Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[N:20]=[C:19]([C:21](OCC)=[O:22])[O:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[N:20]=[C:19]([C:21]([N:37]3[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:39][CH2:38]3)=[O:22])[O:18][N:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: C1CCN(CCC2CCNCC2)C1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)N3CCC(CCN4CCCC4)CC3)n2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.08 mmol), 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (29 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:25]([C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCC
Product: CCCCC#Cc1nc(N)c2nc(NCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-propylaminoadenosine (9, 68 mg, 0.15 mmol) and 1-hexyn (0.73 mmol). The mixture was purified by column chromatography (EtOAc-10% MeOH in EtOAc). Yield 49 mg (0.12 mmol, 80%), mp 184–186÷C; Rƒ 0.60 (10% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 6.98 (t, 1H, J=5.15 Hz, NH), 6.54 (bs, 2H, NH2), 5.87 (d, 1H, J=7.55 Hz, H-1′), 5.75 (t, 1H, J=4.46 Hz, OH-2′), 5.26 (d, 1H, J=6.86 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.55 (q, 1H, J=6.86 Hz, H-2′), 4.06 (m, 1H, H-3′), 3.96 (bs, 1H, H4′), 3.61 (bs, 2H, H-5′), 2.49 (m, 2H, NHCH2), 2.36 (m, 2H, ≡CCH2), 1.60–1.42 (m, 6H, NHCH2CH2CH3, CH2CH2), 0.89 (t, 6H, J=7.55 Hz, 2×CH3); MS m/z 405 (M+H)+; Anal. (C19H28N6O4) C, H, N.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)c(F)c1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Yield: 103.6 %

Procedure:
The title compound (D128) (100 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3,4-Difluorophenol (44.06 mg, 0.338 mmol).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.CC(C)([O-])C.[K+].CS>O.CN(C)C=O>[CH:16]1[C:3]2[CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][C:15]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Agent: CC(C)(C)[O-]
Agent: CS
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Reflux 4.4 gm. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate with 20 ml. of thionyl chloride for 10 minutes. Evaporate excess thionyl chloride and dissolve the residue in 30 ml. of dimethylformamide. Add the mixture to a solution of 3.84 gm. of potassium tert-butoxide in 75 ml. of dimethylformamide saturated with methanethiol. Stir at room temperature for 24 hours, dilute with water and extract with ether. Evaporate to dryness and chromatograph over silica gel, eluting with toluene. Evaporate to dryness to obtain the title product as an oil (yield 3.03 gm., 84%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH2:16][CH3:17])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH2:16][CH3:17])[C:7]=2[N:8]=1)[CH:19]=[CH2:20]
Reactant: C=CCNc1nc(Cl)nc2c(CCC)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(CCC)c2n1
Yield: 56.6 %

Procedure:
189 mg (0.71 mmol) of 4-allylamino-2-chloro-7-propylthieno[3,2-d]pyrimidine and 644 mg (11.3 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 116 mg (yield: 56.9%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>CCO>[Cl:20][C:3]1[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reactant: OB(O)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3ccccc3)cnc21
Temperature: 80 °C
Yield: 87.1 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (3.70 g, 9.96 mmol, see Example 6) and phenylboronic acid (1.27 g, 10.5 mmol) were placed in 2:1 toluene:EtOH (30 mL). The contents were then degassed under Ar and heated to 80° C. for 24 hours. The reaction was cooled to room temperature, diluted with DCM, and poured into water. The organic fraction was filtered, dried, and concentrated. Purification was carried out by column chromatography (1:1 to 1:2 hexane:DCM) to give 4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.20 g, 87.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]([F:28])([F:27])[C:24](O)=[O:25]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]([F:28])([F:27])[F:22])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(F)(F)F)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and trifluoroacetic acid (28.5 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)trifluoracetamide. NMR; δH [2H6]—DMSO 11.25,(1H, s), 8.62,(1H, t), 7.92,(2H, d), 7.60,(1H, dd), 7.55,(1H, d), 7.43,(2H, d), 7.34,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.29 min, MH+377.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.CN.[C:29]([BH3-])#[N:30].[Na+]>CO.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([C:6]2[CH:5]=[C:4]([CH:1]([NH:30][CH3:29])[CH3:2])[CH:15]=[CH:14][C:7]=2[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH:20][CH:19]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)COc1ccc(C(C)=O)cc1-c1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 108.9 %

