Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12](=[O:34])[NH:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:35])[N:7]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][OH:45]>CN(C=O)C>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34][CH2:43][CH2:44][OH:45])=[N:13][N:14]([C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:35])[N:7]=1)(=[O:3])[CH3:2]
Reactant: OCCBr
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (6-chloro-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (504.6 mg, 1.043 mmol) and potassium carbonate (558.3 mg, 4.04 mmol) in DMF (10 ml) was charged with 2-bromoethanol (0.30 ml, 4.25 mmol) and stirred at RT for 6 hr. Quenched with water and extracted 3× with Et2O. Washed organics with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified via flash chromatography (0-100% EtOAc/Hex) to provide (6-chloro-3-(2-hydroxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate. MS: [M+H]+ m/z 528.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.Br[CH2:30][CH2:31][CH2:32][CH2:33]Br>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: BrCCCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N3CCCC3)cc12

Procedure:
383 mg of 6-amino-beta-carboline-3-carboxylic-acid-ethylester in 15 ml of ethanol is heated together with 0.58 ml of ethyldiisopropylamine and 0.18 ml of 1,4-dibromobutane for 6 h under nitrogen at the reflux. This is followed by an addition of 0.4 ml of 1,4-dibromobutane and reflux for 3 h. After evaporation, the mixture is washed with water and boiled with ethanol. 128 mg of 6-(1-pyrrolidinyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 259°-261° C. is obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22])[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C.O>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(O)Cn1ccnc1[N+](=O)[O-]
Yield: 83.3 %

Procedure:
Compound 8 (5 g, 15.8 mmol) was added to a solution of pure hydrazine (608 mg, 18.97 mmol, 1.2 equivalent) in 50 ml of ethyl alcohol and 4 ml of water. The mixture was refluxed for 2 h and then held at room temperature. The white solid (phthalhydrazide) was filtered. The filtrate was concentrated and the residue was redistributed in ethyl acetate and water. The water phase was extracted two times with ethyl acetate and the combined ethyl acetate phase was dried to give a yellowish solid as the HCl salt (9, 2.45 g, 70% yield). 1H NMR (D2O, δppm) (HCl salt): 2.91 (dd, 1H, NH2—CHa, J=13.2 Hz, 9.9 Hz), 3.21 (dd, 1H, NH2—CHb, J=13.2 Hz, 2.7 Hz), 4.19 (tt, 1H, HO—CH—, J=9.0 Hz, 3.0 Hz), 4.28 (dd, 1H, imidazole-CHa—, J=13.8 Hz, 8.7 Hz), 4.57 (dd, 1H, imidazole-CHb—, J=13.8 Hz, 2.7 Hz), 7.09 (d, 1H, J=0.9 Hz, —CH═), 7.35 (d, 1H, J=0.9 Hz, —CH═). 13C NMR (D2O, δppm). 42.06, 53.00, 66.86, 128.06, 128.92, 144.73.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reaction time: 16 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (110 mg, 0.294 mmol), sodium hydroxide (1 mL, 0.294 mmol), and ethanol (10 mL) wherein the stir time was 16 h. The final product was collected as 0.060 g (59%). LCMS E-S (M+H)=347.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.13 (m, 4H) 1.27 (s, 9H) 2.33-2.43 (m, 1H) 3.37 (q, J=5.81 Hz, 2H) 4.44 (t, J=5.94 Hz, 2H) 6.84 (t, J=5.81 Hz, 1H) 7.62 (s, 5H) 8.24 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=O.[OH-].[K+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(C(C)=O)cn1
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(Cl)ccc2Cl)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 2,5-dichlorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid. MS (ESI+): m/z=308.1 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15].Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C1COCC1.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl) amide (1.0 M solution in tetrahydrofuran, 542 mL, 0.542 mol) was added to a solution of 3,5-difluoroaniline (35 g, 0.271 mol) in THF (60 mL) at 0° C. Isopropyl chloroformate (1M solution in toluene, 406 mL, 0.406 mol) was then added dropwise at 0° C. and the mixture allowed to warm to room temperature over 2 h. The reaction mixture was diluted with ether and washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Solvent was removed under vacuum and the residue was triturated in hexanes to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[CH2:3]([N:2]([CH3:1])[S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])[CH:4]([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CNCC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylisobutylamine (0.26 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.45 g, 80%). MS (ISP) 594.7 [(M+H)+]; mp 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH:19]1([CH2:22][N:23]([CH2:29][CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH:19]1[CH2:21][CH2:20]1)[CH2:29][CH3:30])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN(CCCCN)CC1CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)CC1CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine, N1-(cyclopropylmethyl)-N1-ethylbutane-1,4-diamine (Step 1), the title compound is obtained; MS (Found M+1=412).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(O)cc2)CC1
Yield: 90.1 %

