Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[Br:36][C:37]1[N:38]=[N:39][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][CH:42]=1.C(Cl)(=O)C(C)(C)C.P(Br)(Br)(Br)=O>>[C:43]([C:40]1[N:39]=[N:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42][CH:41]=1)([CH3:46])([CH3:45])[CH3:44].[Br:36][C:37]1[N:38]=[N:39][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)c1ccc(Br)nn1
Agent: O=P(Br)(Br)Br
Product: C[C@@H](c1ccc(-c2ccc(C(C)(C)C)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-bromo-6-tert-butylpyridazine following a procedure analogous to that described in Example Step 2. 3-bromo-6-tert-butylpyridazine was prepared from pivaloyl chloride following procedures analogous to those described in Example 4 Steps 1-4 using POBr3 in place of POCl3 in Step 4. LC-MS Method 2 tR=1.208 min, m/z=488.3; 1H NMR (CD3OD) 0.94 (s, 3H), 1.25 (s, 3H), 1.48 (s, 9H), 1.57 (d, 3H), 2.15 (s, 2H), 2.29 (m, 1H), 2.50 (m, 2H), 3.10 (m, 1H), 5.60 (m, 1H), 7.14 (d, 2H), 7.30 (m, 5H), 7.81 (d, 2H), 8.07 (d, 1H), 8.20 (d, 1H)
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:46])[CH:15]([C:20]1[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].[OH2:49].OO.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([C:24]2[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:46])=[O:49])[CH:21]=[C:22]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:41]=3)[CH:23]=2)=[CH:27][CH:28]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a solution of 4-benzyl-3-[2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (3.66 g, 5.7 mmol) in THF (24 mL) was added water (8 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (240 mg, 5.7 mmol) and 30% H2O2 (1.95 mL, 17.2 mmol), and stirred at 0° C. for 15 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (11.5 mL, 17.2 mmol) and stirred at room temperature for 10 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH=2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×50 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoic acid (2.5 g, 92%).
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([NH2:10])[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C@H:4]1[C@@H:9]([NH:10][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C:23]2[CH:31]=[CH:32][CH:33]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=2)[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
Tert-butyl (1R,3R,4S)-3-acetyl-4-aminocyclohexylcarbamate (500 mg) dissolved in DMF (2 mL) prior to the addition of 2-(3-(trifluoromethyl)benzamido)acetic acid (626 mg), 4-methylmorpholine (1.1 mL), and BOP (1.3 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-acetyl-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate (430 mg). MS found: (M+H)+=486.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH3:17]I.[H-].[Na+].O>CN(C)C=O>[CH3:17][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)OC)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate (1.0 g, 4.62 mmol) in N,N-dimethylformamide (10 ml) was added methyl iodide (1 ml), and sodium hydride (222 mg, 5.55 mmol, 60% in oil) was further added at 0° C., and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (30 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-10:1) to give methyl 4-((methyloxy)methyl)-1-naphthalenecarboxylate (898 mg, 84%).
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:13]
Reactant: O=C(Cl)COc1cc(Cl)c(Cl)cc1Cl
Reactant: Nc1ccccn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(COc1cc(Cl)c(Cl)cc1Cl)Nc1ccccn1

