Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6]Cl)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1.[I-].[Na+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(C3OCCOC3CCn3cncn3)ccc2N1
Temperature: 80 °C

Procedure:
10.5 Grams (35.5 mM) of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril was dissolved in 10.6 g (71 mM) of dimethylformamide, to this solution was added 10.6 g (71 mM) of sodium iodide, 5.4 g (78.1 mM) of 1H-1,2,4-triazol and 6.5 ml (46.2 mM) of DBU, and the whole mixture was heated at 80° C. for 7 hours with stirring. The reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue was extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=40:1), and recrystallized from ethanol-n-hexane to yield 8.0 g of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl]-3,4-dihydrocarbostyril. Next, to a solution of 1 g (3.0 mM) of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1yl)butyl] -3,4-dihydrocarbostyril with 10 ml of DMF was added 3 ml of 5%-hydrochloric acid and stirred for 2 hours at room temperature. After concentration by removal of the solvent, the residue was extracted with chloroform:methanol=3:1. The extract was washed with water, dried with an anhydrous magnesium sulfate, then concentrated by removal of the solvent. The resulting residue was recrystallized from chloroform-ethanol to yield 6-[4-(1H-1,2,4-triazol-1-yl)butyryl]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 194.0°- 195.0° C.
Reaction SMILES: CS(O)(=O)=O.OCCCN1[C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2NC1=O.[C:21]1(N2C3(CCNCC3)C(=O)NC2)[CH:26]=CC=C[CH:22]=1.C(=O)([O-])[O-:39].[Na+].[Na+]>CN(C)C=O>[CH3:22][CH2:21][CH2:26][C:18](=[O:39])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)CCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 5.68 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate, 4.62 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.7 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at 60° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of N,N-dimethylformamide and water, yielding 2 parts (24%) of 8-[3-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5[decan-4-one; mp. 255.5° C.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 486 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@H:20]1[CH2:24][C@@H:23]([CH2:25][OH:26])[C@H:22]([OH:27])[C@@H:21]1[OH:28]>CN(C)C=O.O>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:19][C@H:20]2[CH2:24][C@@H:23]([CH2:25][OH:26])[C@H:22]([OH:27])[C@@H:21]2[OH:28])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 4-amino-6-chloro-5-nitropyrimidine (320 mg, 1.83 mmol) in N,N-dimethyl formamide (5 mL) and triethylamine (512 μL, 3.67 mmol) was added (1S,2R,3S,5S)-3-Amino-5-hydroxymethyl-cyclopentane-1,2-diol (293 mg, 2.02 mmol). The mixture was stirred at room temperature and monitored by thin layer chromatography until starting material was no longer detected. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2×10 mL). The organic extract was washed with saturated aqueous sodium chloride (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was recrystallized from hot methanol/water to give a 315 mg of (1S,2R,3S,5S)-3-(6-amino-5-nitro-pyrimidin-4-ylamino)-5-hydroxymethyl-cyclopentane-1,2-diol as a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:27])[C:20](=[O:26])[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[CH:15][CH:14]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:27])[C:20](=[O:26])[O:21][CH2:22][C:23]2([CH3:25])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: C=C(C)COC(=O)N(C)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)OCC1(C)CO1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.2 %

Procedure:
m-Chloroperbenzoic acid (2.5 g, 10.1 mmol) was added to a solution of 2-methyl-2-propenyl N-(4-chlorophenyl)-N-methylcarbamate (1.78 g, 6.7 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 6.5 hours. To which sodium thiosulfate aqueous solution was added and the mixture was filtered, and sodium hydrogencarbonate aqueous solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (2-methyl-2-oxiranylmethyl) N-(4-chlorophenyl)-N-methylcarbamate (1.7 g, quantitative) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:26](=O)[CH2:27][C:28]2[C:29]([C:34]([F:37])([F:36])[F:35])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[NH:40][NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:26](=[N:41]\[NH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])/[CH2:27][C:28]2[C:29]([C:34]([F:36])([F:35])[F:37])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N/N=C(/Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethanone (0.485 g, 0.93 mmol), ethyl carbazate (0.11 g, 1.06 mmol) and p-toluene sulfonic acid (4 mg) in toluene (10 mL) was refluxed until distillation of water ceased. The reaction mixture was cooled to room temperature, the solvents were evaporated to dryness, and the crude solid was triturated with diethyl ether (15 mL), filtered and dried yielding (Z)-ethyl 2-(1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethylidene)-hydrazinecarboxylate, 0.475 g (84%).
Reaction SMILES: C(O)C(O)C.[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].SC(O)C.C(OOC(C)(C)C)(=O)C>>[CH:6]([CH2:17][C:15](=[CH2:16])[C:14]([OH:19])=[O:18])=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)O
Agent: CC(=O)OOC(C)(C)C
Agent: CC(O)S
Solvent: CC(O)CO
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 150 °C

