Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1>O1CCCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(Br)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (253 mg, 6.15 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-bromobenzene (845 mg, 3.38 mmol; Aldrich) was added dropwise. After 30 minutes the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 279 (M+H−NH3)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[Li]CCCC.[C:22](=[O:24])=[O:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([C:22]([OH:24])=[O:23])[S:8][C:6]=2[N:7]=1
Reactant: O=C=O
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-morpholinothieno[2,3-d]pyrimidine (500 mg) was cooled to −78° C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi in hexanes. The reaction was stirred at −78° C. for 30 minutes before warming to −40° C. for several minutes to allow for complete formation of the lithium anion. The reaction was then re-cooled to −78° C. and carbon dioxide gas evolved from dry ice was bubbled in via cannula to the reaction solution for 1 hour. The reaction was then slowly warmed to 0° C. over 30 minutes and the THF was concentrated by rotovap. The reaction was then quenched with water and extracted with Ethyl Acetate to remove any 2-chloro-4-morpholinothieno[2,3-d]pyrimidine. The aqueous layer was then brought to pH of 2-3 by adding concentrated HCl. The resultant solid that crashed out of the aqueous layer was then collected by Buchner funnel, rinsed with water and dried overnight under vacuum to yield 494 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:29][CH3:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)c(F)c1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)c(F)c3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
1-(5-Amino-2,3,4-trifluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and a 40% methylamine solution (88 mg) were added to pyridine (1 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue. Solids were collected by filtration and washed with diethyl ether to obtain the title compound (55 mg) as a yellow powder.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([CH:27]([C:3]2[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7](=[O:8])[CH:2]=2)[CH3:28])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1COCCN1
Product: CCCc1nc(C(C)N2CCOCC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and morpholine (8 mL) was stirred at 90° C. for 12 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.43 g, 83%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:37]#[N:38])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:11]([F:39])[CH:10]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:39])([C:37]#[N:38])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: COc1ccc(Cl)cc1C1C(C(=O)O)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1C1C(C(=O)NCC[C@H](O)CO)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 21.2 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 85c (0.32 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.23 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (65 mg, 21%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[N:18]([O:19][CH3:20])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Yield: 77.6 %

Procedure:
To (RS)-1-(tert-butyloxycarbonyl)-2-piperidine carboxylic acid (2.64 g, 11.5 mmol) in dichloromethane (10 ml) was added sequentially N,O-dimethyl hydroxylamine (1.34 g, 13.7 mmol), triethylamine (6 ml, 43.0 mmol) and Py.Bop (6.60 g, 12.7 mmol). The resultant mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (170 ml) and poured into 1M HCl (22 ml). The organic phase was separated and washed with saturated aqueous sodium hydrogen carbonate (3×25 ml) and brine (25 ml) then evaporated in vacuo. The resultant colourless oil was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to give the title compound (2.43 g, 77%) as a colourless oil.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 57.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16]CC)=[O:15])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:19][CH3:20])[C:14]([OH:16])=[O:15])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:29])[CH3:30])[C@H:23]1[CH3:31]
Reactant: CCOC(=O)C(CC)NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(=O)O

Procedure:
Ethyl 2-({[5-chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyrate (64 mg, 0.145 mmol) in 1,4-dioxane (2 mL) was stirred with 1 M aqueous sodium hydroxide (435 μL, 0.435 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26]C(CCCC)CCC)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1[CH2:40][CH2:39][CH2:38][CH2:37]1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:37][CH2:38][CH2:39][CH2:40][CH2:6][CH2:7][CH2:9][CH3:10])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCC(CCC)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: C1CCOC1
Agent: Cl
Solvent: CO
Product: CCCCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-4-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.0 g.), conc. hydrochloric acid (6.23 g.), tetrahydrofuran (15 ml.) and methanol (120 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.95 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
The ethyl 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoate (12.5 g, 40.4 mmol) was dissolved in tetrahydrofuran-water mixture (120 mL, 2:1), lithium hydroxide (2.8 g, 121.1 mmol) was added and refluxing carried out for 12 h. After evaporation of the organic solvent under reduced pressure, the reaction mixture was extracted with diethyl ether (2×100 mL). The aqueous layer was acidified using 1 N HCl solution to pH=2 and extracted with dichloromethane (3×250 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford 2-(3-fluoro-4-(methylsulfonamido-methyl)phenyl)propanoic acid (9.56 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[N+:37]([C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([O-:39])=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:24])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([C:19]([O:21][C:43]3[CH:44]=[CH:45][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=3)=[O:20])=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.5 %

