Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11](=[O:35])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)[CH2:9][OH:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]([CH2:9][OH:10])[C:11]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)=[O:35]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(CO)NC(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)CO)C1)c1cccc(Cl)c21
Yield: 69 %

Procedure:
A solution of {1-[3-(9-Chloro-3-methyl-4-oxo5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl}-carbamic acid tert-butyl ester, 73 mg (0.14 mmol) in 8 mL of 25% TFA in CH2Cl2 was stirred rt. for three hours then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The organics were washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 40 mg (69%) of the title compound as a white solid. 1H—NMR is consistent with structure. MS (IS) 419.1 (M+).
Reaction SMILES: ClC1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH3:9][O:10][C:11](=[O:24])[CH:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14]Br.C[N:26](C=O)C>CCOC(C)=O>[CH3:9][O:10][C:11](=[O:24])[CH:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][N:26]1[N:3]=[CH:4][CH:5]=[N:6]1
Reactant: CN(C)C=O
Reactant: Clc1ncc[nH]1
Reactant: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(CCn1nccn1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 0.87 g (8.4 mmol) of 2-chloroimidazole in 14 mL of DMF was added 0.40 g (10 mmol) of 60% NaH in mineral oil. After 20 min of stirring, 2.5 g (8.4 mmol) of 4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester in 5 mL of DMF was added. The reaction mixture was heated to 80° C. for 1 h. The mixture was diluted with EtOAc (150 mL), washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-5% MeOH in CH2Cl2) to provide 2.1 g (78%) of 2-tert-butoxycarbonylamino-4-1,2,3-triazol-2-yl-butyric acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C(=O)c1ccccc1)C2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 4-dimethylaminopyridine (0.2 g), and triethylamine (1.5 mL) in CH2Cl2 (8 mL) at room temperature under nitrogen was added neat benzoyl chloride (0.42 g, 3.0 mmol) dropwise. The reaction was stirred overnight, quenched with a solution of saturated sodium bicarbonate, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-50% ethyl acetate/hexane) to provide the title compound (0.835 g, 90% yield): ES-MS (m/z) 464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)=[N:9][NH:8][C:7]2=[O:22].[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH2:23][CH3:24])[CH2:27][CH2:28]3)=[O:18])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:22]
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: CCOC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Yield: 41 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-ethoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The solvent was removed and the crude product dissolved in acetonitrile and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (111 mg, 41.0% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.17-1.46 (2H, m), 1.58-1.92 (2H, m), 2.97-3.42 (4H, m), 3.42-3.55 (3H, m), 4.68 (2H, s), 7.13 (1H, s), 7.21 (2H, t), 7.35 (1H, t), 7.81 (1H, t), 7.94-7.99 (1H, m), 8.32-8.36 (1H, m), 12.91 (1H, s); m/z (LC-MS, ESI+), RT=1.96 (M+H 426.7)
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: CN=C=O
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and 01.7 ml. (excess) of methyl isocyanate are added successively. Addition of the latter gives rise to an exotherm, and the mixture becomes very pasty. The mixture is kept at 45° C. for one hour, and after cooling to room temperature, the solid is collected, washed thoroughly with benzene and then with water. On drying, this gives 1.7 grams (81%) of product, melting point 183° C. to 186° C. Recrystallization from acetone gives 1.23 grams, melting point 187.5° C. to 189° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[NH:32]([C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and phenyl isocyanate: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]1[O:22][C:23]([C:26]2[C:27]([O:36][CH3:37])=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][N:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:27]1[C:26]([C:23]2[O:22][C:21]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:39][CH3:38])=[O:19])=[N:25][CH:24]=2)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)O)NC(=O)OCc2ccccc2)o1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of F5 in DMF (0.1 M) were added HATU (2.0 eq.) and DIPEA (3.0 eq.) followed after 10 min by methylamine (2.0 M solution in THF, 5.0 eq.). Reaction mixture was stirred at room temperature for 16 h. Then, reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography (eluent: Petroleum ether/EtOAc from 1:1 to 100% EtOAc, then EtOAc/MeOH=95:5) to give the title compound as pale yellow solid. MS (ES+) C29H32N4O5: 517 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (silica, 50:46:3:1, hexanes:dichloromethane:methanol:isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2H, J=4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M+H)+. Anal. Calc. for C20H28N2O3+0.175 CHCl3: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:21]3[N:22]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:33]#[N:34])[N:17]=2)[CH:13]=[N:14][CH:15]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:23]1[N:22]([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:21]2[C:16]([C:12]3[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:17][C:18]([C:33]#[N:34])=[CH:19][C:20]=2[N:24]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (5.84 g, 32.8 mmol) was added to a room temperature solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (4 g, 10.9 mmol) stirring in degassed chloroform (54.7 mL). The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C20H19BrClN5 [M+H]+ 444. found 444. 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 3.86 (d, J=6.1, 2H), 1.44 (d, J=12.1, 2H), 1.15-1.05 (broad, 1H), 1.00-0.85 (broad, 1H), 0.85-0.73 (m, 4H), 0.72 (d, J=6.1, 3H), 0.56-0.43 (m 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-:14].[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([F:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
3-Nitrobenzenesulphonyl chloride (10 g) was dissolved in 1,4-dioxane (30 ml) and stirred at room temperature. To this solution was added a solution of potassium fluoride (3.9 g) in water (5 ml) and the stirring continued at room temperature for 5 hours. The reaction mixture was allowed to stand at room temperature overnight and was poured into ice/water. The product was extracted into dichloromethane, the solvent was dried (MgSO4) and evaporated under reduced pressure to give the title compound (8 g). This material was sufficiently pure for the next stage of the synthesis.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>CO.O>[NH2:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g) in methanol (15 ml), and conc. hydrochloric acid (0.52 g) and tetrahydrofuran (3.0 ml) was stirred for 3.0 hours at ambient temperature. The reaction mixture was added to water and ethyl acetata, and adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 3.0 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated under reduced pressure to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.02 g).
Reaction SMILES: [H-].[Na+].[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(Cl)(Cl)Cl>C(#N)C>[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:20][CH:22]2[O:24][CH2:23]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Clc1nc(Nc2ccccc2)nc2c1ncn2CC1CO1
Reaction time: 48 h
Yield: 34.6 %