Procedure:
After filling in a dry 250 ml flask respectively 150 ml of anhydrous benzene and 32.5 g (0.118 mol) of 2,4,5-trichlorophenoxyacetyl chloride synthesized in Example 14, 11 g (0.118 mol) of 2-aminopyridine was added with vigorous stirring, and then 8.1 ml of triethylamine was slowly dropped to be heated and refluxed for 2-3 hours, while the external temperature was maintained at 80°-90° C.
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)=[O:5].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:27]([N:6]([C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1])[CH:26]=[CH2:25]
Reactant: Cc1nonc1NC(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C)c1nonc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
150 mg (0.413 mmol) of 2-methyl-N-(4-methyl-1,2,5-oxadiazol-3-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide and 50 mg (0.413 mmol) of allyl bromide are dissolved in 5 ml of N,N-dimethylformamide, and 0.057 mg (0.413 mmol) of potassium carbonate is added. The reaction mixture is stirred at 80° C. for 8 h and taken up in 5 ml of water and extracted twice with 10 ml each time of dichloromethane. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by means of preparative HPLC (acetonitrile, water). Yield 160 mg (86%).
Reaction SMILES: Cl.CO.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:36]4[CH:35]=[CH:34][S:33][C:32]=4[CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[C:13]([O:37][CH3:38])[CH:12]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[S:33]1[CH:34]=[CH:35][C:36]2[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:14]4[C:15]([CH3:17])=[CH:16][C:11]([NH2:10])=[CH:12][C:13]=4[O:37][CH3:38])[CH2:27][CH2:26]3)=[CH:29][CH:30]=[CH:31][C:32]1=2
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
6N-hydrochloric acid (3 ml) was added to a methanol solution (10 ml) of {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-carbamic acid tert-butyl ester (2.18 g, 4.3 mmol) and the mixture was stirred at room temperature overnight. After stirred at 60° C. for 15 minutes, the mixture was cooled to room temperature and a 6N aqueous sodium hydroxide solution was added thereto to neutralize it. Dichloromethane was added to the reaction mixture, and the substance extracted with dichloromethane was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline (1.26 g) as light yellow solid
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH:30]=O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:30]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(CC=O)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: COc1cccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Methoxy-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 394.0; HRMS: calcd for C23H16F3NO2+H+, 396.12059; found (ESI, [M+H]+), 396.1196.
Reaction SMILES: C([N:6]1[CH2:11][CH:10]([CH3:12])[CH:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[CH:8]([CH3:17])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH:14]1([NH:13][CH:9]2[CH:8]([CH3:17])[CH2:7][NH:6][CH2:11][CH:10]2[CH3:12])[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CC(C)C(NC2CC2)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1CNCC(C)C1NC1CC1

Procedure:
Mixture A of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (3.5 g, 1.45 mmol) was stirred in 5 N NaOH solution (25 ml) at 100° C. for hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture A of isomers of 4-cyclopropylamino-3,5-dimethyl piperidine as oil. Yield 2.1 g (85%), C10H20N2, m/z 169 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:23]([S:42][CH2:43][C@@H:44]([C:46]([NH:48]CC(N)=O)=[O:47])[NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:45][C@H:44]([C:46]([NH2:48])=[O:47])[CH2:43][S:42][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CNC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
1.00 g (3.36 mmol) of N-[(9H-Fluoren-9-ylmethoxy)carbonyl]glycine was dissolved in 30 ml dichloromethane. 1.41 g (3.36 mmol) S-Trityl-L-cysteinylglycinamide, 0.59 ml (3.36 mmol) N,N-diisopropylethylamine and 1.28 g (3.36 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 300 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1, dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.63 g (2.06 mmol, 81% of theory) of the desired product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:2]([CH2:3][C:4]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:5]=2[O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH3:1])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid and 4-chlorobenzenesulfonyl chloride. M+H=514.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[O:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]([C:37]2[CH:38]=[N:39][C:34]([O:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[CH:35][CH:36]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: OB(O)c1ccc(OC2CCOCC2)nc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronic acid (0.49 g), copper acetate (0.53 g), pyridine (0.6 mL), triethylamine (1 mL), molecular sieves 4 A (1 g) and methylene chloride (10 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate 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 (0.25 g, 33%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([NH:9][CH:10]=[O:11])=[CH2:8]>C1(=O)C=CC(=O)C=C1.C[O-].[Na+]>[CH:7]([N:9]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:10]=[O:11])=[CH2:8]
Reactant: C=CNC=O
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: O=C1C=CC(=O)C=C1
Agent: [Na+]
Product: C=CN(C=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 91.9 %

Procedure:
To a 1000 mL three-neck round bottom flask equipped with a cold water condenser and stirrer was added 215 grams (2.5 moles) of methyl acrylate, 195 grams (2.75 moles) of N-vinylformamide, and 0.1 gram of benzoquinone. The mixture was stirred at ambient temperature for two minutes and 1.5 grams of sodium methoxide was added in one portion. The mixture was stirred for approximately 2 hours at ambient temperature and allowed to stand overnight. The reaction mixture was distilled under vacuum and 361 grams of product (92% yield) boiling at 75° C. (0.8 mm Hg) was collected for analysis. 1H NMR analysis confirmed the identity of the 3-(N-vinylformamido) adduct.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].CC([O-])=O.[Na+]>O.CCO>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:12][OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)nc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(F)nc1
Temperature: 50 °C

