Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[C:22](=[O:35])[NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[C:7]([Cl:36])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:36][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:22](=[O:35])[NH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34]
Reactant: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-3-phenyl-isoxazol-5-yl}-phenyl)-acetic acid methyl ester 62 is dissolved in THF (2 mL). A solution of 1 M LiOH in H2O (0.6 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl, DCM (10 mL) is added and the organic layer washed with H2O (3×5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound J1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.66 (m, 2H), 7.51 (d, J=7.9 Hz, 1H), 7.34-7.19 (m, 6H), 7.09 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.04 (t, J=5.6 Hz, NH), 3.86 (t, J=4.9 Hz, 2H), 3.63 (q, J=5.2 Hz, 2H), 3.51 (s, 2H). MS calculated for C26H20Cl3N2O5 (M+H+) 545.0, found 545.0.
Reaction SMILES: [OH-:1].[Na+].[F:3][CH:4]([F:15])[C:5]1[C:9]([C:10](F)=[O:11])=[C:8]([F:13])[N:7]([CH3:14])[N:6]=1.Cl>S1(=O)(=O)CCCC1>[F:3][CH:4]([F:15])[C:5]1[C:9]([C:10]([OH:1])=[O:11])=[C:8]([F:13])[N:7]([CH3:14])[N:6]=1
Reactant: Cn1nc(C(F)F)c(C(=O)F)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 ml of a 1N sodium hydroxide aqueous solution, is added dropwise 67.5 g of a solution (0.1 M) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl fluoride in tetrahydro-thiophene-1,1-dioxide. The temperature is kept below 20° C. during the addition. After 2 hours of stirring at room temperature, the reaction mixture is carefully acidified to pH 2 with concentrated aqueous hydrochloric acid. The resulting white precipitate is filtered, washed with water, and dried to yield 6 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.90 (s, 3H); 7.22 (t, 1H, JHF=53.55 Hz); 13.33 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cccc(OCc3ccccc3)c2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4c(OCc5ccccc5)cccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Sodium hydride (36 mg, 1.5 mmol) was added in portions to a solution of 7-benzyloxyoxindole (360 mg, 1.5 mmol) in THF (8 ml), the mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (204 mg, 0.6 mmol), (prepared as described for the starting material in Example 5), in THF (4 ml) and DMF (1.5 ml) was added. The mixture was stirred for 30 minutes at ambient temperature followed by 1.5 hours at 65° C. The THF was removed by evaporation, the mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with water, ethyl acetate, and ether, and dried under vacuum to give 4-(7-benzyloxyoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (190 mg, 58%).
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[OH-].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>>[C:27]([C:3]1[CH:2]=[C:1]2[CH:24]=[C:22]3[N:23]=[C:19]([CH:18]=[C:16]4[NH:17][C:13](=[CH:12][C:10]5[CH:9]=[CH:8][C:7](=[CH:6][C:4]=1[NH:5]2)[N:11]=5)[CH:14]=[CH:15]4)[CH:20]=[CH:21]3)#[CH:28]
Reactant: Cc1ccccc1
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)C=C5)[nH]4)C=C3
Yield: 90 %

