Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:37][C:7]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1-Hydroxy-1,3-diphenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (200 mg, 0.408 mmol) prepared in Example 7 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 5 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 85 mg of the titled compound (yield: 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1.[CH3:15][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)Cn1ncc(C)cc1=O
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ncc(C)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate (0.132 g, 0.673 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 1M lithium hexamethyldisilazane solution (0.74 mL). The reaction mixture was stirred at −78° C. for 15 min then was added methyl iodide (0.046 mL, 0.74 mmol). After being stirred at −78° C. for 2 h, the reaction mixture was allowed to warm to ambient temperature over 0.5 h. Removal of the volatiles in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl 2-[4-methyl-6-oxopyridazin-1(6H)-yl]propanoate as oil. To 88 mg (0.42 mmol) of the above oil in tetrahydrofuran (0.3 mL), water (0.2 mL) and methanol (0.2 mL) was added 5 N sodium hydroxide solution (0.2 mL). The reaction mixture was stirred at ambient temperature for 3 h then neutralized with 2 N hydrochloric acid and purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. LC/MS 183.2 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>C(O)(=O)C>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
A mixture of nitric acid (1.16 g, 12 mmol) and glacial acetic acid (1 mL) was heated to 40° C. To this mixture was added rapidly a solution of 4-hydroxybenzonitrile (1 g, 8.4 mmol) in glacial acetic acid (4 mL) until the flask temperature rose to 50° C. Then the solution was added at a rate such that the temperature was maintained at 50-60° C. When addition was complete the mixture was stirred for another 20 min at 55° C., and then poured into ice-water (24 mL). The mixture was filtered and the solid was washed with water to give 4-hydroxy-3-nitrobenzonitrile 1.09 g (79%) as a solid.
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 56.8 %

Procedure:
(1S,2S)-2-(N-Oleoylamino)cyclohexanol (3.79 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.52 g of the title compound (yield: 57%)
Reaction SMILES: [H-].[Na+].COP([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)OC.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.O>C1COCC1>[N:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[C:9](\[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]#[N:24])/[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccncc1
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(/C(=C\c2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Sodium hydride (2.28 g, 94.98 mmol) was added to a solution of [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic acid dimethyl ester (20.58 g, 63.3 mmol) in dry THF and the mixture was stirred at room temperature for 15′. Pyridine-4-carbaldehyde (6.78 g, 63.3 mmol) was then added and the reaction mixture was stirred at 50° C. for 3 h under nitrogen atmosphere. In order to affect completion a further addition of pyridine-4-carbaldehyde (0.68 g, 6.33 mmol) was required. Distilled water (40 ml) was slowly poured into the reaction mixture and the solvent (THF) was removed under reduced pressure. The water layer was extracted with EtOAc (3×100 ml), DCM (1×100 ml) and the organic layers were dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product 3-[(E)-2-Pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrile as a brown oil (19.0 g, 62.10 mmol, 98%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:33][N:34]([CH3:35])[C:6]([CH:4]1[CH2:3][C:2]([OH:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:5]1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.050 g, 0.098 mmol) in dry DMF (1 mL) was added HATU (0.056 g, 0.147 mmol), HOBt (0.014 g, 0.107 mmol), DIPEA (0.025 g, 0.196 mmol) and saturated solution of dimethyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred 0° C. for 1 hour and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (5 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), brine (20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.2% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford white solid (0.029 g, 55%). 1H-NMR (400 MHz, CDCl3) δ: 2.53-2.57 (m, 2H), 2.79-2.88 (m, 2H), 3.02 (s, 6H), 3.27-3.31 (m, 1H), 3.67 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.16 Hz), 5.04 (s, 1H), 7.57 (d, 2H, J=8.4 Hz), 7.64-7.65 (m, 4H); LC-MS (m/z): [M+H] 534.8.
Reaction SMILES: [N:1]1([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=2[O:19]1.[BH4-].C(=O)C1C=CC=CC=1.N.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CC(O)C.CO>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[N:1]1([CH2:14][C@@H:15]([NH:17][CH2:23][C:22]2[CH:25]=[CH:26][C:27]3[O:28][CH2:18][O:19][C:20]=3[CH:21]=2)[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3
Reactant: C[C@H](N)Cn1ccc2ccc3ncccc3c21
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Solvent: CC(C)O
Solvent: O=Cc1ccccc1
Solvent: CO
Product: C[C@@H](Cn1ccc2ccc3ncccc3c21)NCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of (S)-1-(1H-pyrrolo[2,3-f]quinolin-1-yl)-2-propylamine (0.025 g, 0.11 mmol), 3,4-methylenedioxybenzaldehyde (0.033 g, 0.22 mmol) and methanol (1 mL) was shaken for 3 h. To the mixture was added Amberlite IRA-400 borohydride resin (2.5 mmol/g —BH4, 0.12 g, 0.3 mmol) and the mixture was shaken for 18 h. To the mixture was added PS-benzaldehyde (2.5 mmol/g —CHO, 0.12 g, 0.3 mmol) and the mixture was shaken for 18 h and filtered. The filter-cake was washed with dichloromethane (2×1 mL) and methanol (2×1 mL) and the filtrate was concentrated in vacuo. The concentrate was dissolved in dichloromethane (2 mL) and Amberlyst-15 (0.5 g) was added. The mixture was shaken for 1 h and filtered. The filter-cake was washed with dichloromethane (2×1 mL) and methanol (2×1 mL), suspended in methanolic ammonia solution (2 M, 1 ML, 2 mmol), shaken for 1 h, and filtered. The filter-cake was washed (dichloromethane) and the filtrate was concentrated in vacuo, treated with a solution of fumaric acid (0.030 g, 0.26 mmol) in 2-propanol (2 mL), cooled to 0° C., shaken for 1 h and filtered. The filter-cake was dried to give the product as a beige solid (0.052 g, 79%): mp 171-175° C. (dec); NMR ΔH (400 MHz, DMSO-d6) 0.99 (3H, d, J 6.5 Hz) 3.15 (1H, m) 3.58 (1H, d, J 14 Hz) 3.73 (1H, d, J 14 Hz) 4.46 (1H, dd, J 8.5, 14.5 Hz) 4.76 (1H, dd, J 6, 14.5 Hz) 5.96 (2H, s) 6.66 (1H, d, J 7.5 Hz) 6.73 (1H, d, J 7.5 Hz) 6.87 (1H, s) 7.47 (1H, dd, J 4.5, 8.5 Hz) 7.50 (1H, d, J 3 Hz) 7.64 (1H, d, J 9 Hz) 7.94 (1H, d, J 9 Hz) 8.64 (1H, d, J 8.5 Hz) 8.77 (1H, d, J 4 Hz).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC

Procedure:
A mixture of 3-trifluoromethylbenzyl bromide (5.74 g, 24.0 mmol) and triethyl phosphite (4.98 g, 30 mmol) was heated at reflux under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 140°-145° C. at 4 mm to yield 6.44 g (90.7%) of analytically pure product as a clear liquid, D.C.I.M.S.[MH+, 297].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6].[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>ClC(Cl)C>[C:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(=O)OCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
Aluminum chloride (111.8 g) was added to dichloroethane (500 ml) in a stream of nitrogen and the mixture was stirred at room temperature. Then, phenethyl acetate (91.8 g) and decanoyl chloride (100 g) were dropwise added thereto under ice-cooling and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with diethyl ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:20) to give 61.3 g of the subject compound (yield 38%) as an oily substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]=1)(=O)=O.[I-].[Na+].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[C:9]3[CH2:8][CH2:7][CH2:6][N:13]3[N:12]=2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)OCCCc1cc(-c2ccc(F)cc2)n[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc3n(n2)CCC3)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude 3-[3-(4-fluorophenyl)-1H-pyrazol-5-yl]propyl methanesulfonate (52 g, 0.122 mol), in 300 mL N,N′-Dimethylformamide is added at 10° C. sodium iodide (1.84 g, 12.2 mmol). Then, sodium hydride (60%, 5.4 g, 0.134 mol) is added portionwise and the mixture is stirred for 30 min at 10° C. followed by 1 h at room temperature. To the resulting brown suspension is added saturated ammonium chloride and the mixture is extracted with ethyl acetate. The extracts are dried and evaporated in vacuo. The obtained crude product is purified by trituration with 50 mL water+50 mL n-hexane. After drying of the solid in vacuo 22.9 g (90%) of the product is obtained and is being used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](N)[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:27].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([OH:27])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1Cl
Reaction time: 0.17 h
Yield: 53 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl ester (320 mg, 0.92 mmol, see U.S. Pat. No. 7,300,907 B2 for preparation) was dissolved in 10 mL 1M H2SO4 plus 4 mL acetonitrile, warmed to 75° C. and treated in portions with sodium nitrite (690 mg, 10 mmol) over 30 minutes. After stirring for 10 minutes more the mixture was cooled and the solid product was collected by filtration, washed well with water, and dried under vacuum at 80° C. to give 170 mg (53% yield) of 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl ester MP 215-217° C.; MS m/z 346; 1H NMR (DMSO-d6): δ 7.47 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.34 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[C:13]([NH:21][NH2:22])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:21][N:22]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Yield: 34 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (55.7 g, 0.27 mol), benzoic hydrazide (41.1 g, 0.30 mol) and triethylamine hydrochloride (41.5 g, 0.30 mol) in p-xylene (0.4 l) was stirred and heated at reflux under a stream of nitrogen for 24 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at this stage. The aqueous phase was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 5%→10%→25% ethyl acetate/dichloromethane to give the title compound, (26.4 g, 34%) as an off-white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 1.90–2.00 (1H, m), 2.12–2.28 (3H, m), 2.48–2.57 (2H, m), 3.69–3.78 (1H,m), 7.49–7.59 (3H, m), 7.97 (1H, s), 8.45–8.48 (2H, m); MS (ES+) m/e 285 [MH]+, 287 [MH]+.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1(O)C=CC=CC=1.[CH3:28][O:29][C:30](=[O:34])[CH:31](Br)[CH3:32]>>[N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:31]([CH3:32])[C:30]([O:29][CH3:28])=[O:34])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)C(C)Br
Reactant: O=[N+]([O-])c1cc(Cn2ncc3ccccc32)ccc1O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Cn2ncc3ccccc32)cc1[N+](=O)[O-]

