Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:22].FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:11]([OH:13])=[O:12])[C:6]1=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2O)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2O)C1=O

Procedure:
A solution of Example 145B (0.127 g, 0.35 mmol) in dichloromethane (1.75 mL) was treated with trifluoroacetic acid (1.75 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was azeotroped twice with ethyl acetate to give crude material which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1COCC1.[CH2:19]([NH2:21])[CH3:20]>ClCCl>[CH2:19]([NH:21][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:20]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Alternatively, 2-chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with Amberlyst A-21 ion-exchange resin (17 g) was treated with a 2M THF solution of ethylamine (45 mL). The mixture was stirred at rt under nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CCCC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-(1-(tert-butoxycarbonyl)-4-(methoxy-carbonyl)piperidin-4-yl)butanoic acid (23.4 g, 0.071 mol) from Step D in 3:1 dichloromethane/methanol (480 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (53 mL, 0.11 mol, 2.0M in hexane). The reaction mixture was stirred for 15 min and then concentrated to afford 25.5 g. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (20.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:22])[CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN1C(C)(C)CC(Nc2ccc(Cl)nn2)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(Cl)nn1)C1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-5, (4.0 g, 14.1 mmol) in DMF (140 mL) cooled to 0° C. was added 60% wt NaH (735 mg, 18.39 mmol) portionwise. The reaction was warmed to RT and stirred for 60 minutes. After 60 minutes methyl iodide (0.88 mL, 14.1 mmol) was added and the reaction was stirred an additional 3 h, then slowly quenched with water at room temperature. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 6-chloro-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-4 (3.98 g). The crude material was carried on without further purification. LCMS Rt=1.16 min (condition B), MS (M+1)=297.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 (d, J=9.6 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 4.79-5.00 (m, 1H), 2.86 (s, 3H), 2.22 (s, 3H), 1.61-1.73 (m, 2H), 1.48-1.57 (m, 2H), 1.14 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25].O>C1C=CC=CC=1>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH:23]([OH:22])[CH2:24][NH:25][CH:2]([CH3:4])[CH2:1][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(COc2ccc(CC(C)=O)cc2)o1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(COc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxymethyl]furan-2-carboxylate (1.76 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.05 g) in dry benzene (100 ml) was heated under reflux with azeotropic removal of water, for 2 hr. The solvent was evaporated and sodium borohydride (2 g) added, in portions, to a stirred solution of the residual oil in methanol (80 ml) with cooling in ice. The mixture was stirred at ambient temperature for 3 hr. the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with methanol:chloroform (4:96) gave an oil which was crystallised from n-hexane to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]furan-2-carboxylate, m.pt 75°-86° C., as a 19:81 mixture of diastereoisomers. The mother liquor was evaporated; crystallisation from Petroleum ether (60:80)--ether gave a second crop, m.pt. 75°-83° C., as a 55:45 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 67.1 %

Procedure:
A mixture of methyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A3) (14.28 g, 1 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (19.6 g, 0.85 equiv), DCE (300 ml), acetic acid (3.8 ml, 0.90 equiv) and sodium triacetoxyborohydride (20.7 g, 1.25 equiv) was stirred at room temperature under nitrogen for 17.5 h. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 4 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, dried over sodium sulfate and filterered through a pad of silica gel which was rinsed with 2.5% methanol in DCM. After evaporation in vacuo, the crude product was crystallised from ether/hexane, finally at ice bath temperature, which after drying yielded a white solid (20.9 g).
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3].[H][H]>[Pd].C(O)(=O)C.CO>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NNC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH2:12]1.Cl>ClC=CCl>[C:5]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[S:13][CH2:12][CH:11]([CH3:10])[CH2:20]2)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: CC1CSc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CC(C)CS2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.13M of AlCl3, 0.12M of propionyl chloride in 150 ml of 1,2-dichloroethylene, 0.1M (16.4 gr.) de 3-methyl-thiochromane are dropwise added at a temperature of ±5° C. After agitating the mixture for 3 hours at room temperature, a mixture of ice and HCl is added and extraction is made with CHCl3. The organic phase is dried on MgSO4, filtered and evaporated. 17.3 gr. of 6-propionyl-3-methyl thiochromane are so obtained, the homogeneity of which is verified by TLC and the structure of which is verified by NMR spectrum.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:2].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccccc1CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccccc1C=O
Yield: 18652 %

