Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:43])[N:21]([CH3:42])[C@@H:22]([C:30](=[O:41])[N:31]([CH3:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:42][N:21]([C@@H:22]([C:30](=[O:41])[N:31]([CH3:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:43])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Reaction time: 0.67 h
Yield: 95.5 %

Procedure:
N-Methyl-N-[(1R)1-(N-methyl-N-{(1R)-1-[N-methyl-N-(2-(pyridinyl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tert-butyl ester (14.9 g, 24.5 mmol) was dissolved in dichloromethane (75 mL). Trifluoroacetic acid (75 mL, 0.978 mol) was added to the stirred solution. The reaction mixture was stirred for 40 min. The solvent was removed in vacuo. The product was dissolved in dichloromethane (50 mL) and sat. aqueous sodium hydrogen carbonate solution (40 mL). The mixture was neutralised with solid sodium hydrogen carbonate. Dichloromethane (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo, to give 11.9 g of (2R)-N-Methyl-2-(methylamino)-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}-3-(2-naphthyl)propionamide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>C(O)C.[Pt]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(CCC=CCCBr)cc1
Agent: O=[Pt]
Solvent: CCO
Product: N#Cc1ccc(CCCCCCBr)cc1
Yield: 98.3 %

Procedure:
A solution of 10.5 g of 4-(6-bromohex-3-enyl)benzonitrile in 200 ml of absolute ethanol was hydrogenated in the presence of 0.25 g of platinum oxide catalyst. Isolation of the product afforded 10.4 g of 4-(6-bromohexyl)benzonitrile as a yellow oil which was distilled at 168°-170° C.(0.01 mm) to produce the compound as a colorless oil which solidfied upon cooling.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCCCCBr
Reactant: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of m-aminophenol (12.6 gm, 0.115 moles) and 1,4-dibromobutane (50 gm, 0.23 moles) was heated to 130° C. for 12 hr. The mixture was cooled to room temperature and triturated with diethylether and then ethyl acetate. The residue was dissolved in ethyl acetate and extracted with 1M NaOH, water, and sat. NaCl. After drying the organic layer with MgSO4, filtering, and evaporating solvent under vacuum, the crude product was purified by silica gel chromatography to give a pale yellow solid. The solid was refluxed with 500 ml toluene and 17 ml triethylamine (0.12 moles) for one hr, cooled to room temperature and washed with water and sat. NaCl. The solution was dried again over MgSO4, filtered, and evaporated under vacuum to give 3-pyrrolidinylphenol as a white solid (6.0 gm, 0.037 moles, 32%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([OH:12])=O.[NH2:20][CH:21]1[C:31](=[O:32])[N:23]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([NH:20][CH:21]1[C:31](=[O:32])[N:23]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CON=C(C(=O)O)C1(CBr)OCCO1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1(CBr)OCCO1
Yield: 100 %

Procedure:
Phosphorus oxychloride (0.54 ml.), N,N-dimethylformamide (438 mg.), 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer, 1.6 g.), 7-amino-3-cephem-4-carboxylic acid (1 g.), trimethylsilylacetamide (3.3 g.) and dry ethyl acetate (21 ml.) were treated in a similar manner to that of Example 11 (1) to give 7-(2-methoxyimino-3,3-ethylenedioxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 2.25 g.)
Reaction SMILES: [H-].[Na+].Br.[N:4]1[C:8]2[C:9]3[C:14]([CH:15]=[CH:16][C:7]=2[S:6][C:5]=1[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>O1CCCC1>[N:4]1[C:8]2[C:9]3[C:14]([CH:15]=[CH:16][C:7]=2[S:6][C:5]=1[NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2c(ccc3ccccc32)s1
Agent: Br
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(ccc3ccccc32)s1)c1ccncc1
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Added sodium hydride (73 mg; 2.89 mmol) to a stirred suspension of 21 (90 mg; 0.27 mmol) in dry tetrahydrofuran under nitrogen at room temperature. After 30 minutes, isonicotinoyl chloride hydrochloride (150 mg; 0.84 mmol) was added and the mixture allowed to stir for 72 hr. at room temperature. The mixture was concentrated in vacuo, the residue taken up into ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. Purification using reverse phase HPLC (eluent: acetonitrile/water/0.1% trifluoroacetic acid) provided 26 mg of N-Naphtho[1,2-d]thiazol-2-yl-isonicotinamide 22. ES-HRMS m/e calcd for C17H11N3OS (M+H) 306.0696, found 306.0691.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][C:16]([NH:18][S:19]([C:22]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=2[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])(=[O:21])=[O:20])=[O:17])[N:8]=1>CC(N(C)C)=O>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][C:16]([NH:18][S:19]([C:22]2[CH:27]=[C:26]([NH:28][C:1](=[O:3])[CH3:2])[CH:25]=[CH:24][C:23]=2[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])(=[O:21])=[O:20])=[O:17])[N:8]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(NC(C)=O)ccc2C(=O)N(C)C)n1

