Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:31][C:1](=[O:3])[CH3:2])(=[O:33])=[O:32])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.11 ml (1.10 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 456 mg (yield: 96.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19].S([O-])(O)(=O)=O.[K+]>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:19]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cccc(C=O)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: O=Cc1cccc(NC(=O)Nc2ccccc2F)c1
Yield: 83.7 %

Procedure:
The product was prepared as described in Example 2, starting with 484 mg of 3-aminobenzaldehyde (4 mmol) (polymerized form) and 548 mg of 2-fluorophenyl isocyanate in 4 ml of DCE. After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 864 mg of the expected aldehyde are isolated in the form of a gum, in an LC/MS purity of 77%. A crystallized fraction is obtained after trituration from ethyl ether. 165 mg of solid are isolated ([M+H]+): 259. RT=4.28 min (acetonitrile/water gradient from 5% to 85%—Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][C@H:32]([CH3:40])[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])=[CH:29][CH:28]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:26][C:27]3[CH:28]=[CH:29][C:30]([O:31][C@H:32]([CH3:40])[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])=[CH:41][CH:42]=3)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1Cl
Reactant: CCCCOC(=O)[C@@H](C)Oc1ccc(O)cc1
Solvent: CCCCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@H](C)C(=O)OCCCC)cc3)cc2)cc1Cl
Yield: 15 %

Procedure:
This was prepared by the methods of Examples 2(b) and 2(c) using butanol instead of propanol and using 4-(3-chloro-4-octoxyphenyl)benzoyl chloride and Butyl (R)-2-(4-hydroxyphenoxy)propanoate (BHPP) in place of the OPBC and PHPTB used in Example 2(c), (yield 15%, SOR: +16°). The results of IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>O1CCCC1>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
Under a nitrogen atmosphere, phenyl isocyanate (52 μL, 0.48 mmol) was added to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reaction mixture was stirred for 20 minutes at which time it had turned homogeneous and thin layer chromatography indicated no starting material remained. Aminomethyl resin (280 mg of 1% cross linked, 100-200 mesh available from BACHEM, Torrance, Calif.) was added and the reaction mixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added and the mixture was concentrated under vacuum to provide a solid. The solid was purified by flash chromatography eluting with 95/5 dichloromethane/methanol to give a white solid which was dried under vacuum at 60° C. to provide 0.12 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea. Analysis: Calculated for C24H29N7O+⅕H2O: %C, 66.25; %H, 6.81; %N, 22.53; Found: %C, 66.27; %H, 6.63; %N, 22.83
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+]>O.CO.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[N:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Yield: 78 %

Procedure:
A mixture of 11.2 g (30.3 mmol) of 4-(3-bromo-phenylamino)-6-nitro-[1.8]naphthyridine-3-carbonitrile, 5.1 g (90.8 mmol) of powdered iron, and 8.1 g (151 mmol) of ammonium chloride was mechanically stirred at reflux in a mixture of 330 ml water and 560 ml methanol for 40 min. The liquid layer was decanted from the solids and diluted with ethyl acetate, saturated sodium bicarbonate, and brine. This mixture was extract multiple times with ethyl acetate (final volume 3500 ml). The combined extracts were dried with magnesium sulfate and filter through a short column of silica gel. The solvent was removed and the residue was stirred with ether. The solid was collected and dried give 8.04 g of the title compound as an orange solid: mass spectrum (electrospray, m/e): M+H 340, 342.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[C:23]([CH3:31])[CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:29]=[CH:30][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:22][C:23]=1[CH3:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.74 mL (35.29 mmol) of methanesulfonic acid chloride was added dropwise at 0° C. to a solution of 10.70 g (29.41 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethanol and 4.08 mL (29.41 mmol) of triethylamine in 500 mL of THF and the mixture was then stirred for 2 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was stirred with diethyl ether and water, and the precipitate was filtered off and dried in vacuo. Yield: 11.00 g (85% of theoretical); C23H20ClNO4S (M=441.928); calc.: molpeak (M+H)+: 442/444 (Cl); found: molpeak (M+H)+: 442/444 (Cl); HPLC-MS: 6.36 minutes (method C).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)cc1
Reaction time: 4 h