Procedure:
Sodium hydride (161 mg, 4 mmol; 60% suspension in mineral oil) was added to a suspension of 2-anilino-6-chloropurine (1 g, 4 mmol; Focher et al. (1988) J. Med. Chem. 31:1496-1500) in anhydrous acetonitrile (240 ml) at room temperature. After stirring for 1 hr epibromohydrin (0.35 ml, 4 mmol) was added, and the suspension was stirred for 48 hr. An equal volume of chloroform was added, and, after filtration through Celite, the filtrate was evaporated to dryness. The residue was chromatographed on silica gel, and the major product was eluted with chloroform to give 417 mg (34% yield) of 2-anilino-6-chloro-9-(2,3-epoxypropyl)purine. 1H NMR δ9.97 (s, 2-NH), 8.24 (s, 8-H), 7.40 (m, C6H5), 4.38 (m, 1'-CH2), 3.45 (m, 2'-CH), 2.72 (m, 3'-CH2). Further elution gave 46 mg (3.8% yield) of the minor 7-isomer.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[NH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O)[C:17]([CH3:19])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:16][C:17]([CH3:19])=[O:18])=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: CC(=O)Nc1ccccc1O
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1OC(=O)CCC1CCN(C(=N)N)CC1
Reaction time: 44 h
Yield: 92.7 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.6 g of o-acetaminophenol was dissolved in 40 ml of dry pyridine. To the solution was added with ice-cooling and stirring 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was allowed to stand at room temperature for 44 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ethyl acetate, and dry ether was then added to the residue to give crystals. The crystals were washed with ether several times, then with warm dichloromethane and finally with ethyl acetate. Dry ether was added to the crystals, and the mixture was evaporated to dryness to obtain 5.8 g (yield: 92.7%) of o-acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride as hygroscopic crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34]CC4C=CC=CC=4)[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[OH:34])[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc([N+](=O)[O-])cc3)cc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(N)cc3)cc2)c(O)c1
Reaction time: 5 h
Yield: 103 %