Procedure:
Using 4-((1H-indazol-1-yl)methyl)-2-nitrophenol 345A as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a light yellow solid: ESI-MS: m/z 356.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 49.2 %

Procedure:
By using 5-bromo-7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (600 mg, 2.10 mmol) synthesized in Reference example 94 and 1-(4-fluorophenyl)piperazine (757 mg, 4.20 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 397 mg (yield 49%).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20].N1C=CC=CC=1.Cl>S(Cl)(Cl)=O>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:6]([C:5]3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[O:8][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (2.00 g, 9.38 mmol) in thionyl chloride (8.2 mL) was heated at 80° C. for two hours. The excess of thionyl chloride was removed under vacuum. The resulting yellow solid was dissolved in DMA (15.4 mL), then (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (2.636 g, 11.26 mmol) and pyridine (6.2 mL) were added. The red solution was heated to 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of cc HCl (10 ml) and ice (80 g), then stirred for thirty minutes. The yellow precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from dichloro-methane-iso-propanol mixture afforded 2.42 g (62%) of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol as yellow crystalline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>[OH-].[Na+]>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Reaction time: 2 h

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (1.50 g), prepared in a similar manner to that described in Example 11, and aqueous sodium hydroxide solution (1M; 40 ml) was stirred for 2 hours. The mixture was filtered, the solid washed with water (2×10 ml) and then dried in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p.234°-235° (1.19 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>CC(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:1])=[O:26]
Reactant: CNc1ccc(O)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: CN(C(=O)CCCCCBr)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
A solution of 69 g (0.56 mol) of 4-methylaminophenol and 73.9 g (0.61 mol) of N,N-dimethylaniline in about 1.5 L of acetone was stirred mechanically under nitrogen in a 3 L flask. A solution of 119.6 g (0.56 mol) of 6-bromohexanoyl chloride in 100 mL of acetone was added as rapidly as the exotherm would allow at about 40° C. The reaction was refluxed for 2 hours on a steam bath, allowed to cool and poured into a solution of about 560 mL of 2N HCl in 2 L of ice. The aqueous solution was extracted twice with ethyl acetate and the ethyl acetate extracts were combined and dried over magnesium sulfate. The ethyl acetate solution was stripped to dryness under high vacuum to yield 143.4 g (85%) of greenish-white, low melting, solid 6-bromo-N-(4-hydroxyphenyl)-N-methylhexanamide.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13]([N:21]1[CH2:25][CH2:24][CH:23](O)[CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:13]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(c1ccccc1)N1CCC(O)C1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(c1ccccc1)N1CCCC1

Procedure:
It has been found that presence of 2–3% glucose in the reaction mixture increases the yield. As shown in table 7, 73% of N-benzoyl-3-hydroxypyrrolidine can be obtained by hydroxylation of N-benzoylpyrrolidine (2 mM) with 3.9 g/L of cells of HXN-200 in the presence of glucose (3%).