Procedure:
To a solution of methyl 2-(4-acetyl-2-(3-trifluoromethylphenyl)phenoxy)acetate (17) (529 mg, 1.5 mmol, 1 eq) in MeOH (5 mL) was added methylamine hydrochloride (603 mg, 9.0 mmol, 6 eq) and sodium cyanoborohydride (93 mg, 1.5 mmol, 1 eq). The reaction mixture was stirred at room temperature for 8 days, diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to give crude compound methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) as white solid (600 mg) which was carried directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15]C)=[O:13].Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH:26]([OH:31])[C:27](=N)OC.O>C(O)C>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:27]([CH:26]([C:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[OH:31])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)CCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a stirred solution of ethyl N-(2,6-diaminophenyl)-beta-alaninate (4.11 g, 18.4 mmol) in ethanol (36.8 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was poured into water (120 mL). The resulting solid was collected by filtration and washed with ethyl acetate to afford the desired product as colorless solid (6.77 g, 16.6 mmol, 90%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[NH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:8]=1
Reactant: FC(F)(F)CN=C(Cl)c1ccc(Cl)cc1
Reactant: C=C(Cl)C(=O)OC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A solution of N-(2,2,2-trifluoroethyl)-4-chloro-benzimidoyl chloride (10.2 g, 0.04 mol) and methyl 2-chloroacrylate (5.8 g, 0.048 mol) in N,N-dimethylformamide is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DEU, 19.5 g, 0.128 mol) over 30 minutes at such a rate that the temperature is kept at 40° C., stirred for two hours, and quenched with water and ethyl acetate. The organic layer is separated, washed sequentially with aqueous HCl and water, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 20% ethyl acetate in heptane solution and crystallization from heptane gives the title product as white crystals (4.2 g, 34.6% yield, mp 120.0-122.5° C.).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>CC(C)=O.O>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][CH:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:16]
Reactant: CSCCC(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSCCC(NC(=O)c1ccccc1F)C(=O)O

Procedure:
To a clear solution of D,L-methionine (10 g, 67.02 mmol) and NaOH (4.0 g, 100.53 mmol) in acetone (100 ml)/ H2O (100 ml) was added 2-fluorobenzoyl chloride dropwise with stirring between each addition. Basicity was maintained by adding 2N NaOH when necessary. After addition was completed, the reaction mixture was acidified to pH 2 with 6N HCl and extracted into EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated to give provide 2-(2-fluorobenzoylamino)-4-methylsulfanyl-butyric acid (intermediate XIIa, 13.6 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH2:18][CH3:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:18]([C:10]1[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)[CH3:19]
Reactant: CCc1nn2ccccc2c1-c1cc(F)cc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 103.8 %