Procedure:
A 1-liter, four-necked, round bottomed flask equipped with a mechanical stirrer, two addition funnels, a distillation head with a variable takeoff, a thermometer, a nitrogen inlet, and a heating mantle atop a thermosensor-controlled pot lifter is charged with 300 g of propylene glycol. This heel charge is heated to 150° C. under nitrogen. The monomer charge (135 g styrene, 165 g methacrylic acid, and 3 g mercaptoethanol) is gradually charged over 5 hours. Simultaneously, the initiator solution (9.0 g of 70% t-butyl peracetate) is added over the same period. After completion of the feeds, an additional 0.9 g of t-butyl peracetate solution is added and the batch held at150° C. for another hour.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:34](=[O:33])[CH2:35][OH:36])[CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2C(=O)CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (180 mg, 0.43 mmol), acetoxyacetyl chloride (51 μL, 0.47 mmol), triethylamine (119 μL, 0.86 mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (130 mg, 64%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.9 (d, J=8.2, 1H), 7.6 (q, J=8.5 and 6.9 Hz, 1H), 7.3 (t, J=8.7 Hz, 1H), 7.1 (t, J=7.9 Hz, 1H), 6.9 (s, 2H), 6.5 (s, 1H), 5.25 (s, 2H), 4.1 (d, J=5.5 Hz, 2H), 3.9 (t, J=8.6 Hz, 2H), 3.42 (t, J=5.4 Hz, 1H), 3.35 (t, J=4.8 Hz, 1H), 3.2 (t, J=8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z 475.1220 (M+H calcd for C24H22ClF2N2O4 requires 475.1231).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(CC)CC)C>C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:15]2[C:10]([N:9]=1)=[N:11][CH:12]=[CH:13][CH:14]=2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.023 ml) was added in one portion to a stirred solution of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.069 ml) in THF (40 ml). The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. The product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness and the resulting solid was triturated overnight with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-methoxy-ethanone (80 mg) as a solid. Mass spectrum: M+H+ 434; RT 2.23 min
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C1COCC1>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:5]=1
Reactant: COC(=O)c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
NaH (60% w/w in mineral oil; 0.532 g, 13.30 mmol) was added (portionwise, over 2 min) to a solution of methyl 3-iodo-1H-indole-5-carboxylate (3.64 g, 12.09 mmol) in THF (30 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 5 min. p-Toluenesulfonyl chloride (2.54 g, 13.30 mmol) was then added (portionwise, over 2 min), and the resulting mixture was stirred at 0° C. for 1 h. H2O (50 mL) was carefully added to the mixture at 0° C. and the reaction was warmed to 25° C. THF was removed in vacuo, and the resulting tan mixture was vacuum filtered. The collected solid was washed with H2O (150 mL) and dried in vacuo to provide crude methyl 3-iodo-1-tosyl-1H-indole-5-carboxylate (5.94 g) as a tan solid: MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.03-8.11 (2H, m), 7.97-8.02 (1H, m), 7.79 (2H, d, J=8.2 Hz), 7.75 (1H, s), 7.26 (2H, d, J=8.2 Hz), 3.94 (3H, s), 2.36 (3H, s).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:29])=[CH:5][CH2:6][O:7][C:8]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]2[C:11]([C:12](=[O:28])[C:13]([CH3:27])=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15]2)=[CH:10][CH:9]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C.O>[CH3:27][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[C:17]([C:18](=[O:20])[CH:19]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([O:7][CH2:6][CH:5]=[C:4]([CH3:29])[CH3:3])=[CH:9][CH:10]=2)[O:15][C:14]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(3-methylbut -2-enyloxy)-8-acetyl-3-methylflavone (2.71 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.3 g of product m.p. 83-84° C., 1H-NMR (CDCl3)δ:1.67 (s, 3H); 1.70 (s, 3H); 2.18 (5, 3H); 4.68 (d, 2H, J=6.4 Hz); 5.30-5.38 (m, 11H); 7.00 (d, 1H, J=16 Hz); 7.02 (d, 11, J=8.9 Hz; 7.24 (d, 1H, J=16 Hz); 7.30-7.45 (m, 6H); 7.48-7.54 (m, 4H);8.30 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].[H][H].[CH:22](=O)[CH3:23]>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH:22][CH3:23]
Reactant: [H][H]
Reactant: CC=O
Reactant: CCCCC(C(=O)OC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC=C(CCCC)C(=O)OC
Temperature: -30 °C
Yield: 25 %

