Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[NH+]1C=CC=C[CH:23]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: c1cc[nH+]cc1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
7.8 g of 11β-fluoro-estr-4-ene-3,17-dione is stirred in 40 ml of 2,2-dimethoxypropane with 780 mg of pyridinium-toluene-4-sulfonate for 5 hours at 80° C. Then, 1.5 ml of triethylamine is added, it is diluted with ethyl acetate and washed with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 11β-fluoro-3-methoxy-estra-3,5-dien-17-one with a melting point of 173° C. is obtained.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: OB(O)c1cccnc1Cl
Product: Clc1ncccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(2-Chloro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-chloro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (48 mg, 40%). LCMS (m/e) 407 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.50-8.44 (m, 1H), 8.23 (d, 1H, J=7.6 Hz), 7.43 (d, 2H, J=7.8 Hz), 7.41-7.34 (m, 1H), 7.10-7.05 (m, 1H), 6.88-6.80 (m, 3H), 6.67 (s, 1H), 3.91-3.82 (m, 4H), 3.13-3.06 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:44][CH3:45])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[CH:28]3)[CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=O)[CH3:8].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C1(C)C=CC=CC=1.O.[OH-].[Na+]>[CH2:44]([N:9]([CH2:10][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[CH:28]3)[CH2:25][CH2:26]2)=[CH:14][CH:13]=1)[CH2:7][CH3:8])[CH3:45]
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3cnc4ccccc43)CC2)c2cccc(OC)c2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccc(C(CCN2CCC(n3cnc4ccccc43)CC2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A suspension of lithium aluminum hydride (9.7 mg) in tetrahydrofuran (0.3 ml) was added with a solution of the 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxy-phenyl)propyl]-4-(1H-benzimidazol-1-yl)piperidine (67.1 mg) obtained in Example 11 dissolved in toluene (1.2 ml) and stirred at room temperature for 18 hours. The reaction mixture was added with one drop of water and one drop of 5 N aqueous sodium hydroxide and further stirred at room temperature for 1 hour. The reaction mixture was added with anhydrous magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure to obtain 64.9 mg of the title compound. Yield: 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Temperature: 70 °C
Reaction time: 14 h
Yield: 34.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-[1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazol-4-yl]-ethanone (270 mg, 719 mol), 3-methylsulfonylphenyl boronic acid (220 mg, 1.08 mmol), PdCl2 dppf (55 mg, 10 mol %), K2CO3 (300 mg, 2.16 mmol), 1,2-dimethoxyethane (11 mL) and H2O (1 mL). The reaction solution was allowed to stir at 70° C. for 14 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4 Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 75% EtOAc to afford 170 mg (52% yield) of product. MS (ES): 451 [M+H]+, 473 [M+Na]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16](C(O)=O)[C:17]([OH:19])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1>CCCCCC>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(C(=O)O)C1c2ccccc2CCc2ccccc21
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(O)CC1c2ccccc2CCc2ccccc21
Reaction time: 0.5 h

Procedure:
200 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonic acid are heated to 180° while stirring for 30 minutes. After cooling to 120°, the residue is treated with about 1 l of benzene and heated to boiling while stirring and under reflux until all crystallized-out material has again dissolved. Subsequently, the mixture is treated with 500 ml of hexane, cooled to about 10° while stirring and while cooling with ice, left to stand in the cold overnight and subsequently the crystal slurry obtained is removed by filtration under suction. After washing with petroleum ether and drying at 50° in a vacuum drying oven, there is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid as beige crystals of melting point 163°-165°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH2:14])=[CH:12][N:11]([CH3:15])[N:10]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33](Cl)=[O:34])=[C:26]2[N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33]([NH:14][C:13]3[C:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][N:11]([CH3:15])[CH:12]=3)=[O:34])=[C:26]2[N:25]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cn1cc(N)c(-c2cc(Cl)ccc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cc(Cl)ccc2Cl)n1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To an ice-cooled solution of 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-amine (121 mg, 0.50 mmol) and triethylamine (101 mg, 1.00 mmol) in dichloromethane (15 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (162 mg, 1.5 mmol). The reaction mixture was warmed to room temperature for 3 hours. The mixture was then washed with saturated aqueous sodium chloride solution. The collected organics were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a solid (110 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): 9.34 (d, J=7.6 Hz, 1H), 9.21 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH2:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(C(C)C)C(C)C)C.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:40])([F:41])[F:42])[C:27]=1[C:28]([NH:14][C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:29]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: CN1CCCC(N)(c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a solution of 205 mg (1.077 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) and 369 ul (2.154 mmol) N-ethyldiisopropylamine in dichloromethane (2.5 ml) was added dropwise a solution of 430 mg (1.4 mmol) 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5) in dichloromethane (2.0 ml) at room temperature. The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 340 mg (69%) of the title compound as a light yellow foam. MS (m/e): MS (m/e): 461.4 (M+H).
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.[H][H]>C(OCC)(=O)C.N1C=CC=CC=1.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@H](C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12