Procedure:
5.5 g. of o-phenylenediamine, 7.6 g. of p-ethylbenzoic acid and 40 g. of polyphosphoric acid were heated at 160°-180° C. under nitrogen gas current with stirring for 4 hours. The reaction mixture was diluted with 400 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 8.2 g. (73% of theory) of the product was obtained. M.P. 258°-258.4° C.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([CH3:15])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH3+:14].[N:16](OCCC(C)C)=O.O>ClCCl.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:14][N:16]=[C:5]2[CH2:4][C@H:3]([OH:2])[CH3:15]
Reactant: COc1ccc([NH3+])c(CC[C@@H](C)O)c1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred suspension of the product from step C (2.66 g, 11.5 mmol) in dichloromethane (150 mL) at ambient temperature was added isoamyl nitrite (2.47 mL, 18.4 mmol, 1.6 equiv.). After 30 minutes tetrabutylammonium acetate (5.54 g, 18.4 mmol, 1.6 eq) was added and the mixture was stirred for 2 hours. Water was added to the mixture and the organic layer was separated and washed with 2 N NaOH and water. After drying and evaporation the crude product was purified by column chromatography (gradient of 20% to 40% ethyl acetate in hexane) to give an oil (1.58 g) that crystallized from ethyl acetate/hexane (1:1) to afford a solid (1.30 g, 55%): mp 89-91° C.; LC/MS (+APCI) m/z 207 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl.[I-:21].[Na+]>CCOCC>[I:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2c(I)ccnc2c1
Reaction time: 0.25 h

Procedure:
The general procedure is described in Drake, N. L.; Creech, H. J.; Garman, J. A.; Haywood, S. T.; Peck, R. M.; Van Hook, J. O.; Walton, E., Synthetic antimalarials. The preparation of certain 4-aminoquinolines. Journal of the American Chemical Society 1946, 68, 1208-13. A dry 250 mL, 1-neck round bottomed flask was charged with 4-chloro-7-methoxyquinoline (1.77 g, 9.1 mmol), and 100 mL dry dioxane. The solution was treated with 20 mL 1N HCl in Et2O. The solution was occasionally swirled over a 15 minute period, and the solvent was removed in vacuo. The residue was dried at 60° C. at 0.1 mmHg for 2 h. To the flask was added a stir bar and 20 mL dry acetonitrile. The flask was fitted with a reflux condenser, and to the stirring slurry was added sodium iodide (4.1 g, 27 mmol). The solution was heated to reflux for 48 h. The solution was cooled, and the solution was filtered. The precipitate was washed with ACN (3×20 mL), and water (3×20 mL). The solid was suspended in 70% CH2Cl2-30% MeOH. To the solution was added Si-carbonate (16 g, 11 mmol). The slurry was swirled for 1 h, and filtered. The silica was washed with EtOH (3×50 mL). The solvent was removed in vacuo to afford 4-iodo-7-methoxyquinoline. 1H NMR (300 MHz, MeOD) δ ppm 4.00 (s, 3 H) 7.35 (dd, J=10.01, 2.48 Hz, 1 H) 7.36 (d, J=2.56 Hz, 1 H) 8.00 (d, J=9.87 Hz, 1 H) 8.01 (d, J=4.75 Hz, 1 H) 8.33 (d, J=4.90 Hz, 1 H). 13C NMR (101 MHz, MeOD) δ ppm 56.46 (s, 1 C) 107.73 (s, 1 C) 113.18 (s, 1 C) 122.61 (s, 1 C) 127.31 (s, 1 C) 132.05 (s, 1 C) 134.27 (s, 1 C) 150.18 (s, 1 C) 150.86 (s, 1 C) 163.35 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 286.0, calcd for C10H8INO+H+=286.0.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][CH:14]=[N:15][C:16]=3[CH3:17])[C:9](=[O:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[NH:13][CH:14]=[N:15][C:16]=4[CH3:17])[C:9](=[O:18])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: Nc1ccc(F)c(Cl)c1
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Yield: 23 %