Procedure:
24.0 g (0.15 mole) of 2-formylphenylacetic acid and 0.1 g of p-toluenesulfonic acid in 250 ml of methanol are refluxed for 2 hours. Thereafter, the solution is evaporated down, the residue is taken up in diethyl ether and the solution is washed with dilute HCl. The organic phase is separated off, dried over MgSO4 and evaporated down. The residue is purified by distillation (90° C., 0.4 mbar). 19.3 g (74%) of methyl 2-formylphenylacetate are obtained as a colorless liquid in this manner.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=O.[Na+].[BrH:18]>O.C(OCC)C.[Cu]Br>[Br:18][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Br
Reactant: CCOC(=O)c1cc(N)ccc1C
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(Br)ccc1C
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A mixture of ethyl 5-amino-2-methylbenzoate (1.50 g, 8.3 mmol) in 48% HBr (12 mL) and water (24 mL) was cooled with an ice-bath for 15 min. Sodium nitrite (0.59 g, 8.6 mmol) was then added dropwise as a solution in water (2 mL), and the resulting mixture stirred for 5 min. After this time, the mixture was added to an ice-cold mixture of copper (I) bromide (1.40 g, 9.90 mmol) in 48% HBr (5 mL) and water (12 mL). The resulting mixture was heated to 70° C. for 1 h. After this time, the reaction mixture was cooled to room temperature and diluted with diethyl ether (150 mL). The organic layer was washed with 1 N hydrochloric acid (50 mL), water (50 mL), and brine (50 mL) then dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 1-10%, hexanes/ethyl acetate) afforded 1.4 g (69%) of ethyl 5-bromo-2-methylbenzoate as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.2, 2.2 Hz, 1H), 7.12 (dd, J=8.2 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ESI MS m/z 404 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[S:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[O:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:15])([CH3:16])[C:7]2=[O:17])[CH2:3]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@@H](O)C2)c2nccnc21
Reactant: Oc1nc2ccccc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)N([C@H]2C[C@H](Oc3nc4ccccc4s3)C2)c2nccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-(cis-3-hydroxycyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.022 g, 0.094 mmol), triphenylphosphine (0.030 g, 0.113 mmol), 2-hydroxybenzothiazole (0.017 g, 0.113 mmol) in THF (2 mL) at 0° C. was added DIAD (0.028 mL, 0.141 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, purified by reverse phase HPLC. The pure fractions were concentrated to minimal H2O, neutralized with saturated aqueous NaHCO3, and the off white solid was collected and dried (18.5 mg, 53.5%). MS (M+1):367.1. 1H NMR (400 MHz, MeOH) δ ppm 8.20 (1 H, d, J=3.1 Hz), 8.15 (1 H, d, J=3.1 Hz), 7.76 (1 H, dd, J=7.9, 0.7 Hz), 7.66 (1 H, d, J=7.6 Hz), 7.39 (1 H, td, J=7.8, 1.3 Hz), 7.19-7.34 (1 H, m), 5.79 (1 H, dt, J=7.0, 3.5 Hz), 5.25-5.42 (1 H, m), 3.40-3.56 (2 H, m), 2.68-2.86 (2 H, m), 1.38-1.50 (6 H, m). MS (M+1):367.1.
Reaction SMILES: [Na+].Cl[Au-:3](Cl)(Cl)Cl.OCCSCC.[SH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]>O>[SH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17].[Au:3]
Reactant: Cl[Au-](Cl)(Cl)Cl
Agent: CCSCCO
Agent: O=C(O)CNC(=O)CCS
Agent: [Na+]
Solvent: O
Product: [Au]

Procedure:
A solution of sodium tetrachloraurate (35 g) in distilled water (200 ml) was slowly added to a solution of ethyl 2-hydroxyethyl sulphide (20.5 g) in distilled water (200 ml). Solid addition of mercaptopropionylglycine (5.21 g) followed by vigorous stirring yielded gold mercaptopropionylglycine as a white solid (yield, based on gold, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][C:6]1=[O:14].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)(=[O:25])=[O:24])[C:6]1=[O:14]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(C)CCn1c(=O)[nH]c2cccnc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2cccc(F)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (20 mg, 0.10 mmol) in THF at room temperature is treated with 3-fluorophenyl-sulfonyl chloride (26 mg, 0.12 mmol), followed by diisopropylethylamine (25 μL, 0.20 mmol) and DMAP (5 mg), stirred at room temperature for 12 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 365, retention time (RT) 2.54 minutes. 1HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formic acid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH2:17])[CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:24]1)=[O:18]
Reactant: C=C(C(=O)OC)C(F)CCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Reaction time: 8 h