Procedure:
0.13 ml of acetyl chloride is slowly added dropwise to a mixture of 0.64 g of N-[(4,6dimethoxypyrimidin-2-yl)aminocarbonyl]-5-amino-2-dimethylaminocarbonylbenzenesulfonamide and 10 ml of dimethylacetamide. After the end of reaction, the reaction mixture is concentrated under reduced pressure and the residue is washed with water and ethyl acetate, to give 0.45 g of the desired product in high purity (>92%, HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH:10]2[CH2:12][CH2:11]2)[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH:10]2[CH2:12][CH2:11]2)[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1C1CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CNCC1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
101.2 To a stirred solution of 1.13 g (3RS,4RS)-1-benzyl-4-cyclopropyl-pyrrolidine-3-carboxylic acid methyl ester at r.t. in 10 ml methanol under an argon atmosphere was added 113 mg 10% Pd/C. The mixture was then stirred at r.t. under a hydrogen atmosphere overnight. The catalyst was filtered off and rinsed with methanol. The filtrate was concentrated to leave 630 mg (3RS,4RS)-4-cyclopropyl-pyrrolidine-3-carboxylic acid methyl ester as a light yellow oil. MS170.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:30][C:31]([OH:33])=O)[CH2:10][N:11]([CH3:29])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH3:25])=[C:16]([Br:26])[C:15]=2[O:27][CH3:28])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=CC2N(O)N=[N:40]C=2C=1.N.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:30][C:31](=[O:33])[NH2:40])[CH2:10][N:11]([CH3:29])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH3:25])=[C:16]([Br:26])[C:15]=2[O:27][CH3:28])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(Br)c(OC)c2ccccc2c1C(=O)N(C)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COc1c(Br)c(OC)c2ccccc2c1C(=O)N(C)C[C@@H](CC(N)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-[2-(3,4-dichlorophenyl)-3-carboxypropyl]—N-methyl-3-bromo-2,4-dimethoxy-1-napthamide (0.26 g, 0.468 mmol) in 5 mL of DMF was added HOBT.NH3 (0.175 g, 1.15 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.184 g, 0.96 mmol). The mixture was stirred at RT for 24 h and treated with saturated NaHCO3. The aqueous layer was extracted with DCM. The combined DCM extracts was dried over MgSO4, filtered and concentrated. Following chromatography purification, the title compound was obtained as light yellow solid (0.21 g, 81% yield). 1H NMR (CDCl3) δ 8.15-8.02 (m), 7.61-7.43 (m), 7.37-7.26 (m), 7.07-7.00 (m), 6.91-6.89 (d), 6.81 (d), 6.70-6.67 (d), 6.56-6.53 (d), 6.14 (s), 5.88 (s), 5.33-5.30 (m), 4.33-4.26 (m), 4.05-3.64 (m), 3.43 (m), 3.25 (s), 3.20 (s), 2.96 (s), 2.89 (s), 2.82-2.55 (m), 1.59 (s). MS m/z 555.0 (M+). Analysis calculated for C24H23BrCl2N2O4, 0.1 H2O, C 51.84, H 4.21, N, 5.04, found C, 51.81, H, 4.31, N, 5.05.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)Cc1cccc(OCc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2cccc(CC(=O)O)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate (0.596 g), tetrahydrofuran (6.0 mL) and methanol (6.0 mL) was added a 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3.0 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless prism crystals (0.566 g, 98%). melting point: 148-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To 3-ethoxy-4-hydroxybenzaldehyde (20.0 g, 120 mmol) in dimethylformamide (250 mL) was added potassium carbonate (33.1 g, 240 mmol) then 2-iodopropane (18 mL, 180 mmol). The reaction mixture was heated to 45° C. and stirred for 3 h. After cooling to rt, the crude reaction mixture was extracted with ethyl acetate (3×). The combined extracts were then washed with water (3×) then brine and dried over sodium sulfate. The solvent was removed to give 24 g of 141A as a yellow oil. LC-MS: 231.17 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](=[O:15])[CH3:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:17][CH2:14][C:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[N:9][O:10][C:11]=1[CH3:16])=[O:15]
Reactant: CC(=O)c1c(-c2ccc(Br)cc2)noc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1onc(-c2ccc(Br)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of 1-[3-(4-bromo-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (2.49 g, 8.89 mmol) in carbontetrachloride (5.8 mL) and AcOH (0.3 mL) at 48° C. was added a solution of bromine (0.48 mL, 8.89 mmol) in carbontetrachloride (4.7 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (20 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=8:2) afforded the title compound (1.49 g, 47%) as a light yellow oil. MS m/e: 355.9/358.1/360.0 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:5])C.[OH-].[Na+:16]>C1COCC1>[Na+:16].[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:4]([O-:5])=[O:3]
Reactant: CCOC(=O)c1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To benzoxazole-2-carboxylic acid ethyl ester (437 mg, 4 mmol) was added 2 mL of THF and 4 mL of NaOH solution (2N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was dried under vacuum to give 160 mg of benzoxazole-2-carboxylic acid sodium salt as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:21]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[O:15])[CH3:22]
Reactant: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O

