Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])(O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[C:6](=[O:7])=[O:5].[C:26]([C:21]1[C:20]([CH3:28])=[C:19]([C@H:13]2[O:12][CH2:11][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:17][CH2:16][N:15]3[CH2:14]2)[CH:24]=[CH:23][C:22]=1[F:25])#[N:27]
Reactant: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Product: O=C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A three-necked, round-bottomed flask equipped with a nitrogen inlet adapter, thermocouple, and a septum was charged with (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (330 g, 840 mmol), TFA (1.65 L, 21 mol), and 3300 mL of DCM. Et3SiH (292 g, 2.52 mol, 3 equiv) was added in one portion and the reaction mixture stirred at room temperature for 24 h. The reaction mixture was concentrated and azeotroped with toluene (100 mL) to remove the TFA. The resulting material was dissolved in DCM (1.7 L) and carefully charged with 2.5 M Na2CO3 (pH should be basic). Boc2O (218 g, 1.2 equiv) was added in one portion and the reaction mixture was stirred at room temperature for 2 h. The organic layer was separated, concentrated, and purified via column chromatography (0-30% acetone-hexanes) to give a mixture of product cis/trans isomers. Chiral SFC purification (Berger MultiGram™ SFC, Mettler Toledo Co, LTD, AD 250 mm*50 mm, 5 um column, A: supercritical CO2, B: methanol, A:B=85:15 at 150 mL/min) afforded the major trans diastereomer 17A as well as the cis diastereomer 17B.
Reaction SMILES: [C:1]1([CH:7]([NH:31]C(OCC2C=CC=CC=2)=O)[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.[N+](C)([O-])=O.C(OCC)(=O)C>[C:1]1([CH:7]([C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[NH2:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CS[C@H]12)c1ccccc1)OCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of benzyl 7β-(α-phenyl-α-carbobenzoxyaminoacetamido)-3-chloro-3-cephem-4-carboxylate (295 mg) in methylene chloride (6 ml) is added a solution of aluminum chloride (267 mg) in nitromethane (3 ml) under ice cooling. After stirring for 2 hours at room temperature, the mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid, and extracted with an aqueous solution of 5% sodium hydrogen carbonate. The extract is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and evaporated. The residue is recrystallized from a mixture of ethyl acetate and ether to give 7β-(α-phenyl-glycinamido)-3-chloro-3-cephem-4-carboxylic acid (167 mg). Yield: 91.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1C(=O)N([Cl:21])C(=O)C1.CCOC(C)=O>CN(C=O)C>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (1.00 g, 5.74 mmol) in DMF (15 mL) was added NCS (843 mg, 6.31 mmol). The reaction mixture was stirred at 25° C. for 16 hours. Diluted the reaction with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column (PE/EtOAc=100/1) gave the product (940 mg, yield 87%).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1>O>[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([O:2][CH3:1])[N:8]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(N)n1
Temperature: 15 °C
Yield: 86.5 %

Procedure:
Sodium methoxide, 7.78 gm (0.144 mole) and methanol 50.0 ml were mixed and cooled to 15° C. To this solution, 25.0 gm of 2-amino-6-chloro-3-nitropyridine (0.144 mole) was added while maintaining the temperature at 15° C. by external cooling. The resulting mixture was heated to 25°–30° C. and maintained at this temperature for 4–5 hrs with constant stirring. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured in water. The precipitate thus obtained was filtered and washed with water. On drying 21.0 gm of 2-amino-3-nitro-6-methoxypyridine (86.5% yield) was obtained, with the HPLC purity of 99.0%. Melting point 167°–169° C.; 1HNMR (CDCl3) δ3.89 ppm (s, -3H, OCH3), 66.14–6.16 ppm (d, 1H), 68.24–8.27 ppm (d, 1H), 68.16 ppm (s, -2H, —NH2)
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.CO.ClCCl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:32])[C:17]=2[N:26]=1
Reactant: [NH4+]
Reactant: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chlioroperoxybenzoic acid (mCPBA) (16.4 g of 77% max, 73.1 mmol) was added to a solution of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10 g, 36.5 mmol) in chloroform (250 mL). The reaction mixture was stirred at ambient temperature overnight. Ammonium hydroxide (100 mL) was added and the reaction was stirred vigorously for 15 minutes. Para-toluenesulfonyl chloride (8.4 g, 43.8 mmol) was added in portions over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for 1 hour and then filtered to remove a precipitate. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 16 g of crude product as a yellow foam. The foam was dissolved in 10% methanol in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g), (available from Biotage, Inc, Charlottesville, Va., USA). The cartridges were eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 2% methanol in 1:1 ethyl acetate:hexanes, and 5% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 6.4 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as an orange foam.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CC#N>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:9]=[C:10]([C:11]([NH2:13])=[O:12])[CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1cccc(O)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCCBr)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