Procedure:
A solution of 500 mg (2.0 mmol) of β-fluoro-α-methylenebenzeneheptanoic acid methyl ester in 50 ml of 1,2-dichloroethane is treated with 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol). The mixture is heated to reflux and maintained under nitrogen for 10.5 hours. An additional 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol) is added and reflux is continued for 8 hours.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:23]=[C:24]([Mg]Br)[CH:25]=[CH:26][CH:27]=1.BrC1C=C(COC2CCCCO2)C=CC=1>C1COCC1>[OH:1][CH:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:21][O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:27]=1)[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Br[Mg]c1cccc(COC2CCCCO2)c1
Reactant: O=CCCc1ccccc1C(=O)O
Agent: Brc1cccc(COC2CCCCO2)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CCC(O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At -10° C., a solution of the aldehyde of Step 4 (5.045 g, 28.3 mmol) in 50 mL of THF was added dropwise to 0.57M 3-((2-tetrahydropyranyloxy)methyl)phenylmagnesium bromide in THF (120 mL, 68.4 mmol, prepared from the bromide of Step 2 and Mg in THF and filtered to remove the excess of Mg) and the mixture as stirred at r.t. for 30 min. At 0° C., 25% aq NH4OAc was added. The title product was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using acetone: toluene: HOAc 5:95:1 and 15:85:1.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:23]([O-])=[O:24].[Na+]>C(OC(=O)C)(=O)C>[N:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:24]
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of N-benzyl-p-toluenesulphonamide (21 g, 80 mmol) and acetic acid (100 ml) in acetic anhydride (400 ml) was added solid sodium nitrite (120 g, 1.7 mol) in portions over a period of 12 hours at 5° C. The temperature was kept below 10° C. all the time. After the addition was finished the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured over an excess of ice water and stirred for 1 hour. The pale yellow precipitate was filtered and washed several times with water. The crude product was recrystallized from ethanol to give the title compound as a tiny yellow needles (19.1 g, 82% yield, m.p. 92°-93° C., (Lit.1 89°-90° C.). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(2H,s); 2.40(3H,s)ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH2:28])=[N:9]1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH:28][C:35]([C@H:32]2[CH2:31][C:30](=[O:29])[NH:34][CH2:33]2)=[O:36])=[N:9]1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2F)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2F)c1)C(F)(F)F
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared in Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19](=[O:30])[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[C:21]=1F)[C:14]([O:16]CC)=[O:15])C>C(O)C>[F:26][C:24]1[CH:25]=[C:20]2[C:21](=[C:22]([F:28])[C:23]=1[F:27])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:19]2=[O:30]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 97.9 %

Procedure:
5.7 g of 4-fluoroaniline are added dropwise to a solution of 16 g of ethyl 3-ethoxy-2-(2,3,4,5-tetra-fluorobenzoyl)-acrylate (5) (X1 --X4 =F) (Appln. Ser. No, 756,469, filed July 18, 1985, now Pat. No. 4,952,695) in 50 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 50 ml of ice-water are added and the precipitate is filtered off cold with suction, rinsed with water and dried at 50° C. over calcium chloride in vacuo. 16.5 g of (6) (R=4-fluorophenyl, X1 --X4 =F) of melting point 93°-95° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.Cl.[N:15](OCCC(C)C)=[O:16]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:15]=[O:16]
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(N)c1N=O
Reaction time: 4 h

Procedure:
To a solution of 17.3 g (0.1 mol) of 5-amino-3-methyl-1-phenylpyrazole in 200 cm3 of absolute ethanol were added dropwise 0.5 cm3 of 12 N hydrochloric acid and then 13.5 cm3 of isoamyl nitrite, at 0° C. The solution was then warmed to and left at room temperature for 4 hours. An orange-coloured solid crystallized out. This solid was filtered off on a sinter funnel and washed with 100 cm3 of isopropyl ether. After drying under vacuum at room temperature, 17 g of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole were obtained in the form of an orange-coloured solid, the melting point of which was from 202 to 204° C.