Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[N:7][CH:8]([Cl:15])[CH:9]([Cl:14])[C:10]([Cl:13])([Cl:12])[Cl:11])[C:5](=[O:16])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[C:3]1=[O:24].[F:25][C:26]1C=[CH:30][CH:29]=[CH:28][C:27]=1N1C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)CN(C)C1>>[F:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:1]=1[N:2]1[C:6](=[N:7][CH:8]([Cl:15])[CH:9]([Cl:14])[C:10]([Cl:12])([Cl:11])[Cl:13])[C:5](=[O:16])[N:4]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:3]1=[O:24]
Reactant: CN1C(=O)N(c2ccccc2F)C(=O)C1=NC(Cl)C(Cl)C(Cl)(Cl)Cl
Reactant: CN1CC(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1
Product: O=C1C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C(=O)N1C1CCCCC1

Procedure:
Similarly the reverse 1-position-3-position isomers of each of the above prepared compounds are prepared by using the corresponding position isomer of formula A as the starting material. For example by using 1-methyl-3-(2-fluorophenyl)-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine-2,4-dione in place of 1-(2-fluorophenyl-3-methyl-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine the following compounds (as well as the other position isomers of the above products) are prepared:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[NH2:10])[CH:6]=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)C
Reactant: CN(N)c1cccc(C(F)(F)F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=NN(C)c1cccc(C(F)(F)F)n1)C(C)C

Procedure:
A solution of 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (12.12 g; 0.069 mol), 3-methyl-2-butanone (5.96 g; 0.069 mol) and p-toluenesulphonic acid (0.13 g) in toluene (70 ml) was heated under reflux, with water removal (azeotrope), for 24 h. The solution was concentrated to yield an oil which was purified by flash-chromatography over silica (eluent: 20% diethyl ether in hexane) to yield 3-methyl-2-butanone 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as an orange oil (11.6 g; 71%). ##STR22##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:15]2)[CH:6]=[C:7]([NH2:13])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][OH:40]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[O:15]2)[CH:6]=[C:7]([NH:13][CH2:38][CH2:39][OH:40])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCI
Reactant: CCCOc1c(N)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-2-(3-methoxy-4-propoxy-5-aminophenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (20 mg, 0.048 mmol), potassium carbonate (0.4 g), and 2-iodoethanol (82.47 mg, 0.48 mmol) was suspended in 2 mL of DMF. The reaction mixture was stirred at room temperature for 20 hours, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to an oil which was purified by column using 3:1 hexane/ethyl acetate as solvent (12.8 mg, 57.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18]O)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][O:10][C:9]2[C:8]([CH3:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[CH3:1])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzonitrile (5.0 g, 34.0 mmol) in THF (40 mL), rac-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (4.49 g, 34.0 mmol) followed by triphenylphosphine (13.4 g, 50.9 mmol) is added. The mixture is cooled with an ice-bath before DEAD (8.87 g, 50.9 mmol, 23.4 mL of a 40% solution in toluene) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 99:1 to 92:8 to give rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g) as a pale yellow oil; LC-MS: tR=0.99 min, [M+1]+=not detected. b) To a solution of potassium tert.-butylate (6.18 g, 55.1 mmol) in methanol (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) is added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in methanol (40 mL) is added. The mixture is refluxed for 72 h before the solvent is removed in vacuo. The residue is purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound (4.85 g) as a pale yellow solid; LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (s br, 1H), 7.28 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CN[CH2:15][CH2:16][CH2:17]C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH2:1][CH2:15][CH2:16][CH3:17]
Reactant: CN(C)C=Nc1ccncc1O
Reactant: CCCCNC
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCCCN(C)C=Nc1ccncc1O
Yield: 64.2 %

Procedure:
A mixture of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.50 g), N-methylbutylamine (8.10 g), ammonium sulfate (0.600 g), and anhydrous toluene (25 mL) was heated at reflux under nitrogen for 2.25 hours. The solution was concentrated under reduced pressure and the crude product chromatographed on silica gel (10% methanol in dichloromethane) to afford 6.04 g of solid. Recrystallization from ethyl acetate/hexanes afforded 3.90 g of a crystalline material, m.p. 83°-85° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15](=[O:16])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:10]=[O:11])[CH2:8][S:9][C@H:4]12.N1C=CC=CC=1>CO>[NH2:2][C@@H:3]1[C:15](=[O:16])[N:5]2[C@@H:4]1[S:9][CH2:8][C:7]([CH:10]=[O:11])=[C:6]2[C:12]([OH:14])=[O:13]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12