Procedure:
3-(3,5-Difluorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (0.48 g, 1.8 mmol), N-bromosuccinimide (0.55 g, 3.1 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) were stirred in carbon tetrachloride (20 mL). The mixture was heated to reflux for 2 hours. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane, washed with water, saturated aqueous sodium sulfite, aqueous sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and concentrated to give the desired compound (0.63 g, 100%). LCMS for C15H12BrF2N2 (M+H)+: m/z=336.8, 338.8. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (m, 1H), 7.70 (m, 1H), 7.30 (m, 4H), 7.02 (m, 1H), 5.63 (m, 1H), 2.17 (m, 3H).
Reaction SMILES: [S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([O-:20])=O)(=[O:3])=[O:2].[NH2:21]O.Cl>CN(C=O)C>[S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([NH2:21])=[O:20])(=[O:2])=[O:3]
Reactant: O=C([O-])[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Step 5—Formation of N-hydroxy-1-[4-(4-fluorophenoxy) phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carbox-amide Methyl 1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate (1.11 g, 2.2 mmol) was dissolved in DMF (17 mls) to which was added 50% aqueous NH2OH (20 mls) and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into cold 1.0N HCl (100-120 mls) and extracted with EtOAc (4×). The combined EtOAc extractions were washed with 10% aqueous LiCl (4×), saturated NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc) and the resulting pure oil was dissolved in 1:1 acetonitrile:water and lyophilized to give N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxamide as a white solid (659 mg, 59%). LC/MS Calcd for [M+H]+ 509.1. found 509.1. 1HNMR (400 MHz, CD3OD): δ 7.69 (d, 2H, J=9.2 Hz), 7.04 (m, 4H), 6.95 (d, 2H, J=9.2 Hz), 4.30 (m, 1H), 3.76 (m, 1H), 3.50 (m, 7H), 3.10 (m, 4H), 2.90 (dd, 1H, J=13.2, 4.4 Hz), 2.72 (m, 1H).
Reaction SMILES: [ClH:1].[N:2]([O-])=O.[Na+].[NH2:6][C:7]1[N:11]([CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:23]1[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:2][N:6]=[C:7]2[N:11]([CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:10]=[C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:8]=12
Reactant: O=N[O-]
Reactant: Cl
Reactant: CC(C)(O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1N
Agent: [Na+]
Product: CC(C)(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To cooled (cooling bath −15° C.) conc. HCl (9 mL) was added sodium nitrite in one portion (121 mg, 1.75 mmol) and the suspension was left to stir for 10 min after which 1-(5-amino-3-phenyl-4-(phenylethynyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (290 mg, 0.88 mmol) was added. After 5 min, the cooling bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction was cooled again (0° C.) and DCM was added followed by water. The aqueous phase was extracted with DCM and the organic phases were combined, dried over MgSO4, filtered and evaporated. Crude material was purified by column chromatography (silica gel, gradient 0 to 50% ethyl acetate/isohexane) yielding 1-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-2-methylpropan-2-ol as an orange oil (56 mg). The material obtained was further purified by preparative HPLC, yielding 34 mg of Compound 85 as a solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])[CH2:14][CH2:13]1)=[O:10])C.O[Li].O.Cl>C1COCC1.O.CCOC(C)=O>[Cl:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([Cl:29])[CH:25]=1)[CH2:21][O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[CH2:13][CH2:14]1)=[O:19]
Reactant: CCOC(=O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3,5-dichlorobenzyl 4-(6-ethoxy-6-oxohexanamido)piperidine-1-carboxylate (step 1) (130 mg, 0.283 mmol) in THF (3 mL)/water (1 mL) was added LiOH.H2O (26.1 mg, 0.623 mmol) and the reaction mixture stirred at RT for 3 hrs. The resulting mixture was diluted with water and EtOAc and the aqueous portion acidified with 0.1 M HCl solution (pH 5-6). The resulting precipitate was collected by filtration and washed with water to afford the title product;
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)[C:7]#[CH:8].C([OH:20])(C)C.O>CC(C)=O.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:20])=[O:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]
Reactant: CC(C)O
Reactant: C#CCC1CCC(CO)CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of chromium trioxide (600 mg, 6.0 mmol) in 1.5 M H2SO4 (2.6 mL, 150 mmol) was cooled to 5° C. and added to a solution of 86 (280 mg, 1.84 mmol) in acetone (15 mL). The mixture was allowed to warm to room temperature and allowed to stir overnight. Isopropanol (4 mL) was added to the green/black solution, which turned light blue after 1 hr. After adding water (15 mL), the solution was extracted with CHCl3 (6×25 mL). The organic layers were pooled and concentrated in vacuo to yield a white solid. The solid was dissolved in ether (50 mL) and extracted with 1 M NaOH (2×30 mL). The basic extracts were pooled, acidified w/10% HCl, and re-extracted with ether (3×30 mL). The ether layers were combined, dried with sodium sulfate and concentrated in vacuo to yield a white solid. The product was recrystallized from acetone/water to yield 88 (222 mg, 73%) as white needles: mp 84-85° C.; 1H NMR (CDCl3) δ 2.30-2.23 (m, 1H), 2.17-2.11 (m, 2H), 2.07-2.03 (m, 2H), 1.97-1.91 (m, 3H), 1.51-1.39 (m, 3H), 1.13-1.01 (m, 2H); 13C NMR (CDCl3) δ 182.5, 83.8, 69.6, 40.7, 37.7, 32.3, 29.6, 26.5; APCI m/z (rel intensity) 165 (M−, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([C:8]([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=3)[CH2:24][CH2:25][CH2:26]2)=[O:10])=[CH:11][C:12]([F:15])=[CH:13][N:14]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1
Reactant: Cc1ccc2c(c1)CCCN2
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)cnc1Oc1ccc(F)c(Cl)c1)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(3-chloro-4-fluoro-phenoxy)-5-fluoro-nicotinic acid and 6-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 401.0 [M+H]+.
Reaction SMILES: [S:1]([F:13])([O:4][C:5](F)(F)C(F)=C(F)F)(=[O:3])=[O:2].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=C(F)F.[B].B(OC)(OC)[O:25]C>>[C:15]([CH:16]([S:1]([F:13])(=[O:3])=[O:2])[F:20])([F:22])([F:21])[F:14].[C:5](=[O:4])=[O:25]
Reactant: COB(OC)OC
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [B]
Product: O=C=O
Product: O=S(=O)(F)C(F)C(F)(F)F