Procedure:
6.646 g of ethyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate (26.53 mmol, 1 eq.) are placed in 150 mL of ethyl acetate in a Parr bottle under nitrogen. 0.77 g of 10% palladium-on-charcoal (0.72 mmol, 0.03 eq.) is added and the reaction medium is placed under 50 psi of hydrogen for 3 hours at 25° C. The reaction medium is filtered and concentrated to give 6.27 g of ethyl [4-(4-hydroxyphenyl)cyclohexyl]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18]=3[CH:36]=2)=[CH:4][CH:3]=1.[OH:37]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)([CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[C:18]=3[CH:36]=2)=[O:37])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH:1]1([C:5]2([CH2:9][OH:10])[CH2:8][O:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>ClCCl.N1C=CC=CC=1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][CH2:9][C:5]2([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:8][O:7][CH2:6]2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: OCC1(C2CCC2)COC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCC1(C2CCC2)COC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyclobutyl-3-hydroxymethyloxetane (2.84 g, 20 mmol) in dry dichloromethane (40 ml) and pyridine (3 ml) at 0° C. under nitrogen was added a solution of 4-iodobenzoyl chloride (5.33 g, 20 mmol) in dry dichloromethane (10 ml). The solution was stirred overnight at room temperature, washed with water, dried over anhydrous sodium sulphate and evaporated. (3-Cyclobutyloxetan-3-yl)methyl 4-iodobenzoate was obtained as a white solid (7.42 g, 99%) which was not purified further.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1O>>[F:18][C:14]1[C:13]2[O:6][C:4]([C:3]3[C:2]([NH2:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[N:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: Nc1cccc(F)c1O
Product: Nc1ncccc1-c1nc2cccc(F)c2o1
Temperature: 200 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A mixture of 2-aminonicotinic acid (9.4 g), 2-amino-6-fluoro-phenol (8.65 g) and polyphosphoric acid (90 g) was stirred at 200° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, quenched with water and basified with sodium hydroxide solution 6N until pH 12 to give a solid which was collected by filtration and dried under vacuum; The resultant product was diluted in dichloromethane/methanol and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated to dryness to give 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (7.5 g) as a solid. NMR Spectrum: (DMSOd6) 6.76 (dd, 1H), 7.33-7.46 (m, 2H), 7.66 (bs, 2H), 7.68 (dd, 1H), 8.26 (dd, 1H), 8.30 (dd, 1H); Mass spectrum: M+H+ 230.
Reaction SMILES: [CH:1]1([C:16]([O:18]CC)=[O:17])[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[OH-].[Na+]>C(O)C.O>[C:12]([O:11][C:9]([N:6]1[CH2:5][CH2:4][C:3]2([CH:1]([C:16]([OH:18])=[O:17])[CH2:2]2)[CH2:8][CH2:7]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C1CC12CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(=O)O
Temperature: 15 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To the solution of 165c (500 mg, 1.76 mmol) in ethanol (8 mL) was added sodium hydroxide (212 mg, 5.3 mmol) in water (4 mL). See FIG. 6. The mixture was stirred at 15° C. for 12 h. The solvent was evaporated under reduced pressure. The aqueous solution was acidified with dilute hydrochloride acid (0.5 M) slowly under ice bath until pH˜4, and extracted with EtOAc (10 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid 165d (390 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 3.52-3.42 (m, 3H), 3.38-3.35 (m, 1H), 1.75-1.72 (m, 2H), 1.58-1.56 (m, 1H), 1.46-1.43 (m, 11H), 1.23-1.21 (m, 1H), 1.02-1.01 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:16][CH2:15][NH:11][CH2:12][CH2:13][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: OCCNCCO
Product: Clc1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-chlorophenylboronic acid and diethanolamin.
Reaction SMILES: [F:1][C:2]([F:16])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)[CH2:3]OS(C)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O>[N:17]([CH2:3][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([F:16])[F:1])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C(F)(F)COS(C)(=O)=O)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cccc(C(F)(F)CN=[N+]=[N-])n1
Temperature: 180 °C
Yield: 92.2 %