Procedure:
2.64 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine (hydroxylactone of the hydrochloride of 7-amino-3-formyl-3-cephem-4-carboxylic acid) are dissolved in 50 ml of methanol. A solution of 0.78 g of pyridine in 10 ml of methanol is added dropwise to this solution whilst stirring and cooling with ice. The precipitated product is filtered off under nitrogen whilst excluding moisture, washed with a little methanol and dried over a drying agent in vacuo at room temperature. (6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is thus obtained in the form of a light brown powder.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26].C(OCC)(=O)C.CC(C)=O.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Br-:20].[CH3:31][S:28]([NH:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)NC(=O)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 77.6 %

Procedure:
A stirring mixture consisting of triphenylphosphine (13.2 g, 24.4 mmol) and 5-bromo-N-(methylsulfonyl)pentanamide (prepared in Step A, 5.55 g, 21.5 mmol) in xylene (15 mL) was brought to reflux for 4 hours. Subsequently, ethyl acetate was added to the hot reaction mixture and stirring was continued for the next 15 minutes. The crude product was isolated from acetone-ethyl acetate to afford the title intermediate (8.68 g, 78%); melting point 189-190° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CCCN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN(CC)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 3-diethylaminopropylamine (4.13 g, 31.7 mmole) in methylene chloride (50 mL) was added palmitoyl chloride (9.15 g, 33.3 mmole) in small portions. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide (90 mL), chloroform (100 mL) and methanol (200 mL). The solution was transferred to a separatory funnel then chloroform (100 mL) and IN aqueous sodium hydroxide (100 mL) was added and the layers separated. The aqueous layer was extracted twice with chloroform (100 mL portions). The solution was transferred to a separatory funnel then chloroform. The organic layer was dried over magnesium sulfate and the salts removed by filtration. The solvent was removed under reduced pressure to give the title compound (11.6 g, 100%) as a gum. 1H NMR (300 MHz, CDCl3): δ0.881 (3H, t, J=6.6 Hz), 1.053 (6H, t, J= 7.1 Hz), 1.252 (24H, bs), 1.56 to 1.67 (2H, m), 2.129 (2H, t, J=7.7 Hz), 2.50 to 2.57 (6H, m), 3.31 to 3.37 (2H, m), and 7.392 (1H, bs). IR (neat): 3307, 3219, 3152, 3085, 2949, 2920, 2850, 1734, 1642, 1082 cm-1. Analysis calculated for C23H48N2O.3/4H2O: C, 74.94; H, 13.12; N, 7.59. Found: C, 74.68; H, 13.11; N, 7.52.
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[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[F:36][C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[F:36][C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCc4ccc(F)cc4F)c(F)c3)c2cc1OC
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (5.0 ml) and triethylamine (1.0 ml) with heating. A solution of triphosgene (103 mg) in dichloromethane (1.0 ml) was then added to the solution, and the mixture was heated under reflux for 3 min. Next, 2,4-difluorobenzylamine (54 mg) was added thereto, and the mixture was heated under reflux for additional 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 123 mg (yield 80%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9](C)[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].O.[CH3:22]N(C)C=O>>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][CH:10]([Cl:11])[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(CCl)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Solvent: O
Product: CC(Cl)CN(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 80 °C
Reaction time: 2.33 h

Procedure:
An optically-active compound of [benzyl-(2-chloro-1-methylethyl)-amino]acetic acid tert-butyl ester (172.9 g) was dissolved in N,N-dimethylformamide (520 ml), and stirred at 80° C. for 140 minutes. The reaction mixture was cooled to 0° C. Then, thereto was added water (1200 ml), and the mixture was extracted with n-hexane/ethyl acetate (2/1, 1000 ml). The organic layer was sequentially washed with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted with n-hexane/ethyl acetate (2/1, 600 ml) again. The combined organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1 to 40/1) to give the titled compound (127.0 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ncccc1-c1ccncc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 2-fluoro-3-(pyridin-4-yl)pyridine (1.0080 g, 5.787 mmol), 4-aminophenol (0.7102 g, 5.793 mmol), and cesium carbonate (2.387 g, 6.945 mmol) in dimethyl sulfoxide at 90° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)C)c1F
Yield: 76.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-2, step-2 using ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-2, step-1, 1.00 g, 4.32 mmol), isobutyryl chloride (690 mg, 6.48 mmol) and DIPEA (1.67 g, 12.96 mmol) in THF (30 mL) to afford 1.0 g of the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([NH2:30])[CH:17]=1)=[O:15]>N1C=CC=CC=1.O>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([NH:30][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH:17]=1)=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CN(C)S(=O)(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 4.7 g (32.8 mmol) of dimethylsulfamyl chloride in 5 ml of dry pyridine is added to 5.0 g (16.4 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone in 100 ml of dry pyridine at 0°-10° C. The reaction mixture is stirred in the cold overnight and then poured in water and extracted with ether. The ether extract is washed with water and extracted with dilute aqueous KOH. This basic extract is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried organic extract is evaporated in vacuo to give 4-benzyloxy-3-dimethylsulfamoylaminophenyl 2-pyridyl ketone. Hydrogenation over PcO2 according to the procedure of Example 3 gives α-(4-hydroxy-3-dimethylsulfamoylaminophenyl)-2-piperidylcarbinol.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC([O:18]O)(C)C>>[C:1]1(=[O:18])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)OO
Product: O=C1C=CC=C2C1=Cc1ccccc12

