Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Yield: 80.4 %

Procedure:
A mixture of 4.7 g of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate in 45 ml of ethyl acetate was hydrogenated in the presence of 500 mg of 10% palladium hydroxide on barium sulfate and 6.5 ml of quinoline and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 5.1 g of oil residue were chromatographed over silica gel and eluted with a 70-30-1 mixture of hexane-ethyl acetate-acetic acid to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][CH2:28][CH2:29][OH:30])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:45]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][CH2:28][C:29]([OH:45])=[O:30])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCCO)c(Cl)cc3[nH]c2=O)c1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-hydroxy-propyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (176 mg in 3.0 mL methylene chloride) was added 20 mg powdered 4 Å sieves, 73 mg of 4-methylmorpholine-N-oxide, followed by 11 mg tetrapropylammonium perruthenate(VII) and the mixture stirred at room temperature. After 3 hours, the solvent was removed in vacuo and the crude aldehyde product resolvated in a mixture of tert-butanol (2 mL) and sodium phosphate (1 mL of a 1.25M solution). To this was added 1.86 mL of a 1M aqueous solution of potassium permanganate. After 30 minutes, the mixture was extracted with ethyl acetate, dried over sodium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:1; then methylene chloride:methanol, 90:10) to give the title compound (107 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.[CH2:19]([NH:26][C:27](=[O:31])[C:28](O)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27](=[O:31])[C:28]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C(=O)NCc1ccccc1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Yield: 90 %

Procedure:
The coupling of 4-(4-amino-2-fluorophenoxy)picolinamide to 2-(benzylamino)-2-oxoacetic acid was carried out in a manner similar to that which is described in Step C of Example 1 to give the title compound (90%) as a tan solid. 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 9.63 (t, 1H, J=6 Hz), 8.56 (d, 1H, J=5.6 Hz), 8.15 (br s, 1H), 8.02 (dd, 1H, J=12.8, 2 Hz), 7.82 (d, 1H, J=9.2 Hz), 7.75 (br s, 1H), 7.47 (t, 1H, J=8.8 Hz), 7.39-7.23 (m, 7H), 4.41 (d, 2H, J=6.4 Hz); MS(ESI+) m/z 409.22 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(C)c(CCNC(C)=O)c(-c3ccccc3)c2c1
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (75 mg, 0.22 mmol) in 2 mL of dichloromethane was added triethylamine (0.076 mL, 0.54 mmol), followed by acetyl chloride (0.017 mL, 0.24 mmol). After 45 minutes, the mixture was partitioned between EtOAc and 10% citric acid solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product as a colorless oil. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H22N2O3 (M+H+): 351.1703. Found 351.1681.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=4[N:7]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3ccc4[nH]ccc4c3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 16.7 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 5-indolylboronic acid (42 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated to 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 115 as a white solid (11 mg, 17%). LCMS: RT=4.37 min, [M+H]+=367. 1H NMR (400 MHz, CDCl3): δ 8.67 (1H, s), 8.28-8.20 (2H, m), 7.39 (1H, d, J=8.6 Hz), 7.23-7.19 (1H, m), 6.61 (1H, broad s), 3.91 (2H, s), 3.90-3.82 (8H, m), 1.48 (6H, s)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH2:12][CH2:11]1
Reactant: NCC1CCC(CN)CC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylsulfamoyl chloride (one mol-equivalent, ClSO2N(CH3)2) was added to a stirred solution of 1,4-bis-aminomethylcyclohexane (3 mol-equivalents) and diisopropylethylamine (1 mol-equivalent) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure and chromatographed (silica) to give the desired product as viscous oils. (Scheme 1A).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:27].[Na+].[CH2:29]([O:31][P:32]([OH:36])[O:33][CH2:34][CH3:35])[CH3:30].Cl>O>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[OH:27])=[C:2]([P:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(N=Nc2c(O)ccc3cc(S(=O)(=O)[O-])ccc23)c(Br)c1
Reactant: CCOP(O)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(OCC)c1cc([N+](=O)[O-])ccc1N=Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Reaction time: 1 h

Procedure:
27 parts of sodium 1-(2'-bromo-4'-nitrophenylazo)-2-hydroxy-6-naphthylsulphonate are stirred with 130 ml of water, and 20 parts of copper sulphate 5-hydrate in 70 parts of water are added. The pH value is adjusted to 7-8 and the mixture is stirred for one hour. Thereafter, 35 parts of phosphorous acid diethyl ester are added dropwise at pH 8. The mixture is subsequently stirred at room temperature for 4 hours and acidified with hydrochloric acid. The precipitate is filtered off, washed and dried and gives 23 parts of diethyl 5-nitro-2-[2'-hydroxy-6'-sulphonaphthylazo]-phenylphosphonate almost free from starting compounds and by-products.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)CCC>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCCCO
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=O)[nH]n2)c1