Procedure:
To 2-(diethylphosphono)hexanoic acid methyl ester (53.2 g, 0.2M) in dry tetrahydrofuran (300 ml) was added sodium hydride (5.3 g, 0.22M) under an atmosphere of argon at 0° C. with continuous stirring. The reaction was allowed to warm to room temperature over 1 hour when the evolution of hydrogen had ceased. The reaction was then cooled to -30° C. and acetaldehyde (30 g, 0.66M) added dropwise to the continuously stirred solution over 10 minutes. The reaction was allowed to warm to 20° C. over 16 h and then concentrated in vacuo to a gum which was dissolved in ether. The etherial solution was washed with aqueous saturated sodium hydrogen carbonate, dried over sodium sulphate and concentrated in vacuo. Vacuum distillation of the resulting gum afforded E and Z 2-(butyl)-but-2-enoic acid methyl ester (7.8 g) B.p. 50°-60° C. at 0.8 mm Hg (Found: C, 65.0; H, 10.1 C9H16O 2 +0.5 H2O requires: C, 65.4; H, 10.4%); δ(CDCl3) 0.84 (3H, t, J=8 Hz, CH3CH2); 1.34 (4H, m, 2×CH2); 1.8 and 1.96 (3H each d, each J=7 Hz, CHCH); 2.32 (2H, m, CH2 --C); 3.72 and 3.74 (3H, each s, CH3O); 5.96 and 6.84 (1H, each q, each J=7 Hz, CH).
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:22][Mg]Br>C1COCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:20])[CH3:22])=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous THF (200 mL) at 0° C. was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol). After stirring at 0° C. for 2 h, the reaction was quenched with MeOH (5 mL) and 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2×200 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compoun, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H), 2.90 (dd, 1H), 2.03 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:7]([CH3:19])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])C.[OH-].[K+]>O.C(O)C>[CH3:19][C:7]1[C:6]([CH2:5][C:4]([OH:20])=[O:3])=[C:10]([CH3:11])[N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:8]=1
Reactant: CCOC(=O)Cc1c(C)nn(-c2ccc(C)cc2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C)c(CC(=O)O)c2C)cc1
Yield: 81.6 %

Procedure:
8.2 grams of the 3,5-dimethyl-1-(p-tolyl)pyrazol-4-acetic acid-ethyl ester, produced by the method of Example (4a), were mixed with a solution of 2.5 grams potassium hydroxide in 15 milliliters water and 15 milliliters ethanol, and the ester saponified and the free acid isolated by the method described in Example (1b). 6.0 grams of 3,5-dimethyl-1-(p-tolyl)-pyrazol-4acetic acid, melting at 119°-121° C. were obtained, representing a yield of 82%.
Reaction SMILES: BrC1C=CC(O)=C(C(=O)C)C=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:41]2[CH:42]=[CH:43][CH:44]=[C:45]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:23]=3)[CH:46]=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: CC(=O)c1cc(Br)ccc1O
Product: CCOC(=O)c1cncc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1

Procedure:
Following the procedure of Example 23 but substituting N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide for 5′-bromo-2′-hydroxyacetophenone and ethyl 5-bromonicotinate for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide the title compound was obtained as a beige solid.
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[CH:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40].[Cl-].[Na+].[CH3:51]N1CCCC1=O>>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:23]=[CH:22][C:21]([OH:25])=[CH:20][C:19]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:28][N:29]([CH3:51])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:47])([F:48])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42]
Reactant: CN1CCCC1=O
Reactant: CNCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2O
Agent: [Cl-]
Agent: [Na+]
Product: CN(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 466 mg of 7α-(5-bromopentyl)-11β-fluorooestra-1,3,5(10)-triene-3,17-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred at a bath temperature of 80° C. for 3 hours with 1.0 g of methyl-(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amine. For work-up, the mixture is added to saturated sodium chloride solution, extracted with ether, dried over sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel using ethyl acetate/methanol. 546 mg of 11β-fluoro-7α-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-oestra-1,3,5(10)triene-3, 17β-diol are obtained as a foam, [α]D=+39° (c=0.5 in CHCl3)