Procedure:
The starting material, perfluoroallyl fluorosulfate (FAF), CF2 =CFCF2OSO2F, may be prepared as described in U.S. Pat. No. 4,206,138 to D. C. England. England prepared FAF by reacting hexafluoropropylene with SO3 under anhydrous conditions in the presence of a small amount of a trivalent boron compound such as trimethyl borate at 0°-100° C. A possible byproduct is hexafluoropropylene sultone, ##STR2## which is difficult to separate from FAF by distillation. The sultone in the FAF mixture can be hydrolyzed with ice water to give CF3CFHSO2F+HF+CO2 (gas). This product, CF3CFHSO2F, is also difficult to separate from FAF by distillation, but it does not react with Br2 and can be separated from the Br2 adduct of FAF by distillation.
Reaction SMILES: BrC1C=C2C(=CC=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][CH3:25])[CH:18]=[CH:17]2>>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:5][CH2:6][C:7](=[O:12])[CH3:8])[CH:23]=[CH:22]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(CCC(C)=O)ccc2c1

Procedure:
The process of claim 1 which also comprises methylating the 6-bromo-2-naphthol to 6-bromo-2-methoxynaphthalene and then converting the 6-bromo-2-methoxynaphthalene thus obtained to 4-(6-methoxy-2-naphthyl)-2-butanone.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:14]#[N:15].[Cl-].[NH4+].N>C(OCC)(=O)C.O.CN1CCCC1=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]#[N:15])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1I
Reactant: N#C[Cu]C#N
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 190 were added copper cyanide (1.16 g) and N-methylpyrrolidone (21 mL) and the mixture was stirred at 60° C. for 1 hr. Under cooling with water, ethyl acetate, saturated aqueous ammonium chloride solution and aqueous ammonia were added and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated aqueous ammonium chloride solution and aqueous ammonia, once with saturated aqueous ammonium chloride solution and once with saturated brine, and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.39 g).