Procedure:
In order to obtain the deprotected ethyne, porphyrin 20 was first metalated with zinc (J. Rodriquez et al., J. Chem. Soc. Perkin Trans I 1997, 709-714) under standard conditions giving porphyrin 23 (FIG. 30). Deprotection of the ethyne by refluxing-with sodium hydroxide in toluene (L. Della Ciana and A. Haim, J. Heterocyclic Chem. 1984, 21, 607-608) (98% yield) gave building block 24. Demetalation of 24 with TFA (J. Lindsey et al., Tetrahedron 1994, 50, 8941-8968) afforded free base mono-ethynyl porphyrin 14 in 83% yield (FIG. 30). The metalation step was performed in order to suppress possible decomposition of the free base porphyrin upon exposure to sodium hydroxide. Subsequently, and to our surprise, we found that reaction of porphyrin 20 with sodium hydroxide in refluxing toluene proceeded smoothly to give porphyrin 14 in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:4]=2[N:3]=1.CO.O.[NH2:25]N>C(O)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[N:3]=[C:2]([NH:1][NH2:25])[CH2:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:5]=2[CH:17]=1
Reactant: COc1ccc(C2=NCC(N)=Nc3ccc(Cl)cc32)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3 parts of 2-amino-7-chloro-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine in a mixture of 50 parts by volume of methanol and 0.6 part by volume of glacial acetic acid is added dropwise with stirring 1.5 parts by volume of 100% hydrazine hydrate. The mixture is stirred for 30 minutes and poured into ice water, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene yields 7-chloro-2-hydrazino-5-(p-methoxypheyl)-3H-1,4-benzodiazepine as colorless crystals melting at 214° C to 220° C.
Reaction SMILES: [CH3:1][C:2]([NH2:13])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[O:14]([CH2:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].CO>C(#N)C>[ClH:25].[O:14]([CH2:21][CH2:22][CH2:23][NH:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCOc1ccccc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a stirred suspension of 50% KF-Celite (0.35 g, 3 mmol) in anhydrous acetonitrile (10 mL) was added 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.27 g, 1.5 mmol) and 3-phenoxypropyl bromide (0.484 g, 2.25 mmol). The reaction mixture was refluxed under nitrogen for 6 hours, followed by stirring at room temperature for 62 hours. The mixture was filtered and the filtrate, was evaporated. The hydrochloride was prepared by dissolving the residue in HCl/methanol. The resulting solution was concentrated and dried on a lyophilizer. The residue was redissolved in dry methanol and diluted with diethyl ether, which caused precipitation of 210 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 298 (M−15, 2), 193 (15), 192 (100), 120 (13), 107 (5), 98 (9), 77 (8), 72 (7), 71 (8), 70 (6), 41 (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.N1CCCCC1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)[C:8]2=[O:13]
Reactant: O=Cc1ccncc1
Reactant: COc1cccc2c1CCCC2=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cccc2c1CCC(=Cc1ccncc1)C2=O
Temperature: 130 °C
Yield: 49.8 %

Procedure:
A mixture of 5-methoxy-1-tetralone (0.1 g; 0.56 mmol), pyridine-4-carboxaldehyde (91 μl ; 0.85 mmol), piperidine (16.8 μl; 0.17 mmol) and acetic acid (9.7μl ; 0.17 mmol) was heated at 130° C. for one hour. The mixture was taken up in CH2Cl2 and washed in water and in a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2 /CH3CN (7/3) to give 5-methoxy-2-(4-pyridylmethylene)-1-tetralone (74 mg; 52%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc(C#N)c2ccn(Cc3ccccc3)c(=O)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(=O)n(Cc3ccccc3)ccc12
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A mixture of 6-benzyl-1-cyano-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (27 mg, 0.081 mmol), glycine (805 mg, 10.7 mmol), and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 33 mg of the title compound. MS: (+) m/z 379.00 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(CN2CCCC2)occ1OCCCCCOc1ncnc2ccccc12
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). Pyrrolidine (48 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1.5 h. .CH2Cl2 (75 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL), brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=90:10. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-((pyrrolidin-1-yl)methyl)-4H-pyran-4-one EHT 5317 was obtained (30 mg, 35% yield) as a colourless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH:18]([C:20]([F:23])([F:22])[F:21])[O:17][CH:16]([CH3:24])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:19][C@H:18]([C:20]([F:23])([F:21])[F:22])[O:17][C@H:16]([CH3:24])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1OC(C(F)(F)F)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C(F)(F)F)O1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Dry LiAlH4 (797 mg, 21 mmol, Aldrich) is suspended in dry, inhibitor free THF (15 ml) and treated with a solution of 4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (2.73 g, 10 mmol) in dry, inhibitor free THF (15 ml). The mixture is heated to 60° C. with stirring for 30 minutes. The mixture is diluted with MTBE (25 mL) and quenched sequentially with H2O (0.8 mL), 6.0 M NaOH (0.8 mL) and H2O (2.4 mL). The white slurry is filtered and the inorganic salts were washed with MTBE (200 mL). The solvent is removed by rotary evaporation and the product is purified in 3 portions on Biotage Flash 40M+ cartridges using a 10 minute linear gradient of 3% -10% MTBE in heptane. The products are combined and dried under high vacuum yielding a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[C:11]([C:13]12[N:19]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)#[N:12].[CH3:30][O:31][C:32]([C:34]#[C:35][C:36]([O:38][CH3:39])=[O:37])=[O:33]>CO>[CH3:30][O:31][C:32](=[O:33])[C:34]([O:10][N:9]=[C:11]([NH2:12])[C:13]12[N:19]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=[CH:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: N#CC12CCC(CC1)N2C(=O)OCc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C=C(ON=C(N)C12CCC(CC1)N2C(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyl amine (1.5 eq.), hydroxylamine hydrochloride (1.3 eq.) were added to a solution of benzyl 1-cyano-7-azabicyclo[2.2.1]heptane-7-carboxylate (C-37) in absolute methanol. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was dissolved in chloroform and treated with dimethylacetylene dicarboxylate (2 eq.) for 14 hours at 60° C. The reaction mixture was then concentrated and the resulting crude oil was purified by flash chromatography (petroleum ether/EtOAc 1:1) to give the titled compound (C-38) as a mixture of isomers.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]N(C=O)C.[H-].[Na+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[N:36]([CH3:37])[CH:35]=[CH:34][N:33]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ncc[nH]2)O3)ccc1OC(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2nccn2C)O3)ccc1OC(C)C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
[8-Benzyl-10-(1H-imidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (233 mg, 0.48 mmol) was suspended in a mixture of anhydrous DMF (1.5 mL)/THF (0.1 mL) under an atmosphere of nitrogen at 0° C. NaH (19 mg, 0.48 mmol) was added and the reaction mixture was stirred for 30 minutes, then MeI (68 mg, 30 μL, 0.48 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched with water and diluted with EtOAc, the layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were washed with brine solution (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-5% MeOH in DCM to yield [8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (205 mg, 86%) as a white foam. ESI-MS m/z calc. 502.3. found 503.1 (M+1)+; Retention time: 1.51 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.38-7.30 (m, 4H), 7.25 (ddd, J=8.4, 5.9, 2.2 Hz, 1H), 7.19 (d, J=7.0 Hz, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.96 (t, J=5.9 Hz, 1H), 6.75 (d, J=1.1 Hz, 1H), 4.96 (ddd, J=9.9, 6.7, 2.4 Hz, 1H), 4.68-4.59 (m, 1H), 3.70 (s, 3H), 3.53 (td, J=13.6, 9.0 Hz, 3H), 3.30-3.15 (m, 2H), 2.93 (dd, J=11.1, 0.7 Hz, 1H), 2.74-2.69 (m, 1H), 2.66-2.52 (m, 2H), 2.13 (s, 3H), 1.95-1.86 (m, 1H), 1.61-1.33 (m, 4H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=1.CCCCCC>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:24][CH:25]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:19]([Cu])#[N:20]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]#[N:20])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:14][CH3:15]
Reactant: CCCN(CCC)c1nccc2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nccc2ccc(C#N)cc12
Temperature: 25 °C