Procedure:
Methanesulfonic acid 2,2-difluoro-2-(6-methyl-pyridin-2-yl)-ethyl ester (900 mg, 3.83 mmol), as prepared in the preceding step, was dissolved in DMSO (2 mL). To this solution was added sodium azide (498 mg, 7.65 mmol) and the reaction mixture was heated at 180° C. under microwave irradiation for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4 and concentrated to afford a brown residue (700 mg, 92%). 1H NMR (CDCl3) δ 7.73 (t, J=7.82 Hz, 1H), 7.52 (d, J=7.76 Hz, 1H), 7.26 (d, J=7.79 Hz, 1H), 4.02 (t, J=13.23 Hz, 2H), 2.50 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[N:43][OH:44])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:45])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[N:43][OH:44])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:45])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 1 mL of an ethyl acetate solution containing 83 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-(hydroxyimino)propyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 51 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-5-(1-(hydroxyimino)propyl)-1,2-dihydro-2-oxoquinoline hydrochloride as a green solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=C(O)[CH:24]=[C:25]([CH3:27])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2Cl)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To 177 mg (0.823 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 195 mg (0.785 mmol) of 3-(2-chlorobenzyloxy)-5-methylphenol, as prepared in the preceding step, 262 mg (1.02 mmol) of triphenylphosphine, and 250 μL (2.27 mmol) of N-methylmorpholine in 3 mL of tetrahydrofuran was added 140 μL (0.892 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred overnight, quenched with saturated NaCl (50 mL), and extracted into ethyl acetate (50 mL). The organic extract was dried (MgSO4), and the product was partially purified by flash chromatography (ethyl acetate/hexane (1:4)), to give 230 mg of impure title compound (contaminated with 3-(2-chlorobenzyloxy)-5-methylphenol). This material was used as is in the next reaction.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1)C1C=CC=CC=1.C(OC1C=CC(C([CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=2[CH:45]2[CH2:54][CH2:53][C:52]3[CH:51]=[C:50]([O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH:49]=[CH:48][C:47]=3[CH2:46]2)=O)=NC=1)C1C=CC=CC=1>>[CH2:35]([N:36]([C:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)=[O:17])[C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[CH:45]1[CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH:49]=[CH:48][C:47]=2[CH2:46]1)[CH3:34]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(OCc3ccccc3)cn2)c1
Product: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1

Procedure:
Synthesized from 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 5-benzyloxypyridine-2-carboxylic acid according to an analogous synthetic method to Example 152, pivalic acid 6-{2-[(5-benzyloxypyridine-2-carbonyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (163 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (124 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetronitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCOCC3)nncc2c1
Temperature: 180 °C

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.1 g, 411 μmol), morpholine (72 mg, 821 μmol) and potassium carbonate (57 mg, 411 μmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. All the starting material was converted to product (M+1=296, 298). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give 6-bromo-1-morpholinophthalazine as yellow solid. Found MS (ES+): 296, 298(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH3:22])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)n1C
Yield: 85 %

Procedure:
A solution of methyl 5-(3-bromo-4-methoxyphenyl)-4-methyl-1H-pyrrole-2-carboxylate (prepared according to the procedure reported in J. Org. Chem., 2009, 74(2), 903-905, Org. Lett., 2007, Vol. 9, 25, 5191-5194, 1.40 g, 4.32 mmol) in DMF (3 ml) was added to a solution of sodium hydride (0.21 g 60% in paraffin oil, 4.75 mmol) in DMF (2 ml) at 0° C. under stirring. Methyl iodide (0.67 g, 0.29 ml, 4.75 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml) and then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product was further purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound 10a (1.25 g, 85%).