Procedure:
We initially studied oxidation of methylene substituted benzylic aromatics to ketones (Scheme 1, R≠H). When a mixture of fluorene with 10 equivalents 70% aqueous TBHP was irradiated with microwave in a sealed vessel for 10 minutes (250 W, 170° C.), an almost quantitative yield of fluorenone was isolated (Table 1). As a control experiment, when we simply refluxed the same reaction mixture by conventional oil bath heating for 8 hours, only a trace amount of fluorenone could be detected by TLC. Oxidation of another substrate with a doubly activated benzylic position, diphenylmethane, also afforded benzophenone in high yield. For the mono-activated methylene units, ethylbenzene to acetophenone and tetrahydronaphthalene to alpha-tetralone, the oxidations under this green protocol also went smoothly. The results are summarized in Table 1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([OH:30])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1.[CH2:33](O)[CH2:34][CH3:35].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:30][CH2:33][CH2:34][CH3:35])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CCCO
Reactant: CSc1nc2c(O)nc(Cc3ccc(Cl)cc3)nc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(SC)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8.7 mmol of polystyrene-bound triphenylphosphine (Argonaut) and 1.5 g of diethyl azodicarboxylate (DEAD) in 55 ml of tetrahydrofuran was stirred for 15 min at 0° C. Then 2.2 g of 5-(4-chloro-benzyl)-2-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol, 0.65 ml of propan-1-ol and 1 ml of triethylamine were added. The reaction mixture was stirred at room temperature for 3 h. The polymer was filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed in vacuo and the title compound isolated by silica gel chromatography (method SC1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.[CH2:37]([OH:40])[C:38]#[CH:39]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:26])([F:27])[F:25])[N:17]=[C:16]2[O:40][CH2:37][C:38]#[CH:39])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: C#CCO
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-5-fluoro-6 -oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and pyridine in propargyl alcohol there is obtained isopropyl 2-chloro-5-[5-fluoro-6-oxo-4 -pentafluoroethyl-2-(2-propynyloxy)-1(6H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.86 ppm (d,1H), 7.43 ppm (d,1H), 5.27 ppm (m,1H), 4.97 ppm (d,2H), 2.53 ppm (t,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H);
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[C:6]([CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][C:18]([OH:20])=O)=[O:15])[CH:7]=[CH:8][N:9]=2)[CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.CC#N.CN([P+](O[N:45]1N=N[C:47]2[CH:48]=CC=C[C:46]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:61]([O:64][CH2:65][CH3:66])(=[O:63])[CH3:62]>>[CH2:65]([O:64][C:61](=[O:63])[CH2:62][C@@H:46]([C:47]#[CH:48])[NH:45][C:18](=[O:20])[CH2:17][N:16]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:1]2)[CH:21]1[CH2:23][CH2:22]1)[CH3:66]
Reactant: O=C(O)CN(C(=O)CCCc1ccnc2c1CCCN2)C1CC1
Reactant: CCOC(C)=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: C#C[C@H](CC(=O)OCC)NC(=O)CN(C(=O)CCCc1ccnc2c1CCCN2)C1CC1
Reaction time: 20 h

Procedure:
To a stirred solution of acid 23-6 (40 mg, 0.1256 mmol), amine 21-6 (33 mg, 0.1884 mmol), NMM (70 μl, 0.5024 mmol) and CH3CN (1 ml) was added BOP reagent (61 mg, 0.1382 mmol). After 20 h at ambient temperature, the solution was diluted with ethyl acetate and then washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40:1:1 CH2Cl2/MeOH/AcOH) gave the ester 23-7 as a colorless oil.
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[N:28]=[CH:29][C:30]2[C:31](=[O:45])[N:32]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=[CH:34][C:35]=2[C:36]=1[OH:37])=O>C(Cl)Cl.CCOC(C)=O>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[N:28]=[CH:29][C:30]2[C:31](=[O:45])[N:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:33]=[CH:34][C:35]=2[C:36]=1[OH:37])=[O:15])(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (77 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (2 mL). NaOMe was added with vigorous stirring until pH about 8. The resulting cloudy solution was transferred to a microwave vial containing 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 20 mg of the title compound as an off-white solid. MS: (+) m/z 417.30 (M+1).