Procedure:
5.0 g of this colorless oily substance, i.e., (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran, was dissolved in a mixed solvent of 100 ml of ethyl acetate and 3 ml of pyridine, and after 150 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere of 1 atm. After the catalyst was filtered by celite, extraction was carried out by adding100 ml of ethyl acetate to the reaction mixture solution. The organic layer was washed with 100 ml of 2N hydrochloric acid solution and saturated sodium chloride solution, and was then dried by magnesium sulfate. After filtration, the solvent was distilled off under a reduced pressure, and a colorless oily substance was obtained (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4,7-dimethylcyclopenta[c]pyran.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][C:19]1[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:17]1[CH:16]=[C:15]([CH:29]=[CH:28][CH:27]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2cccc(CO)c2)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3cccc(C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.396 g, 2.20 mmol), [3-(3-methylphenoxy)phenyl]methanol (0.429 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions, the temperature was raised to room temperature and the mixture was stirred for 18 hrs. Hexane (15 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-20% ethyl acetate/hexane) and preparative HPLC (10-95% acetonitrile/water, containing 0.1% trifluoroacetic acid) to give the title compound (0.414 g, yield 55%) as a pale-yellow oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:25][CH2:24][CH2:23][C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1.C([BH3-])#N.[Na+].O>C(O)C.ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:21]([O:20][C:18]([C@@H:17]1[CH2:23][CH2:24][CH2:25][N:15]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:16]1)=[O:19])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (12.40 g, 62.2 mmol) and (R)-ethyl nipecotate (1.05 eq, 65.3 mmol, 10.27 g) was added titanium tetraisopropoxide (1.25 eq, 23 mL) under nitrogen. A viscous, clear golden yellow solution was formed. After 1 h a solution of sodium cyanoborohydride (0.7 eq, 2.74 g) in anhydrous ethanol (65 mL) was added. An exothermic reaction took place and some gas evolution occurred. The solution was stirred overnight at ambient temperature then water (13 mL) was added slowly, along with additional ethanol as necessary to permit stirring to continue. The mixture was stirred for 30 minutes then filtered through a large pad of Celite®, washing through with ethanol. The filtrate was evaporated to dryness, toluene added and again evaporated to dryness. The residue was purified by chromatography on 150 g silica gel eluting with 5% methanol-dichloromethane. Fractions containing product were combined and evaporated to dryness to give an oil which became semi-solid on standing. The product was dissolved in dichloromethane, washed with dilute sodium hydroxide solution to remove titanium-containing impurities, dried over anhydrous sodium sulfate and evaporated to yield the title compound as a colorless oil, 21.14 g (containing a small amount of the isopropyl ester from transesterification).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:31][CH:30]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:39]=[C:28]([C:29]4[CH:30]=[CH:31][C:32]([S:35]([NH2:36])(=[O:37])=[O:38])=[CH:33][CH:34]=4)[N:27]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/hexane) as a light yellow solid (159 mg, 59%). MS (ISN) 535.3 [(M−H)−]; mp 283° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][CH2:23][O:24]C2CCCCO2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[OH:32])[CH:3]=1.C(O)(=O)C.O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][CH2:23][OH:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[OH:32])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CCOC2CCCCO2)c2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCO)c2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Temperature: 40 °C
Yield: 50.8 %