(Method D) K2CO3 (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH3CN (100 ml). The mixture stirred for 10 min at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 60° C. for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-117° C. HPLC-MS (method 1): m/z 300 [M]+, 302 [M+2H]+, Rt=4.08 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:16])[CH:5]=1)(=O)[CH3:2].[CH2:17]([O:19]/C(/C)=C/C(OCC)=O)[CH3:18].Cl.[C:29](=O)=O>CN(C)C=O>[Cl:16][C:6]1[CH:5]=[C:4](/[C:1](/[CH3:29])=[CH:2]/[C:17](=[O:19])[CH3:18])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)c(Cl)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: O=C=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)/C=C(\C)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
208.0 Gm (1.85 mols) of potassium tert.-butylate were added all at once to a solution of 284.0 gm (1.23 mols) of 4-acetyl-2-chloro-biphenyl and 292.0 gm (1.85 mols) of ethyl (E)-3-ethoxy-crotonate in 1.8 liters of anhydrous dimethylformamide. The temperature rose at once from +20°C to +38°C, and the mixture turned red. The mixture was stirred for 1 hour at 32° to 35°C, then 200 ml of concentrated hydrochloric acid were added dropwise to the warm batch, and the resulting mixture was heated at a temperature of 90°-100°C for 30 minutes. After the carbon dioxide evolution had ceased, the cooled mixture was poured into 2 liters of ice water and extracted exhaustively with ether. The combined ether extracts were washed with water, with a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. The oily residue was distilled in a moderate vacuum (b.p. 170°-175° C at 0.3 mm Hg) and subsequently recrystallized from cyclohexane and petroleum ether. 273.6 Gm (82% of theory) of pale yellow crystals, m.p. 66°-67°C, were obtained.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N>C(O)C.Cl>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1ccccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccn1
Yield: 40.5 %

Procedure:
1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) (0.05 g; 0.149 mmol) and 2-hydrazinopyridine (0.021 g; 0.194 mmol) are dissolved in a sealed tube in ethanol (0.6 ml) with catalytic amounts of HCl and irradiated at 160° C. for 5 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.023 g (40.5%) of the final product. MS: M=382.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1-bromo-3-methylbenzene.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32](O)[CH:33]=3)[CH:28]=2)[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:11][C@H:8]4[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]4)[CH:33]=3)[CH:28]=2)[CH2:20][O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)COC(C)(C)OC1

Procedure:
The title compound was prepared from cis-4-tertbutylcyclohexanol and [5-(6-hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester in 42% yield according to the method of Example 53.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(CN=[N+]=[N-])c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 2-choro-4-cyanobenzyl azide (5.8 g, 30.1 mmol) in THF/H2O (3:1), was added triphenyl phosphine (12.3 g, 46.7 mmol). The reaction was stirred at room temperature overnight, then neutralized with 1N sodium hydroxide, extracted with ethyl acetate (150 ml×3). The organic layer was dried over sodium sulfate, and then solvent was removed in vacuo. The product was purified by silica-gel chromatography column with methanol/ammonia hydroxide/ethyl acetate (20:1:69) to give 4.5 g (90%) of 2-chloro-4-cyanobenzylamine. NMR (CDCl3): δ 4.0 (s, 2H, CH2), 7.58 (d, 2H, HAr), 7.62 (s, 1H, HAr)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH:25]1([CH2:24][C:4]([CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 2-phenyl-propionic acid methyl ester (3.0 g, 18.27 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with the lithium hexamethyldisilazide (21.9 mL, 1M in tetrahydrofuran, 21.9 mmol) and stirred for 1 hour. Bromomethyl-cyclohexane (3.09 mL, 21.92 mmol) was added to the reaction and the reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 2.5% ethyl acetate in hexane, and 5% ethyl acetate in hexane to give the title compound (4.02 g, 84%). 