Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:31]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 1.00 g (3.36 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 1.00 g (9.91 mmol) of triethylamine, and 35 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6M hydrochloric acid and 20 ml of glacial acetic acid and was heated at 60° C. for two hours. The solution was concentrated to an oil which was triturated with isopropanol. The solid was filtered and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, mp >300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>C1COCC1.CCCCCC>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)[CH2:11][CH2:12]1
Reactant: CN(C)C=O
Reactant: CN1CCN(CCc2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(CCc2ccc(C=O)cc2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 87 mL of a solution of 8.7 g of 1-[2-(4-bromophenyl)ethyl]-4-methylpiperazine in THF cooled to −70° C. was added dropwise 21.1 mL of a solution of n-butyllithium (1.6 mol/L) in hexane, and the mixture was stirred at the same temperature for 30 minutes. While the reaction mixture was stirred at the same temperature, 3.6 mL of N,N-dimethylformamide was added dropwise. The mixture was stirred at the same temperature for 30 minutes. The cooling bath was removed, and the mixture was allowed to warm to −10° C., poured into a mixture of 12 mL of 1 N hydrochloric acid and 100 mL of cold water, and subjected to extraction with CHCl3. The obtained extract was dried over MgSO4 and concentrated to give 7.04 g of the title compound (98%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[O:17]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:9](/[C:11](=[CH:28]\[C:27]1[CH:30]=[CH:31][C:24]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][CH:26]=1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C/c1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Potassium phosphate (0.751 g, 3.54 mmol) was added to a solution of ethyl 2-cyanoacetate (2.00 g, 17.68 mmol) and 4-phenoxybenzaldehyde (3.50 g, 17.68 mmol) in ethanol (50 mL). After 1 h at room temperature, the mixture was quenched with water (20 mL). The ethanol solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (150 mL), washed with brine (2×10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5 to 20% ethyl acetate in hexanes, gave (E)-ethyl 2-cyano-3-(4-phenoxyphenyl)acrylate as tan liquid. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, s), 7.92-8.05 (2H, m), 7.37-7.48 (2H, m), 7.24 (1H, t, J=7.42 Hz), 7.10 (2H, δ, J=7.70 Hz), 6.98-7.07 (2H, m), 4.38 (2H, q, J=7.15 Hz), 1.40 (3H, δ, J=7.15 Hz); MS (ES+) m/z: 294 (M+H); LC retention time: 4.405 min (analytical HPLC Method B).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[CH2:13]([O:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccc2occc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCCc2ccc3occc3c2)cc1

Procedure:
The title compound is prepared by benzylation of 5-(2-hydroxyethyl)benzo[b]furan with benzyl bromide in the presence of sodium hydride.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH3:6][C:7]1[C:8]([CH2:16][S:17][C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[N:9][CH:10]=[CH:11][C:12]=1[N+]([O-])=O>C(O)(=O)C>[CH2:3]([O:5][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:16][S:17][C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:21]=3[N:22]=2)[C:7]=1[CH3:6])[CH3:4]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Reaction time: 1 h

Procedure:
600 mg of sodium hydride dispersion (55-60% in oil) were dissolved in 50 ml of abs. ethanol under argon. 3.68 g of 2-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole were added thereto and the solution was left to stir at 70° for 1 hour. The solution was neutralized with glacial acetic acid and the mixture was then evaporated in a vacuum. The residue was treated with aqueous sodium bicarbonate solution and methylene chloride. The organic phase was separated and the aqueous phase was extracted several times with methylene chloride. The combined organic phases were dried and concentrated The residue was chromatographed on silica gel with methylene chloride/methanol (9:1), using the medium pressure flash chromatography method, pressure was produced with nitrogen gas. There was obtained 2-[[(4-ethoxy-3-methyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole. After recrystallization from ethyl acetate/ether the product melts at 173°-177°.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:19][CH3:20])[C:9]([O:17][CH3:18])=[N:10]2)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:14]1[C:5]([NH:4][C:1](=[S:30])[CH3:2])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:16])[N:10]=[C:9]([O:17][CH3:18])[C:8]([O:19][CH3:20])=[N:7]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NC(C)=O)c2nc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(NC(C)=S)c2nc1OC
Yield: 135.7 %