Procedure:
The title compound (23% yield) was prepared from 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to the HCl salt. 1H NMR (360 MHz, DMSO-d6) δ 13.45 (br s, 1H, NH), 11.76 (br s, 1H, NH), 9.19 (s, 1H), 8.31 (s, 1H, H-vinyl), 7.92 (s, 1H), 7.73 (m, 1H), 7.45 (m, 2H), 7.36 (m, 1H), 2.33 (s, 3H7CH3). MS 371.4 [M++1].
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)(=O)C>[C:9]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CCC=CO1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC=CO1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of (±)-3,4-dihydro-2H-pyran-2-methanol (514 g, 4.51 mol, 1 eq) and acetic anhydride (621 g, 6.09 mol, 1.35 eq) was cooled to 0° C. To the resultant mixture was added pyridine (35.6 g, 0.45 mol, 0.1 eq) and the resultant reaction mixture was allowed to warm to room temperature with stirring. The resultant reaction mixture was allowed to stir for an additional 8 hours after reaching room temperature and was shown to be complete by thin-layer chromatography (2:1 hexanes:ethyl acetate, 12 staining). The reaction mixture was concentrated in vacuo at 35° C. and the resultant residue was diluted using ethyl acetate (2 L). The resultant mixture was transferred to a separatory funnel and sequentially washed with deionized water (3×1 L), saturated aqueous NaHCO3 (2×10 L), and brine (1.0 L). The organic layer was dried over sodium sulfate and concentrated in vacuo at 35° C. to provide (±)-3,4-dihydro-2H-pyran-2-yl-methyl acetate as a clear liquid (605.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 1.6-2.2 (m, 4 H), 2.1 (s, 3 H), 4.2 (m, 3 H), 4.8 (m, 1 H), 6.4 (m, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:52][OH:53])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]6)[CH2:39]5)=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][NH:42][CH2:41]6)[CH2:39]5)=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[C:18]=1[CH2:52][OH:53])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CNC4)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (169 mg, 234 μmol) was combined with DCM (10 ml) and TFA (2 ml) to give a yellow solution. The reaction mixture was stirred at 25° C. for 21 h. Conc. in vacuo to afford the title compound as a yellow solid in quantitative yield. (M+H)+=623 m/e.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH2:25][C:24](=[O:26])[CH:23]=[CH:22][N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[CH2:23][C:24](=[O:26])[CH:25]=[CH:20][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C1C=CN=C(Br)C1
Agent: Cl
Product: O=C1C=CN=C(NCCCOc2cccc(CN3CCCCC3)c2)C1
Yield: 58.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (14.84 g) and 2-bromopyrid-4-one (5.20 g) were stirred together at 165°-170° C. for 4 hours. The reaction mixture was cooled to give a dark orange glassy solid which was dissolved in 2N hydrochloric acid to give a solution having a pH of 4.5. This solution was washed thoroughly with diethyl ether (8×) and chloroform (4×) to remove residual 2-bromopyrid-4-one and some by-product. The aqueous phase was taken to pH 9-10 with 2N sodium hydroxide and extracted into chloroform (9×). The chloroform extracts were combined, dried and evaporated under reduced pressure to afford a dark orange oil. This oil was subjected to medium pressure column chromatography on silica gel using gradient elution; ethyl acetate→10% methanol:90% ethyl acetate. The desired fractions were collected, combined and evaporated under reduced pressure to give the title compound (6.0 g) as a yellow-orange oil which was washed with diethyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=1.NC(N)=[S:14]>CO>[CH3:8][C:6]1[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=[C:2]([SH:14])[N:7]=1
Reactant: Cc1nc(Cl)cc2cnnn12
Reactant: NC(N)=S
Solvent: CO
Product: Cc1nc(S)cc2cnnn12
Temperature: 0 °C