1H NMR (300 MHz, CDCl3): δ ppm 1.11 m, 10 H) 1.55 m, 4 H) 1.80 m, 1 H) 2.04 m, 1 H) 3.64 m, 3 H) 7.29 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH2:39][CH2:40][CH:41]([OH:46])[CH2:42][CH2:43][CH2:44][CH3:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:46][CH:41]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH2:39][CH2:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC(O)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CCCC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 73.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 70%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]1=[O:13].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CC(C)=O>[C:24]1([N:14]2[C:12](=[O:13])[C:11]([CH2:10][CH2:9][CH2:8][CH3:7])([CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:16](=[O:17])[N:15]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(COC(=O)C(C)(C)C)C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 5 %

Procedure:
Potassium carbonate (2.26 g, 0.016 mole) was suspended in an acetone (125 ml) solution of phenylbutazone and the suspension was refluxed overnight. The next day pivalyloxymethyl chloride (4.99 g, 0.033 mole) was added to the resulting solution and the solution was refluxed overnight. The suspension was cooled and filtered; the residue (2.00 g, 83%) was potassium chloride. The filtrate was concentrated in vacuo and the residue was suspended in ether, then filtered. The residue was washed with ether until the washings did not contain any product by TLC. The residue from the ether suspension was the potassium salt of phenylbutazone (2.25 g, 20%). The ether was then concentrated in vacuo and the residue was absorbed on silica gel and chromatographed on neutral silica gel (CC-7, Mallinckrodt) using petroleum ether bp 30°-60° C.--ether (1:1) as the eluent to give two fractions. The first fraction (Rf 0.46, silica gel, heptane-ether, 1:1) was crystallized from heptane-petroleum ether bp 30°-60° C., 1:1 to give 0.63 g (mp 116°-117° C., 5% yield) of 1,2-diphenyl-4-butyl-4-pivalyloxymethyl-3,5-pyrazolidinedione. nmr (CDCl3) δ 4.40 (S, 2, ##STR14##
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>C1COCC1.O.CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc(=O)[nH]c2nc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Agent: [Ni]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(=O)[nH]c2nc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Reaction time: 5.5 h
Yield: 88.4 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methyl-1H-[1,8]naphthyridin-2-one (880 mg, 1.92 mmol) was dissolved in THF (50 mL) and added to a Parr bottle containing a suspension of Raney-Nickel (1.5 mL of a settled suspension in water) in EtOH (50 mL). The mixture was hydrogenated at 45 psi for 5.5 h. The reaction was not complete so additional Raney-Nickel (1 mL of a suspension in water) was added and the mixture was hydrogenated at 45 psi for 2.5 h. The reaction mixture was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated to give a white solid. Purification by column chromatography (10% MeOH/EtOAc) afforded the title compound as a white solid (780 mg, 88%). mp 195–196° C.; 1H NMR (CDCl3, 400 MHz): δ 9.16 (br s, 1H), 7.88 (d, 1H), 7.18–7.12 (m, 2H), 7.06 (d, 1H), 7.00–6.92 (m, 1H), 6.50 (s, 1H), 3.14–3.00 (m, 4H), 2.85 (t, 2H), 2.72–2.54 (m, 4H), 2.46 (d, 3H), 2.42 (t, 2H), 1.85–1.72 (m, 2H), 1.64–1.52 (m, 2H), 1.48–1.36 (m, 2H); MS ES: m/z=459.08, 461.03.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[S:7])[NH:4][C:3]1=[O:8].[CH3:9][I:10]>C(O)C>[IH:10].[CH3:9][S:7][C:5]1[NH:6][CH:2]([CH3:1])[C:3](=[O:8])[N:4]=1
Reactant: CI
Reactant: CC1NC(=S)NC1=O
Solvent: CCO
Product: CSC1=NC(=O)C(C)N1
Product: I
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 5-methyl-2-thiohydantoin (15 g.) and methyl iodide (16.3 g.) in dry ethanol (130 ml.) was heated under reflux for 11/2 hours, and then allowed to stand at 0° overnight. The crystalline product was filtered and washed with ether to give 2-methylthio-5-methyl-2-imidazolin-4-one hydroiodide (17.8 g.), m.p. 170°-173°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N+:13]([O-:21])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1ccc(-c2ccncc2)cc1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Part B. A solution of 4-(4-isopropyl-phenyl)-pyridine (1.01 g, 5.1 mmol) in dichloromethane (20 mL) is cooled to 0° C., and a solution of m-chloroperoxybenzoic acid (1.33 g, 7.6 mmol) in dichloromethane (20 mL) is added dropwise. The mixture is allowed to warm to ambient temperature over 12 h. with stirring, then heated to reflux for 2 h. An excess of m-chloroperoxybenzoic acid (0.5 g) is added, and reflux continued for 2 h. The solution is cooled and washed successively with 10% aq. sodium sulfite, 10% aq. sodium carbonate and saturated brine. The organic phase is dried over anhydrous magnesium sulfate and evaporated. The residue is separated by flash chromatography to afford 4-(4-isopropyl-phenyl)-pyridine-N-oxide (0.85 g, 78%).