Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](Cl)=[O:32])[CH:26]=1>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:27]5[CH:28]=[CH:29][CH:30]=[N:25][CH:26]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccnc1
Yield: 43 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and pyridine-3-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (89 mg, yield 43%) was obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[B:14](OC)([O:17]C)[O:15]C.Cl>C1COCC1.C(O)(=O)C>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([B:14]([OH:17])[OH:15])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)c(F)c1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc(B(O)O)c(F)c1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:30])[CH2:29][C:23]2=[C:24]([CH3:28])[S:25][C:26]([CH3:27])=[C:22]2[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:30][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][C:22]2=[C:26]([CH3:27])[S:25][C:24]([CH3:28])=[C:23]2[CH2:29]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (443 mg, 1.85 mmol), HATU (878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (88) as a pale yellow solid (599 mg, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:30]1[CH:29]=[N:28][CH:27]=[C:26]([F:25])[CH:31]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncc(F)c3)c2)c2ccccc21
Yield: 31 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 (Scheme #10, D) in 31% yield using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. 1H NMR (DMSO-d6) δ 8.63 (d, J=2.78 Hz, 1 H), 8.57-8.51 (m, 1 H), 8.50-8.42 (m, 2 H), 7.95-7.86 (m, 2 H), 7.85-7.78 (m, 1 H), 7.56-7.46 (m, 4 H), 7.36-7.27 (m, 3 H), 6.96 (br s, 2 H), 1.91 (s, 2.5 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[CH:12][CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: CC(C)(CO)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)Oc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a solution of 2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropan-1-ol (5.8 g, 15.6 mmol) in THF (23 mL) was added a solution of HCOOK (9.16 g, 10.9 mmol) in water (7.8 mL), followed by a catalytic amount of Pd/C (5%, 53%˜55% water content). The mixture was heated to 45° C. and stirred for 12 hours, and then filtered through a celite pad. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to afford a yellow foam solid. The title compound was purified by a silica gel chromatography (EtOAc/DCM=1/1) to give a light yellow solid (4.0 g, 75%).
Reaction SMILES: Cl.[CH:2]([NH:6][OH:7])([CH2:4][CH3:5])[CH3:3].C(=O)(O)[O-].[Na+].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>COCCOC>[C:13]1([NH:19][C:20]([N:6]([CH:2]([CH2:4][CH3:5])[CH3:3])[OH:7])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(C)NO
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C)N(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 500 ml of ethylene glycol dimethyl ether, 209.1 g (1.5 moles) of 90% pure N-sec.-butylhydroxylamine hydrochloride and 151.2 g (1.8 moles) of sodium bicarbonate was stirred at room temperature for 1 hour and 178.5 g (1.5 moles) of phenyl isocyanate were then added at 0° to 5° C. The mixture was subsequently stirred at 10° C. for 1 hour, the salt was then filtered off and the filtrate was evaporated in vacuo. 310 g (99% of theory) of N-phenyl-N'-sec.-butyl-N'-hydroxyurea remained as a colourless powder with a melting point of 107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=O)=[N:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([B:24]4[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:23][C:17]=3[O:16][CH3:15])=[O:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To 6-methoxy-1H-indazole-3-carboxylic acid (64 mg, 0.333 mmol) in dichloromethane (10 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (166 mg, 0.666 mmol), O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.500 mmol) and N,N-diisopropylethylamine (0.174 ml, 0.999 mmol). The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was purified by column chromatograpy (silica gel; dichloromethane/methanol 99/1) and thereafter by column chromatograpy (silica gel; heptane/ethyl acetate 2/1) to give 6-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (54 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:29]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:29]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)cccc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1c(F)cccc1I