Procedure:
To a solution of 1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (25 g) in DMF (215 mL) was added a sodium hydride 60% dispersion in mineral oil (6.5 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and iodoethane (17 mL) was added slowly thereto. The reaction mixture was stirred under ice-cooling for 2 hr, and poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:16][CH2:15][CH2:13][OH:14])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: NCCO
Product: Nc1cc(Cl)cc(NCCO)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.05 mole (11.2 g) of 2-amino-4,6-dichloronitrobenzene (Recueil. Trav. Chim. 68, p. 88 [1949]) in 45 ml of ethanolamine was heated for 2 hours over a boiling water bath. The reaction medium was diluted with 150 ml of ice water. After acidification with 80 ml of hydrochloric acid, the desired product precipitated out. It melted at 183° C. after recrystallization from 400 ml isopropanol.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([C@H:25]2[C:34]3[C:33](=[O:35])[CH2:32][C@@H:31]([CH2:36][CH2:37][CH3:38])[CH2:30][C:29]=3[NH:28][C:27]([CH3:39])=[C:26]2[C:40]#[N:41])[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]([C@H:25]2[C:34]3[C:33](=[O:35])[CH2:32][C@@H:31]([CH2:36][CH2:37][CH3:38])[CH2:30][C:29]=3[NH:28][C:27]([CH3:39])=[C:26]2[C:40]#[N:41])[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1[O:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Reactant: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(O)c(OCC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2[N+](=O)[O-])c(OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (4,5-difluoro-2-nitro-phenyl)-methanol (Example 72f, 5.1 g), (4R,7S)-4-(3-Bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (Example 72e, 10.0 g) and polymer-supported triphenylphosphine (13.5 g, 3 mmol/g loading) in THF (500 ml), cooled to 0° C., was added diisopropyl azodicarboxylate (DIAD) (5.3 ml). After 1.5 h, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 4/1-2/3 (v/v) as eluent.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].N1C=CC=CC=1.[S:14](Cl)(Cl)=[O:15]>C(Cl)Cl>[O:15]=[S@:14]1[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@H]1CCCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[S@@]1OCC2CCCN21
Temperature: 25 °C
Yield: 100 %

Procedure:
(R)-2-Pyrrolidinemethanol (1.00 g; 9.88 mmol), prepared according to Example 1, and 6 mL methylene chloride were added to a 50 mL, 3-neck round-bottom flask equipped with a reflux condenser topped with a CaCl2 drying tube, an addition funnel and a magnetic stirrer. Pyridine (1.63 mL; 20.16 mmol) was added, and the solution stirred in a room temperature water bath. Thionyl chloride (1.20 g; 10.08 mmol) in 4 mL methylene chloride was added over 15 minutes and washed in with 1 mL methylene chloride. After stirring for 45 minutes at ambient temperature, the reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature and stirred for an additional 2 hours. Hexanes (11 mL) was added and the mixture was stirred in a 0°-5° C. ice bath for 1 hour. After filtration to remove precipitated pyridine hydrochloride, the solvent was removed on a rotary evaporator with a 40° C. water bath to yield 1.47 g (9.88 mmol) of (R)-1-oxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine as a brown oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:24]=CC.N1C=CC=CC=1.Cl.O1CCOCC1>ClCCCl.C(O)(=O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:11](=[O:12])[C:4]2[C@H:5]3[C:8]([CH3:10])([CH3:9])[C@:2]([CH3:1])([CH2:7][CH2:6]3)[C:3]=2[NH:24]1
Reactant: CC=NNc1ccc(F)cc1F
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
A solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; ˜15 mmol) in 1,2-dichloroethane (25 mL) was added by syringe over a period of 5 min to a cooled (0° C.) solution of N-(2,4-difluoro-phenyl)-N′-ethylidene-hydrazine (Intermediate 26; 2.32 g, 13.6 mmol) and pyridine (1.8 mL, 22.3 mmol) in 1,2-dichloroethane (15 mL). The flask containing the acid chloride was rinsed with 1,2-dichloroethane (10 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 45 min. A solution of HCl in dioxane (Aldrich; 4 M, 11 mL, 44 mmol) was added. The solution was stirred for 5 min at room temperature and then acetic acid (18 mL) was added. The reaction mixture was stirred at 100° C. under argon for 1 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (150 mL) and 1:1 water/brine (75 mL). The organic layer was washed with 1:1 water/brine (50 mL), and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate extracts were washed with brine (100 mL), dried (sodium sulfate), filtered, and evaporated to give a dark brown semi-solid which was stored in the freezer overnight and then triturated with diethyl ether. The solid was filtered off, washed with ether and air-dried to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.93 g, 47%) as a light brown solid which was used directly in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc(Br)c(Br)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc(Br)c(Br)s1

Procedure:
58.3 Using general method H, 4,5-dibromo-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(4,5-dibromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 598.8 ([M+H]+)
Reaction SMILES: O.NN.[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:36]=[CH:35][C:21]([CH2:22][O:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[CH:20][CH:19]=1.O1CCCC1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23][NH2:24])=[CH:35][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Hydrazine monohydrate (1.15 ml) was added to a solution of N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (5.22 g) in ethanol (40 ml)-tetrahydrofuran (40 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (3.32 g, yield 90%) as colorless crystals. m.p. 68-69° C.