Procedure:
5-Acetamido-6,7-dichloro-2,3-dimethoxyquinoxaline (20.49 g, 64.8 mmol) was added to a stirred suspension of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (15.7 g, 38.9 mmol) in toluene (432 ml) at room temperature under nitrogen. The mixture was warmed to the reflux temperature 25 minutes and was maintained at that temperature for a further 90 minutes. After being cooled the mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel, eluting with dichloromethane. 6,7-Dichloro-2,3-dimethoxy-5-thioacetamidoquinoxaline (17.54 g, 81%) was obtained as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as a yellow foam (103 mg, 45%). LCMS (m/e) 566 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=9.2 Hz), 8.02 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.26-7.19 (m, 1H), 7.03 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 6.56 (s, 1H), 6.51 (d, 1H, J=9.0 Hz), 3.93 (s, 3H), 3.95-3.88 (m, 4H), 3.30 (s, 2H), 3.19-3.13 (m, 4H), 3.16 (s, 3H), 2.99 (s, 3H), 2.95-2.89 (m, 4H), 2.76-2.68 (m, 4H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](O)([OH:23])[CH2:21][CH3:22]>>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([O:18][CH2:22][CH2:21][CH2:20][OH:23])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)O
Reactant: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Product: C[C@H](C(=O)OCCCO)c1cccc(C(=O)c2ccccc2)c1
Yield: 56.1 %

Procedure:
Compound 18 was synthesized as described above for compound 10 from (S)-(+)-3-benzoyl-α-methylbenzeneacetic acid (ketoprofen, 17) (3.8 g, 15 mmol) and propanediol (9) (5.7 g, 75 mmol). The compound was purified by flash chromatography on a silica gel column using 200:1 CH2Cl2—MeOH as the eluent to give 2.63 g (56%) of the compound 18 as a colorless oil; 1H NMR (CDCl3) δ1.54 (d, 3H), 1.82 (m, 2H), 1.82-1.82 (b, 1H, ex D2O), 3.58 (m, 2H), 3.79-3.83 (q, 1H), 4.25 (m, 2H), 7.42-7.80 (m, 9H); MS (ES) m/z 313.1 (M+H)+ (C19H21O4 requires 313.3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31](O)[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:38])([F:17])[F:37])=[CH:24][N:23]=3)=[CH:30][CH:29]=2)[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:12][CH:13]=1
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (232 mg, 1.04 mmol) and 1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-pentan-1-ol (258 mg, 0.830 mmol) in toluene (5.0 mL) is degassed and filled with nitrogen for 3 times. Tributyl-phosphine (0.310 mL, 1.50 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (316 mg, 1.50 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. The 3-(4-{1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-pentyloxy}-benzoylamino)-propionic acid methyl ester (205 mg, 0.40 mmol), 47%, is obtained in purified form after flash column chromatography.
Reaction SMILES: [I-].[C:2]([CH2:4][C:5]1[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N+:9]=1[CH2:10][CH3:11])#[N:3].CO/[CH:18]=[CH:19]/[CH:20]=[C:21]1\[S:22](=[O:32])(=[O:31])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26].C(Cl)(Cl)Cl.CO.C([O-])(=O)C.[Na+]>CO>[O:31]=[S:22]1(=[O:32])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25](=[O:26])/[C:21]/1=[CH:20]/[CH:19]=[CH:18]/[C:4](=[C:5]1\[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N:9]\1[CH2:10][CH3:11])/[C:2]#[N:3]
Reactant: CO/C=C/C=C1/C(=O)c2ccccc2S1(=O)=O
Reactant: CC[n+]1c(CC#N)sc2ccccc21
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1/C(=C(C#N)/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)Sc2ccccc21
Temperature: 25 °C