Reaction time: 0.42 h
Yield: 83 %

Procedure:
2-Fluoro-6-iodobenzonitrile (10.274 g) was dissolved in toluene (100 ml), followed by the dropwise addition of 1.5M diisobutyl aluminium hydride/toluene solution (31 ml) in nitrogen atmosphere at −70° C., and the mixture was stirred for 25 min. Subsequently, it was stirred at room temperature for further 45 min. To the mixture was added 5% sulfuric acid, and it was stirred for 1 hr. Sequentially, the resulting solution was extracted with ethyl acetate, and the resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (8.683 g, yield; 83%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25](C)[C@H:24](O)[O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH:14]=1)(C(C)(C)C)(C)C.C(O[C:35]([NH:37][C:38]1[CH:42]=[CH:41][O:40][N:39]=1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:40]1[CH:41]=[CH:42][C:38]([NH:37][CH2:35][C@@H:24]2[O:23][C:22](=[O:28])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([N:13]4[CH:14]=[C:10]([CH2:9][OH:8])[N:11]=[CH:12]4)=[C:16]([F:29])[CH:17]=3)[CH2:25]2)=[N:39]1
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Reactant: CC1[C@H](O)OC(=O)N1c1ccc(-n2cnc(CO[Si](C)(C)C(C)(C)C)c2)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(-n2cnc(CO)c2)c(F)c1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-hydroxy-methyloxazolidin-2-one (842 mg, 2 mM, see WO 97-31917) and 3-(t-butoxycarbonyl-amino)isoxazole (405 mg, 2.2 mM) were suspended by stirring in dry tetrahydrofuran (15 ml) under nitrogen in an ice-bath. Tributylphosphine (444 mg, 2.2 mM) followed by 1,1′-(azo-dicarbonyl)dipiperidine (555 mg, 2.2 mM) dissolved in tetrahydrofuran (10 ml) were added. The mixture was then stirred 18 hours, allowing the temperature to rise to ambient, then filtered, and the filter cake washed with tetrahydrofuran. The combined filtrates were evaporated and the residue purified by chromatography on a 10 g reversed phase C18 column, eluting with a gradient from 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid. Relevant fractions were combined, evaporated, and the residue rechromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (104 mg). MS (ESP): 474 (MH+) for C22H24FN5O6
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[N:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: COC(=O)[C@@H](C)Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(c1ccc(Cl)cc1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of (2R)-4-chlorophenylalanine methylester (213 mg, 1.00 mmol) in DCM (5 mL) was added dropwise TEA (280 μl, 2.00 mmol) and then methanesulfonylchloride (100 μl, 1.3 mmol) at 0° C. After 30 min, the reaction mixture was quenched with water and extracted with DCM and EtOAc. The organic solution was washed with 1N HCl, dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (280 mg, 96.1%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(COc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In tetrahydrofuran (40 mL) was dissolved methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g), 2N aqueous sodium hydroxide solution (10 mL) was added to the solution, and the mixture was stirred at room temperature overnight. After adding methanol (10 mL) to the mixture, the resulting mixture was refluxed for 3 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure were added ethyl acetate and 1N hydrochloric acid, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(4-bromophenoxy)-2,2-dimethylpropanoic acid (2.886 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[OH:32]>C(OCCO)C>[OH:32][C:31]1[CH:30]=[C:29]([CH3:33])[CH:28]=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(N)c(O)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)cc3O)c2cc1OC
Yield: 85.7 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 6-amino-m-cresol to give 287.5 mg (85.8%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 335.9.