Procedure:
A mixture of 14.5 g (85 mmole) of 5-chloro-7-methyltriazolo[1,5-c]pyrimidine and 15 g (200 mmole) of thiourea in 100 ml of methanol was heated at reflux for one hour, and then cooled to 0° C. The product was collected by filtration and recrystallized from a 50:50 mixture of ethanol and hexanes with treatment with decolorizing charcoal to provide 7-methyltriazolo[1,5-c]pyrimidine-5-thiol. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[CH:30][C:25]=1[O:26][CH2:27]CO.[Na]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH2:17][CH2:27][O:26][C:25]3[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:24]=3[Cl:23])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: OCCOc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Agent: [Na]
Solvent: CC(C)=O
Product: CC(Oc1ccc(COc2ccc(Cl)cc2)cc1)C(=O)OCCOc1cc(Cl)c(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A mixture consisting of 2.2 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate, 2.4 gm of 2-(2,4,5-trichloro-phenoxy)-ethanol and 0.03 gm of sodium was heated at about 120°-150° C. and a pressure of 150 mm Hg for four hours. After cooling, the reaction mixture was briefly boiled with acetone, the cooled solution was filtered, and the solvent was removed from the filtrate in vacuo. The residue was recrystallized from ethanol/water, yielding 1.3 gm (36% of theory) of the compound of the formula ##STR19## which had a melting point of 83° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][N:4]=1)#[N:2].[CH2:11]([NH2:14])[CH2:12][NH2:13]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:13][CH2:12][CH2:11][NH2:14])=[CH:5][N:4]=1)#[N:2]
Reactant: NCCN
Reactant: N#Cc1ccc(CCl)cn1
Solvent: CC#N
Product: N#Cc1ccc(CNCCN)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A solution of 2-cyano-5-pyridylmethyl chloride (4.6 g) in acetonitrile (20 ml) was added dropwise to a solution of ethylenediamine (9 g) in acetonitrile (50 ml) at 5° to 10° C. After the addition, the mixture was stirred at room temperature for 3 hours. Acetonitrile and the excess of ethylenediamine were distilled off under reduced pressure from the reaction mixture. Dichloromethane was added to the residue, and a portion of it soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure. Volatile materials were removed at 50° C. and 1 mmHg to give N-(2-cyano-5-pyridylmethyl)ethylenediamine (4.5 g) as a colorless oil.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=2)[CH:20]=[O:21])=[CH:11][CH:10]=1)#[N:8]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.N1C=CC=CC=1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=2)[C:20]([OH:2])=[O:21])=[CH:26][CH:27]=1)#[N:8]
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C=O)c2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1
Reaction time: 1 h
Yield: 125.2 %

Procedure:
Potassium permanganate (6.18 g, 39.1 mmol) was added in portions to a stirred solution of 13.8 g (48.9 mmol) of 5-(4-cyanobenzyloxy)-2-nitrobenzaldehyde and 1.58 g (4.89 mmol) of tetrabutylammonium bromide in 70 mL of pyridine. After 1 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. Sodium hydrogen sulfite was added to destroy excess permanganate and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with 1N sodium hydrogen sulfate, brine, dried over anhydrous magnesium sulfate, and concentrated to give 14.6 g of 5-(4-cyanobenzyloxy)-2-nitrobenzoic acid as a powder, used without further purification. 1H NMR (300 MHz, d6 -acetone) d 8.07 (1H, d, J=8.8 Hz, O-Ar-H), 7.86 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.78 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.39 (1H, d, J=2.9 Hz, O-Ar-H), 7.36 (1H, dd, J=8.8, 2.9 Hz, O-Ar-H), 5.48 (2H, s, ArCH2O).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(=O)Nc1ccc(SCCCCN)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(SCCCCNS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 7.2 g of 4-[4-(acetamido)phenylthio]butaneamine (Example 70) in 100 ml of dichloromethane containing 8 ml of triethylamine is added 6.2 g of 4-methylbenzenesulfonyl chloride. The mixture is then stirred under reflux for six hours. The solvents are removed in vacuo. The residue is triturated with 2 portions of 100 ml of water. The insoluble portion is recrystallized from aqueous ethanol. Initially, the product precipitates as an oil, but after standing, crystals are obtained, m.p. 104°-105° C.; yield, 6.6 g.