Procedure:
To a 200-ml, round bottom flask was added, 1-(6-fluoropyridin-3-yl)ethanone (Method 65, 2.5 g, 17.9 mmol), hydroxylamine hydrochloride (2.5 g, 35.8 mmol), and NaOAc (3.7 g, 44.8 mmol) in a solution of water-EtOH (65 ml, 3.3:1). The resulting mixture was heated to 50° C. for 1 hour. The reaction was then allowed to cool to room temperature, partitioned with EtOAc, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound in quantitative yield. 1H NMR: 11.49 (s, 1H) 8.47 (s, 1H) 8.17-8.27 (m, 1H) 7.21 (dd, J=8.29, 3.01 Hz, 1H) 2.17 (s, 3H).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20]Cl)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8]([NH:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][I:1])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice cooled solution of sodium iodide (900 mg, 6 mmol) in acetone was added a solution of diphenylmethyl 7-t-butoxycarbonylamino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (VIa) (1.08 g, 2 mmol) in acetone (2.5 ml). The mixture was stirred while being cooled in an ice bath for 3.5 hours, and was concentrated under reduced pressure. The residue was diluted with ethyl acetate and aqueous sodium thiosulfate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated. 923mg of the title product was obtained as a yellow powder after crystallization from a small volume of ethanol (73% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCCCC2)cc(N)[n+]1[O-]
Temperature: 155 °C
Yield: 55 %

Procedure:
A quantity (1.50 g., 0.0077 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, above) with 6.0 ml. piperidine, and 10.0 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 155° C. for 3.5 hrs. The aqueous reaction mixture was then cooled to 25° C. and diluted with 50 ml. water. The diluted reaction mixture was then extracted with three 50.0 ml. portions of chloroform. The combined chloroform extracts were treated with charcoal, dried over anhydrous sodium sulfate, filtered, and the chloroform was removed by evaporation under reduced pressure. The solid residue thus obtained was crystallized from acetone to give 0.88 g. (55% yield) of 2-amino-6-methyl-4-piperidinopyridine-1-oxide as off-white needles having a melting point at 260° C. (with decomposition). The crystals sinter at about 250° C.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:20][CH:21]=[CH2:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[O:31]1[CH2:22][CH:21]1[CH2:20][CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
A mixture of 12.92 g (43.6 mmole) of t-butyl 2-(1-naphthylmethyl)-4-pentenoate (prepared as described in Preparation 10), 11.29 g (65.4 mmole) of m-chloroperbenzoic acid and 100 ml of methylene chloride was stirred at room temperature for 24 hours. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 5: 95 by volume mixture of methanol and methylene chloride), to afford 4.57 g (33.6%) of the title compound as a pale yellow oil.
Reaction SMILES: ClC1C=C(C=C(C=O)N=1)C(OC)=O.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[C:23]([C:31](O)=[O:32])[N:22]=2)=[CH:17][CH:16]=1>>[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[C:23]([CH:31]=[O:32])[N:22]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(C(=O)O)nc(-c2ccc(F)nc2)c1
Agent: COC(=O)c1cc(Cl)nc(C=O)c1
Product: COC(=O)c1cc(C=O)nc(-c2ccc(F)nc2)c1

Procedure:
methyl 6′-fluoro-6-formyl-2,3′-bipyridine-4-carboxylate was synthesized from methyl 2-chloro-6-formylisonicotinate and converted to 6′-fluoro-4-(methoxycarbonyl)-2,3′-bipyridine-6-carboxylic acid following the general procedures as described herein.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[N:8]1[C:13]2[NH:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[NH:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:19])[NH:18][C:12]2[CH:11]=[CH:10][CH:9]=[N:8][C:13]1=2)=[O:6]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)CCCCl
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCl)c2ccccc21

Procedure:
A solution of 4-chlorobutyryl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in xylene was reacted to obtain 11-(4-chlorobutyryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from ethyl acetate melted at 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:10][C:11]2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-]=C=[O:20].C(C1C2C(=CC=CC=2)C=CC=1)#N>>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([N:10]=[C:11]=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: [N-]=C=O
Reactant: Cc1c(Nc2ccccc2)ccc(C#N)c1Cl
Agent: N#Cc1cccc2ccccc12
Product: Cc1c(N=C=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 4D in a manner similar to that described in the preparation of compound 1B.