[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.O>CS(C)=O>[F:23][C:21]1[C:20]([N:42]2[CH2:41][CH2:40][N:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)[CH2:44][CH2:43]2)=[C:19]([F:25])[C:16]2=[N:17][C:18]3[N:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH:10]=[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:26])[C:13]=3[CH:14]=[C:15]2[CH:22]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A suspension of 1.5 g of ethyl 1-(2,4-difluorophenyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate and 1.8 g of 4-(4-fluorophenyl)piperazine in 20 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature around 100° C. for approximately 1 hour. After cooling to approximately 20° C., the reaction mixture was poured into 100 cm3 of water and extracted 3 times with 50 cm3 of trichloromethane. The combined organic extracts were washed 1 time with 50 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 1.7 g of ethyl 7,9-difluoro-1-(2,4-difluorophenyl)-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 298-299° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [N:1]([CH:4]([N:15]1[CH:18]([SH:19])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[N+:2]=[N-:3].Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1.[Ag]>[N:1]([CH:4]([N:15]1[CH:18]([S:19][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Ag]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reaction time: 22 h

Procedure:
To a cooled solution of silver salt at the mercapto group of benzyl 2-azido-2-(3-phenoxyacetamido-4-mercapto-2-oxo-1-azetidinyl)acetate (3.08 g.) in hexamethylphosphoramide (12 ml.) was added 2,2,2-trichloroethyl chloroformate (1.15 ml.) over a period of 3 minutes, and the resultant mixture was stirred at room temperature. After stirring for 22 hours, the mixture was diluted with benzene (15 ml.) and filtered through a pad of Celite. The filtrate was poured into cold water and extracted with ethyl acetate (100 ml.). The extract was washed with water, a dilute aqueous solution of sodium bicarbonate, water and then an aqueous solution of sodium chloride successevely. Drying and removal of the solvent left an oil (3.40 g.), which was chromatographed on silica gel (60 g.) with a mixed solvent of methylene chloride and ethyl acetate (20:1 by volume) as an eluent to give benzyl 2-azido-2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]acetate (2.20 g.). Further, the same product (160 mg.) was recovered from the other fractions.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc(O)ccc2n1
Reactant: BrCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(OCCCCCCCCBr)ccc2n1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 40 mg) was suspended in DMF (2 ml), and was cooled to 0° C. in ice water bath. 6-Hydroxy-2-methoxyquinoline (171 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. 1,8-Dibromooctane (0.37 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (225 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)Cl>[Br:15][CH2:9][C:8](=[O:10])[C:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:12]
Reactant: CC(=O)C(C)(C)Oc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)CBr
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
110.2 g (0.5 mol) of 3-(4-chlorophenoxy)-3-methyl-butan-2-one were dissolved in 500 ml of methylene chloride, and 83 g (0.52 mol) of bromine were added dropwise at room temperature in a manner such that continuous decoloration occurred. When the addition had ended, the mixture was subsequently stirred for 30 minutes, the organic phase was washed twice with 300 ml of water and twice with 300 ml of saturated sodium bicarbonate solution and was dried over sodium sulphate and distilled. 105.9 g (70% of theory) of 1-bromo-3-(4-chlorophenoxy)-3-methyl-butan-2-one of boiling point 115° to 118° C./0.1 mm Hg were obtained. ##STR811##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:16][C@@H:15]([C:17]([OH:19])=O)[C@H:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:13]1)(=[O:11])=[O:10].[NH2:29][C:30]1([C:33]#[N:34])[CH2:32][CH2:31]1>>[C:33]([C:30]1([NH:29][C:17]([C@@H:15]2[CH2:16][CH:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[CH2:32][CH2:31]1)#[N:34]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1
Product: N#CC1(NC(=O)[C@@H]2CC(S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in analogy to example 68 step 11 using (1R,2R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture, example 143 and 144 step 6) and 1-aminocyclopropanecarbonitrile. Light orange oil (51%). MS (EI): 493.4 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[N:25]([CH2:24][CH2:23][CH2:22][O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:26][CH2:27][OH:28])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCNCCCOCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)CCCOCc1ccccc1
Yield: 66.6 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-alanine (90 mg, 0.48 mmol), 2-(3-benzyloxy-propylamino)-ethanol (100 mg, 0.48 mg), N,N-diisopropylethylamine (185 mg, 1.43 mmol), 1-hydroxybenzotriazole (71 mg, 0.52 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (101 mg, 0.52 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 18 h, then partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (121 mg, 67%). Colorless oil, MS (ISP)=381.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]1[O:8][CH2:7]1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:24]([N:23]([CH2:7][C@H:6]([OH:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]=1[NH2:1])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Solvent: CO
Product: Nc1c(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.9 %

Procedure:
(S)-3-(2-Amino-3-nitrophenoxy)-1,2-epoxypropane (8.0 g, 38.1 mmol) was dissolved in 250 mL of methanol and treated with dibenzylamine (8.05 mL, 42.0 mmol, d=1.026). The mixture was stirred at reflux for 10 hours and then cooled to 0° C. The resulting orange precipitate was filtered and washed with cold methanol, then dried to yield 12.1 g (78%) of a pale orange solid that was pure by NMR and TLC analysis. The material was used without further purification. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:5]([C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(OC)(O[CH3:27])(=O)=O.C(=O)(O)[O-].[Na+].O>CC(C)=O>[CH3:27][O:7][C:6](=[O:8])[C:5]1[C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: COc1ccc(C(F)(F)F)c(C(=O)O)c1NC(=O)C(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(C(F)(F)F)ccc(OC)c1NC(=O)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 3-methoxy-2-pivalamido-6-(trifluoromethyl)benzoic acid (1 eq), dimethyl sulfate (1 eq) and sodium bicarbonate (1.3 eq) in acetone was refluxed for 4 h. The reaction mixture was poured to water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide product as yellow solid in 95% yield. ES/MS m/z 334.1 (MH+). Proceeds for next step without any purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:27]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.02 h