Procedure:
A solution of 4-(4′-nitrobiphenyl-2-carboxamido)-N-(2-benzyloxy-4-methylphenyl)-N-methylbenzamide (430 mg), 20% palladium hydroxide (80 mg) in methanol (20 ml) and 1,4-dioxane (30 ml) was stirred under atmospheric pressure of hydrogen at 30° C. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 3% methanol in chloroform) to give 4-(4′-aminobiphenyl-2-carboxamido)-N-(2-hydroxy-4-methylphenyl)-N-methylbenzamide (350 mg) as amorphous.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]2[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C([OH:28])(C)C.Cl.[OH-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:19][CH2:20][C:21]([NH2:22])([CH3:24])[CH3:23])=[O:28])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)O
Reactant: CC1(C)COC(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 45 °C

Procedure:
In a 1-liter, three-neck, round-bottom flask equipped with a thermometer, stirrer and condenser were placed 66.2 g (0.2 mole) 2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]-4,4-dimethyl-2-oxazoline, prepared as disclosed in inventors' application Ser. No. 043,787, filed on May 30, 1979, now abandoned and application Ser. No. 181,325, filed on Aug. 25, 1980 which is a continuation of said application Ser. No. 043,787, entitled "Derivatives of 2-Oxazolines as antioxidants," assigned to Uniroyal, Inc. and filed concurrently herewith, the disclosure of which is hereby incorporated herein by reference, 400 ml isopropanol and 33 ml 6 N hydrochloric acid. The mixture was heated to 45° C. for 2 hours and then cooled. To this stirred solution were added 250 ml of water and 33 ml of 6 N sodium hydroxide. The product was removed by filtration and dried. The title compound, (52 g), thus obtained, melted at 97°-99° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)C>CN(C)C=O>[CH3:18][S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:21][C:19](=[O:22])[CH3:20])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Yield: 98.6 %

Procedure:
A solution of 4′-bromomethyl-3-methylsulfonylbiphenyl (190 mg, 0.57 mmol) (WO 01/70753) and potassium thioacetate (78 mg, 0.68 mmol) in N,N-dimethylformamide (4 mL) was heated at 150° C. in a microwave for 3 min. The reaction mixture was poured into diethyl ether (30 mL) and washed with water (3×15 mL), brine (15 mL), dried with magnesium sulfate, filtered, and concentrated to give a crude yellow oil. The crude oil was purified by flash column chromatography to yield 1.35-A (180 mg, 89%) as a thick light yellow oil. LCMS found for C16H17O3S2 (M+H)+: m/z=321.
Reaction SMILES: [CH3:1][O:2][S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[O:19])[CH:13]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[OH:5][S:3]([C:6]([F:9])([F:8])[F:7])(=[O:4])=[O:2].[CH3:1][N:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]1[CH:18]=[O:19]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COc1ccnc(C=O)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC1=CC(C=O)N(C)C=C1
Product: O=S(=O)(O)C(F)(F)F
Reaction time: 20 h
Yield: 93.3 %

Procedure:
A 3 mL glass vial was equipped with a rubber septum and magnetic stir bar. The vial was brought into a glove box and charged with MeOTf (116 μL, 1.06 mmol) by micropipette. The vial was sealed and removed from the glove box. A separate 3 mL vial was charged with 4-methoxy-2-pyridinecarboxaldehyde (Astatech C10253, 145 mg, 106 mmol) and was dissolved in PhMe (1 mL). The solution of pyridine was added via syringe onto the MeOTf at room temperature. The vial which contained the pyridine was rinsed with PhMe (0.5 mL) and the rinse solution was injected into the reaction vial. The reaction vial was kept at room temperature and stirring was maintained at ca. 400-600 rpm. After 20 h, hexanes (2 mL) were added after which stirring was stopped. Any solid or oil was allowed to settle and the solvent was removed by glass pipette. The solid or oil was then rinsed with several portions of hexanes followed by diethyl ether. Residual solvent was then removed in vacuo to provide the compound N-methyl-4-methoxy-2-pyridinecarboxaldehyde triflate (300 mg, 94%). This oil was used for oxime formation without further purification.