Reaction SMILES: [CH:1]1([C@@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([OH:17])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N#N>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:17][C@@H:9]2[CH2:8][C@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O[C@H]1Cc2ccccc2[C@@H](C2CCCCC2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2Cc3ccccc3[C@@H](C3CCCCC3)C2)cc1
Yield: 62 %

Procedure:
(Wyrick S D, Booth R G, Myers A M, Owens C E, Kula N S, Baldessarini R J, McPhail A T, and Mailman R B (1993) Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity. J Med Chem 36:2542-2551) (2R,4R)-4-Cyclohexyl-1,2,3,4-tetrahydronaphthalen-2-ol 2a (0.23 g, 0.1 mol), p-toluenesulfonyl chloride (0.20 g, 0.11 mol), and pyridine (1.5 mL) was stirred in solution for 24 hours at rt, under inert atmosphere (N2). The solvent was removed and the crude material was purified by column chromatography (Si-gel) to give 3a in a 62% yield. HRMS m/z Calcd for C23H28O3S 407.1651 [M+Na]+. Found 407.1631.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[C:26](O)(=[O:30])[C@H:27]([CH3:29])[OH:28].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])=[CH:22][CH:23]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: C[C@H](O)C(=O)O
Reactant: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
1-{4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]phenyl}methanamine (19 mg, 0.055 mmol), L-lactic acid (9.9 mg, 0.11 mmol, 2 equiv), N,N-diisopropylethylamine (48 μL, 0.27 mmol, 5 equiv) and (1H-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium tetrafluoroborate (43 mg, 0.082 mmol, 1.5 equiv) were combined in dichloromethane (1.5 mL) and stirred for 15 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.33 (1H, t, J=6.9 Hz), 8.30 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=8.7 Hz), 7.36-7.32 (4H, m), 4.72 (2H, d, J=7.2 Hz), 4.41-4.33 (2H, m), 4.08-4.03 (1H, m), 1.46-1.38 (1H, m), 1.27 (3H, d, J=6.6 Hz), 0.60-0.55 (2H, m), 0.53-0.50 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 419.1700 [(M+H)+; calculated for C21H22F3N4O2: 419.1689].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[CH3:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1csc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-methylbenzenesulfonamide (E102) (120 mg, 0.26 mmol) and (4-methyl-2-thienyl)boronic acid (73 mg, 0.51 mmol) in DME (3 ml) was added potassium tert-butoxide (263 mg, 2.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E108). MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9]COC(=O)C)[C:7]([C:15]2[N:19]3[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CN.[N+](C1N(CCOC(=O)C)C(C2N3N=[C:47]([NH:50][CH3:51])[CH:48]=[CH:49][C:44]3=NN=2)=NC=1)([O-])=O>O1CCOCC1>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:15]2[N:19]3[N:20]=[C:21]([N:50]4[CH2:47][CH2:48][CH2:49][CH2:44][CH2:51]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: CNc1ccc2nnc(-c3ncc([N+](=O)[O-])n3CCOC(C)=O)n2n1
Agent: CN
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N3CCCCC3)nn12
Reaction time: 1 h

Procedure:
0.42 g. crude 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine (see Example 14 for the preparation thereof) was dissolved in 3 ml. dioxan, mixed with 0.36 ml. 33 percent aqueous methylamine solution, maintained at 60° C. for half an hour, then evaporated in a vacuum at a bath temperature of 50° C. The residue was dissolved in 2 ml. isopropanol, left to stand for about one hour at ambient temperature and the precipitated crystals then filtered off with suction, washed with isopropanol and ether and recrystallized (0.1 g.) from about 5 ml. isopropanol, with the addition of charcoal, to give 0.054 g. of the desired 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-methylamino-s-triazolo-[4,3-b]pyridazine, which has a melting point of 221° - 233° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13](=[O:17])[NH:14][CH2:15][CH3:16])[N:10]=[CH:9]2)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:15]([NH:14][C:13]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:18][C:19](=[O:21])[CH3:20])[C:4]=2[CH2:1][CH:2]2[CH2:3][O:30]2)[CH:9]=[N:10]1)=[O:17])[CH3:16]
Reactant: C=CCc1c(OC(C)=O)ccc2cnn(C(=O)NCC)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCNC(=O)n1ncc2ccc(OC(C)=O)c(CC3CO3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step D (2.70 g, 9.4 mmol) in dichloromethane (15 mL) was added 3-chloro-perbenzoic acid (2.31 g, 10.3 mmol, 77% pure) and the mixture stirred at ambient temperature for 1 h. Additional 3-chloro-perbenzoic (0.2 g, 0.9 mmol) was added and the reaction continued for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL). The extract was dried (MgSO4) and evaporated to a white solid (1.59 g, 56%): mp 110-111° C.; LC/MS (+APCI) m/z 304 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(C2(OCc3ccccc3)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(OCc3ccccc3)CC2)cc1
Yield: 88.3 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (150.0 mg, 83%) was isolated by chromatography (0-3% EtOAc-hexanes) as a pale-yellow oil.