Procedure:
2-[(t-Butyloxycarbonyl)(methyl)amino]-8-methoxyquinoline-5-carboxylic acid (0.311 g), ethyldimethylaminopropylcarbodiimide hydrochloride (0.269 g), 4-nitrophenol (0.195 g), N,N-dimethylaminopyridine (20 mg) and dichloromethane (20 ml) were combined and then stirred at room temperature for 17 h. The reaction mixture was evaporated in vacuo onto silica and purified by flash chromatography to give the title compound (0.384 g) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C, Example 8 (126 mg) and pyrrolidine (1.5 mL) were heated at 85° C. for 4 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (6 mL) and half-saturated sodium bicarbonate solution (6 mL). The aqueous portion was extracted with additional ethyl acetate (6 mL) and the organic portions combined and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (50.3 mg). 1H-NMR (CD3OD) δ 8.18 (d, 7.0 Hz, 1H), 7.91 (s, 1H), 7.77 (m, 2H), 7.25 (s, 1H), 6.94 (m, 2H), 6.68 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 2.71 (m, 2H), 2.64 (m, 4H), 2.37 (s, 3H), 2.01 (m, 2H), 1.83 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: Cl
Product: COC(=O)CCc1oc(C)nc1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid (10.0 g), methanol (50 ml) and 20% methanolic hydrogen chloride (50 ml) was allowed to stand at room temperature for 2 hours. The solvent was distilled off, followed by addition of water. The mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give crystals of methyl 4-(4-chlorophenyl)-2-methyloxazole-5-propionate, yield 7.7 g (68.8%), b.p. 162° C./0.7 mmHg, m.p. 74°-75° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:23][C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(CCCc1ccccc1)C(=O)CCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CN(CCCc1ccccc1)C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Methyl 2-(5-phenyl-N-(3-phenylpropyl)pentanamido)acetate (34.2 mg, 0.0931 mmol) was dissolved in 0.5 mL of methanol and then 100 μL of 20% aqueous sodium hydroxide solution was added. The reaction mixture was then stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 3 mL of ethyl acetate and neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 26.2 mg (0.0741 mmol, 80%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrC1C=CC=C(C=1)OC1C=CC=CC=1C#N.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: N#Cc1ccccc1Oc1cccc(Br)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a quantitative yield from 5-bromo-2-fluoro-nitrobenzene and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.31 9d, 1H), 7.86(dd, 1H), 7.45(t, 2H), 7.25(t, 1H), 7.13(d, 1H), 7.08(d, 2H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 12.70 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[F:17][C:18]([F:23])([F:22])[CH2:19][CH:20]=O>C1COCC1>[F:17][C:18]([F:23])([F:22])[CH2:19]/[CH:20]=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16]
Reactant: O=CCC(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
To a stirred suspension of NaH (60% in oil, 2.15 g, 53.5 mmol) in dry THF (50 mL) was added dropwise ethyl(diethoxyphosphoryl)acetate (11 g, 49 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 10 min and then cooled to −70° C. A solution of 3,3,3-trifluoropropanal (5.0 g, 44.5 mmol) in dry THF (50 mL) was added to the mixture at −70° C. After the addition, the stirred mixture was allowed to warm to −20° C. over 2 hrs. The reaction mixture was quenched by addition of 5% aqueous NH4Cl (100 mL) at 0° C. and extracted with EtOAc (100 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=100:1) to give the title compound (3.0 g, 37%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:5].C1COCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:13][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Br:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1Br
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(NC(=O)c2ccccc2Br)c1
Yield: 65.5 %

Procedure:
2-Bromo-N-(3-nitrophenyl)benzamide (6.89 g, 21.5 mmol) was added to a 1 L flask with stir bar and dissolved with THF (143 mL). Sodium dithionite (37.4 g, 215 mmol) (aka sodium hydrosulfite) was added to a separate flask and dissolved with water (143 mL). The resulting cloudy solution was added to the solution of substrate, and the flask was sealed and flushed with nitrogen, then stirred vigorously for 16 h with a vent line to an oil bubbler. After this time LC-MS analysis showed complete conversion to a mixture of the desired product plus its N-sulfate. To hydrolyze the sulfated material, saturated aqueous ammonium chloride (30 mL) was added, and the mixture was refluxed for 4 h. The layers were then separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, then dried over Na2SO4, filtered, and concentrated. The crude material was then dissolved with dichloromethane and ethyl acetate, leaving an insoluble gum behind. The solution was purified by column chromatography (EtOAc/hexanes gradient), to yield the title compound as a pale yellow solid (4.10 g, 66%). LRMS (ESI+) (M+H): 291.96.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([O:4][C:5]([N:7]([CH2:32][C:33]1S[CH:35]=[CH:36][CH:37]=1)[CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:6])[CH3:3].CC(C)([O:42]C(N(CC1OC=CC=1)CCC(O)=O)=O)C.ClC1C=CC2OC3C=CC=CC=3CN(C(NN)=O)C=2C=1>>[CH3:1][C:2]([CH3:38])([O:4][C:5]([N:7]([CH2:32][C:33]1[O:42][CH:35]=[CH:36][CH:37]=1)[CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1cccs1
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccco1
Agent: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1ccco1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)amino]-1-oxopropyl]hydrazide (24) was prepared in the same manner as 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-thienylmethyl)amino]-1-oxopropyl]hydrazide (17), as described above in Example 17, on a 0.63 mmol scale from 3-[[(1,1-dimethylethoxy)carbonyl]-(2-furanylmethyl)-amino]propanoic acid (23), prepared as described above in Example 23, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, to yield 0.24 g (71%) of product.