Procedure:
4-(Hydroxymethyl)-1-(triphenylmethyl)imidazole, as described in Example 1, Step A, (1.97 g, 5.72 mmol) and 4-(dimethylamino) pyridine (280 mg, 2.29 mmol) were stirred in CH2Cl2 (15 mL) and tert-butyldimethylsilyl chloride (905 mg, 6.01 mmol) was added. After 1 min, triethylamine (0.88 mL, 6.31 mmol) was added dropwise over 3 min. The reaction mixture was stirred for 45 min, then CH2Cl2 (150 mL) was added and the solution was washed with 0.1 N HCl (50 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—30% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:46]3[CH:51]=[C:50](Br)[CH:49]=[CH:48][C:47]=3[F:53])([CH2:35][O:36][C@@H:37]([C:42]([F:45])([F:44])[F:43])[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.C(OCC)(=O)C.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:53][C:47]1[CH:48]=[CH:49][C:50]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:51][C:46]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([C:42]([F:45])([F:43])[F:44])[O:36][CH2:35]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](C(F)(F)F)C[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](C(F)(F)F)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 7 h
Yield: 14.5 %

Procedure:
2-Fluoropyridine-3-boronic acid (63.9 mg), tetrakis(triphenylphosphine)palladium (26.2 mg) and a 1 N sodium carbonate solution (453 μl) were added to a solution of (±)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,6R*,8aS*)-8a-(5-bromo-2-fluorophenyl)-6-trifluoromethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (138 mg) in DMF (9.9 ml), and the mixture was stirred in a nitrogen atmosphere at 85° C. for seven hours. The reaction solution was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane (4.0 ml) and TFA (1.0 ml) were added to the residue, and the mixture was stirred at room temperature for four hours. When the reaction was completed, the reaction solution was diluted with dichloromethane and ice was added, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography. The resulting white solid was washed with diethyl ether to obtain the title compound (14.0 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:14]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C(F)(F)F)cc1
Reaction time: 12 h
Yield: 51.3 %

Procedure:
4-(Trifluoromethyl)phenol (1.50 g, 9.25 mmol), allyl bromide (14.55 g, 12.03 mmol), Cs2CO3 (3.62 g, 11.10 mmol), and water (15 drops) were combined in DMF (40 mL) and the mixture stirred for 12 h. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 0.96 g (51%) of the title compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.32 (d, 1H), 5.43 (d, 1H), 6.05 (m, 1H), 6.97 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.I[CH2:15][CH3:16]>O1CCCC1.[Cl-].[Na+].O>[CH2:15]([N:6]1[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([I:3])=[N:5]1)[CH3:16]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC)nc1I
Temperature: -45 °C
Reaction time: 4 h

Procedure:
A 500 mL flask was charged with the sodium hydride (0.584 g, 14.61 mmol) and tetrahydrofuran (100 mL). To the resulting suspension was added a solution of EXAMPLE 59A (3.11 g, 11.69 mmol) in tetrahydrofuran (50 mL) dropwise over about 20 minutes and the reaction was stirred for 4 hours under nitrogen. The reaction mixture was cooled to −45° C. and a solution of iodoethane (3.77 mL, 46.8 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. The reaction mixture was allowed to come to ambient temperature and stirring was continued for 42 hours. The reaction was diluted with brine (400 mL) and extracted with ether (400 ml, 2×200 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on the ISCO chromatography system on a silica gel cartridge (150 g) eluting with a 0, 10, 25, and 50% ethyl acetate/hexane step gradient to give the title compound. MS DCI+) m/e 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.O.C([O-])(O)=O.[Na+]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([F:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(F)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
92.7 g (0.43 mol) of 3-Benzyloxy-4-fluoro-phenylamine, 57 ml (0.45 mol) of ethyl acetoacetate and 0.81 g (4 mmol) of p-toluenesulfonic acid monohydrate in 370 ml of cyclohexane were heated at reflux for 3 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, ACOEt (1 l) and saturated aqueous NaHCO3 solution (0.5 l) were added, the layers were separated and the organic layer once extracted with AcOEt (0.3 l). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 140 g (100%) of the desired 3-(3-benzyloxy-4-fluoro-phenylamino)-but-2-enoic acid ethyl ester as yellow-orange crystalline solid. Melting point: 79° C.-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) and pyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionyl chloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at room temperature for 1 hour, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:18]1[N:19]=[C:20]2[C:25](=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)[CH:24]=[CH:23][CH:22]=[CH:21]2.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:18]2[N:19]=[C:20]3[C:25](=[C:26]4[C:31]=2[CH:30]=[CH:29][CH:28]=[CH:27]4)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1nc2ccccc2c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3c3ccccc23)C[C@H]1C(=O)O

Procedure:
(2S,4R)—N-Boc-4-hydroxyproline can be reacted with 6-chlorophenanthridine in NMP, in the presence of sodium t-butoxide, to produce (2S,4R)-1-(tert-butoxycarbonyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxylic acid. Methyl tertiary butyl ether (MTBE) and water can then be added. The aqueous layer is separated, washed, and then HCl is added, followed by extraction with MTBE. The extracted product can be mixed with diisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and then reacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylate tosylate salt in dimethylformide (DMF) and toluene. The reaction produces (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-1-carboxylate, which can be extracted with MTBE and washed with HCl, further extracted, washed, dried, and dissolved in 2-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].O>N1C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg) in pyridine (15 ml) was added ethyl isocyanate (680 mg) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]-N′-ethylurea (986 mg, 86%).