Procedure:
A solution of 7-bromo-N,N-dipropylisoquinolin-1-amine (350 mg, 1.1 mmol) and CuCN (204 mg, 2.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to provide 1-(dipropylamino)isoquinoline-7-carbonitrile (279 mg, which was used without any further characterization.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)O1>>[NH:31]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:33]=[N:32]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cn[nH]c3)ccn2c1=O
Yield: 49.1 %

Procedure:
Methyl 8-(1H-pyrazol-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (120.8 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (54 mg, 49%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19]OS([O-])=O.[K+].[OH2:25]>CO>[C:1]1([S:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[O:18])=[CH:10][CH:9]=2)(=[O:19])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ccc(Sc3ccccc3)cc21
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=C1CCCc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 25 °C
Yield: 59 %

Procedure:
7-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one ( ) was dissolved in 50 mL of MeOH and stirred at room temperature. OXONE™ (13.5 g, 22 mmol) was dissolved in 10 mL of water and added to the stirring reaction. The reaction mixture was stirred for 8 hours, and then evaporated under reduced pressure. The resulting aqueous residue was diluted with 200 mL of water and extracted three times with 100 mL of EtOAc. The combined extracts were dried over MgSO4, and the solvent was removed under reduced pressure to yield an oil which was eluted through silica gel with 1:1 EtOAc/hexanes. Removal of solvent under reduced pressure afforded 1.7 g (5.9 mmol, 59%) of 7-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one as an oil. MS: 287 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([O:13][CH2:12][CH2:11][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCOc2ccccc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCN1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.4 %

Procedure:
To a solution of 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethanol (17.0 g, 94.9 mmol) in pyridine (200 ml) was added methanesulfonyl chloride (16.31 g, 142.0 mmol) dropwise at 0° C. The reaction mixture was stirred for 10 h at 25° C. Ice water (200 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with 2N HCl (3×75 ml), water (75 ml), brine (50 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure. The residue was triturated with 5% ethyl acetate in pet. ether to afford the title compound (15.0 g, 61%) as brown solid. mp. 92-95° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][NH2:37])=[CH:35][C:30]=2[O:29][CH2:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCO4)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=466.2 (M+H)+