Procedure:
6-[5-Acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone was reacted with chloranil in boiling butanol to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)=[O:4].Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:21][C:9]=3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A mixture of 142 (0.45 g, 1.6 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, concentrated to give a solid which was triturated. with CH2Cl2 and filtered to give 143 (0.23 g, 58%): Mp>300° C.; 1H NMR (DMSO-d6) δ 12.87 (br s, 1 H), 9.86 (br s, 1 H), 8.21 (d, 1 H, J=1.6 Hz), 7.86 (dd, 1 H, J=8.8 Hz, 1.5 Hz), 7.76 (d, 2 H, J=8.8 Hz), 7.67 (d, 1 H, J=8.8 Hz), 7.29 (s, 1 H), 6.89 (dd, 2 H, J=7.7 Hz, 2.0 Hz); MS 253 (M−H)−
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:9]3[CH:10]=[CH:11][N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[O:13])[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: O=c1[nH]ccnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-morpholinopyrazin-2(1H)-one (317 mg, 1.75 mmol) in DMF (8 mL) at 0° C. was added NaH (60% in mineral oil, 105 mg, 2.63 mmol). After stirring for 20 min, a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (400 mg, 1.75 mmol) in DMF (2 mL) was added dropwise, and the mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (625 mg, 95.4%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J=6.6 Hz, 1H), 6.92 (d, J=4.2 Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 8H), 2.80 (s, 3H). LCMS (ESI) m/z 375 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.I[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Nc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2nccs2)c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
The mixture of 2-tributylstannylthiazole (1.57 mL, 5.00 mmol), 3-iodoaniline (0.50 mL, 4.16 mmol) and Pd(Ph3P)4 (465 mg, 0.4 mmol) in 50 mL toluene was degassed using Ar. The mixture was then stirred under Ar at 115° C. for 3 h. The mixture was concentrated and subjected to flash column (0 to 4.5% MeOH in DCM) to isolate 3-(thiazol-2-yl)aniline (709 mg, 95% yield).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:1][CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)cccc1OCCO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
90 mg of ethyl 2-hydroxy-6-methylbenzoate are dissolved in 2 ml of dry DMF, and 23 mg of a 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives ethyl (1R,3S)-2-methyl-6-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy}benzoate as a yellowish oil. C30H37NO6 (507.63), MS (ESI): 508 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.C[N:29](C=O)C.C(Cl)(=O)C(Cl)=O.N>C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([NH2:29])=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)c(CC(C)CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the acid of Example 7, Step 6, (600 mg, 1.39 mmol) in benzene (10.0 mL) was added at 0° C. DMF (50 mL) and oxalyl chloride. After a period of 30 min at 0° /C., THF (10.0 mL) was added to the resulting mixture and ammonia gas was bubbled until saturation. The mixture was stirred for 4 h at r.t. The reaction was poured over water, extracted with EtOAc, dried over Na2SO4, evaporated in vacuo and filtered over silica gel (50% EtOAc in THF) to provide the desired amide (530 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35]([CH2:36][CH3:37])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, propanoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([OH:7])[NH:4][N:3]=1.[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C)C>C(Cl)Cl>[CH:8]([O:7][C:5]1[NH:4][N:3]=[C:2]([NH2:1])[CH:6]=1)([CH3:13])[CH3:9]
Reactant: Nc1cc(O)[nH]n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1cc(N)n[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound may be prepared via the following procedure: To a suspension of 3-amino-5-hydroxypyrazole (0.50 mol) in CH2Cl2 is added triphenylphosphine (0.59 mol) and the resulting mixture is cooled to 0° C. Diisopropyl azodicarboxylate (0.59 mol) is added drop-wise over a period of 35 minutes (the temperature of the reaction mixture is kept below 2° C.) to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. A precipitate may be observed after 30 minutes of the reaction. Isopropyl alcohol (1.25 mol) is then added drop-wise over a period of 30 minutes at 0° C. as the slurry thins considerably to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. The reaction mixture is warmed slowly to ambient temperature and is then held at ambient temperature overnight. The reaction mixture is filtered to remove undissolved solids. The filtrate is dried (MgSO4) and concentrated under reduced pressure to give an oil. Purification by column chromatography (5%→10% MeOH in CH2Cl2) affords the title compound. (400 MHz, DMSO-d6) δ ppm 10.3 (br s, 1H), 4.84 (br s, 2H), 4.65 (s, 1H), 4.52 (m, 1H), 1.20 (m, 6H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH2:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: Nc1n[nH]c2c(F)c(F)ccc12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(F)ccc12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
0.61 cm3 of butyryl chloride is added to 1 g of 6,7-difluoro-1H-indazole-3-amine described above, in 15 cm3 of pyridine, after having cooled to about 3° C., and the mixture is then left at ambient temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The organic phase is washed with 25 cm3 of distilled water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, filtering and concentrating under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (98/2 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa ; 40° C.), 596 mg of N-(6,7-difluoro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 191° C.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1O.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[C:1]1([C:5]([O:7][C:16]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:15]=2[F:14])=[O:6])[CH2:4][CH2:3][CH:2]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)C1=CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
Cyclobut-1-enecarboxylic acid (0.51 mmol, 50 mg) was dissolved in 0.5 ml dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (0.51 mmol, 43 μl) was added. The temperature of the solution was raised to room temperature, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 2,3,4,5,6-Pentafluorophenol (0.51 mmol, 94 mg) and triethylamine (1.02 mmol, 142 μl) were dissolved in 0.5 ml dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The reaction was quenched with 1 N HCl, and was extracted with CH2Cl2 (30 ml). The CH2Cl2 solution was washed with 5% NaHCO3 (2×10 ml), dried over Na2SO4, concentrated by rotary evaporation, and then purified by flash column chromatography (100% CH2Cl2) to yield 13 as a colorless oil (59 mg, 44%). 1H-NMR (500 MHz, CDCl3) δ 7.12 (s, 1H), 2.86 (m, 2H), 2.60 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ 156.7, 152.6, 142.1, 140.3, 138.8, 138.3, 135.2, 53.3, 30.6, 29.2. HRMS (ESI) calcd. for C11H6O2F5 [M+H]+ 265.0293, found 265.0288.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2>>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:16][N:15]=[CH:14]2
Reactant: CC(O)C(F)(F)F
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Product: CC(Oc1nncc2cc(Br)ccc12)C(F)(F)F

Procedure:
This compound was prepared according to the procedure described in Example 2b, but starting with 1,1,1-trifluoropropan-2-ol, sodium hydride and 6-bromo-1-chlorophthalazine. MS (ESI, pos. ion) m/z: 321.9 (M+1).