Procedure:
To 0.479 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxy-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzenesulfonamide dissolved in 4.7 ml of THF are added 9.15 ml of acetic acid and 2.25 ml of water, and the mixture is maintained at 40° C. for 48 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a cyclohexane/ethyl acetate solvent mixture to give 0.209 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:23][CH3:24])[C@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]4.C(=O)([O-])[O-].[K+].[K+].[N:31]#CBr>C(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:23][CH3:24])[C@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:31]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Yield: 99.9 %

Procedure:
To a solution of 3,14-dimethoxy-8α,17-dimethylmorphinan-6-one (24) (0.1 g, 0.303 mmol) in methylene chloride (3 ml) was added anhydrous potassium carbonate (0.23 g) followed by cyanogen bromide (0.2 g). The mixture was refluxed overnight under a nitrogen atmosphere with stirring. After cooling, the solution was filtered and the residue washed with excess methylene chloride. The filtrate was concentrated under reduced pressure to give 0.103 g (99% theory) of 17-cyano-3,14-dimethoxy-8α-methylmorphinan-6-one (25) as a foamy solid. Examination by thin layer chromatography showed a single spot (silica gel plates; solvent system CHCl3 :MeOH, 90:10). The product was used in the next reaction without purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O.CNC>C1COCC1>[NH2:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([N:16]([CH3:17])[CH3:14])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 4-carboxybenzenesulfonamide (5 g; 24.8 mmol; 1 eq) in THF (75 mL) at 0° C. is added in one portion 1,1′-carbonyl diimidazole (4.8 g; 29.8 mmol; 1.2 eq) and the reaction mixture is stirred for 3 h at room temperature. A solution of dimethylamine (37.3 mL; 2 M; 74.6 mmol; 3 eq) in THF is added dropwise over 20 min and the reaction mixture is stirred at room temperature for 1 h. The solvent is removed under reduced pressure and the residue is diluted with EtOAc (100 mL) and the organic phase is washed with a 10% solution of NaHCO3 (30 mL). The white precipitate formed in the aqueous phase is filtered off, washed with water and dried under vacuum to afford 4.1 g (72%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.86 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (s, 2H), 3.00 (s, 3H), 2.88 (s, 3H). HPLC (max plot) 99%; Rt 1.07 min. LC/MS: (ES+): 229.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:19](O)=[O:20])[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:46]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:45]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)CC)C>ClCCl.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19](=[O:20])[NH:46][CH3:45])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C

Procedure:
To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 43, (1.0 g, 1.6 mmol) and PyBOP (1.1 g, 2.0 mmol) in anhydrous dichloromethane (10 mL) are added 2 M methyl amine solution in THF (0.9 mL, 1.6 mmol) and triethyl amine (0.6 mL, 3.9 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (100 mL) are added, the organic layer is decanted and the aqueous layer is extracted with EtOAc (3×75 mL). All organic layers are combined and washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo and purified over silica (EtOAc/Hexane, 1:1) to provide 1.0 g (quantitative yield) of the desired product. 1H NMR (CDCl3, 300 MHz): δ 7.72–7.50 (m, 4H), 7.29–7.14 (m, 4H), 7.10–7.04 (m, 2H), 7.00–6.97 (m, 3H), 5.60–5.51 (m, 1H), 4.73–4.66 (m, 1H), 4.30–4.11 (m, 1H), 3.45–3.26 (m, 2H), 3.15–3.05 (m, 1H), 2.86–2.79 (m, 3H), 2.75–2.59 (m, 5H), 2.56–2.47 (m, 1H), 2.43–2.29 (m, 1H), 2.05–2.01 (m,1H), 1.61 (s, 9H), 0.64–0.54 (m, 2); 13C NMR, (CDCl3, 75 MHz): δ 171.9, 170.3, 170.0, 155.0, 137.4, 137.2 135.3, 135.1, 133.6, 132.8, 132.2, 131.2, 131.1, 131.0, 128.7, 128.6, 128.4, 127.9, 127.8, 127.6, 127.5, 126.4, 126.0, 125.4, 124.7, 118.6, 110.4, 79.6, 69.9, 55.4, 50.9, 50.2, 46.4, 39.8, 37.9, 32.0, 32.6, 28.4, 26.5, 26.1, 23.0, 22.0, 10.6, 10.0.