Procedure:
In a one-necked round bottom 100-mL flask equipped with magnetic stir bar and reflux condenser were added 2-(cyanomethyl)-3-ethyl-1,3-benzothiazol-3-ium iodide (1.00 g, 3.03 mmol), (2Z)-2-[(2E)-3-methoxyprop-2-en-1-ylidene]-1-benzothiophen-3-(2H)-one 1,1-dioxide (1.00 g, 4.00 mmol) and CHCl3-MeOH mixture (1:1, 20 mL). The flask was heated on an oil bath with stirring until boiling began, and a solution of sodium acetate (320 mg, 4.00 mmol) in 10 mL of methanol was added to the flask. The stirring was continued under reflux for an additional 30 min. The flask was cooled to room temperature and the precipitated solid was filtered, washed with methanol and dried. Green crystals. The yield was 730 mg (57% of theory).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CCCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([O:8][NH2:9])[CH:5]=[CH:6][CH3:7].[C:10]([CH:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:15][C:14]1=[O:33])(=O)[CH3:11].Cl>CN(C)C=O.O>[CH2:4]([O:8][NH:9][C:10](=[C:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH2:15][C:14]1=[O:33])[CH3:11])[CH:5]=[CH:6][CH3:7]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CC=CCON
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=CCONC(C)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To the suspension of 0.3 g of sodium hydride (60% oil dispersion) in 10 ml of dimethylformamide, 0.09 g of 2-butenyloxyamine hydrochloride was added under cooling with ice-water bath and then stirred. After 30 minutes, 0.21 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was added to the resulting solution which was then stirred for 7 hours under cooling with ice-water bath. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with ether. After removing ether, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.22 g of 2-[1-(2-butenyloxyamino)ethylidene]5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].COC(N1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])=O.O1CCCC1.Cl>C(=O)(O)[O-]>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[CH3:11]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CCOC(CCCN)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(CCCN1C(=O)C=CC1=O)OCC
Reaction time: 0.25 h

Procedure:
As shown in FIG. 2, to a solution of 4-aminobutyraldehyde diethylacetal (5 g, 31 mmol) in 100 ml of saturated bicarbonate was added N-methoxycarbonylmaleimide (4.91 g, 31.6 mmol) at 0° C. (icebath). After 15 minutes, tetrahydrofuran (100 ml) was added at room temperature and the resultant mixture stirred for 1 hour. The resultant mixture was then acidified with 1 N hydrochloric acid to pH 6-7 and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate/petroleum ether 1:2 to yield 4-maleimidobutyraldehyde diethylacetal as a yellow oil (4.31 g; 58%), TLC Rf=0.65, ethyl acetate/hexane 1:1.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[S:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.I[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[S:15][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CCCI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=S)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Yield: 83 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thione (4.04 g, 13.8 mmol), 1-iodopropane (6.80 mL, 69.7 mmol) and potassium carbonate (3.79 g, 27.5 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 8 hours. The reaction solvent was evaporated under reduced pressure. Water was added to the residue, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate/hexane to give the title compound (3.83 g, 83% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH2:16])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[NH:16][C:23]1=[O:24])[CH3:2]
Reactant: CCOC(=O)CCNc1cc(C#N)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-Amino-5-cyano-phenylamino)-propionic acid ethyl ester (0.65 g, 2.8 mmol) in CHCl3 (10 mL) was added CDI (0.68 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.6 g (83%) of the desired priduct as a brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:8][NH:7][C:6]2=[O:17].[H-].[Na+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:6]2=[O:17]
Reactant: ClCc1ccncc1
Reactant: Cc1onc2c(=O)[nH]nc(-c3ccccc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1onc2c(=O)n(Cc3ccncc3)nc(-c3ccccc3)c12
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a stirred suspension of 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (1.5 g, 6.6 mmol) (Renzi, G.; Pinzauti, S., II Farmaco Ed. Sci. 1969, 24, 885-889), 60% sodium hydride (0.63 g, 15.8 mmol) was added portionwise and the mixture stirred for 15 minutes. Then 4-(chloromethyl)pyridine hydrochloride (1.3 g, 7.9 mmol) was added portionwise and the final mixture was stirred at 50° C. for 7 h, then poured onto water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo to yield a crude product that was crystallized from isopropyl ether/petroleum ether to yield the title compound (1.66 g, 79% yield) as a light brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:24])[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCC(C)c1ccc(OCc2ccccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCC(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 74.4 %

Procedure:
A mixture of 14 g of ethyl 4-[4-(2-ethoxycarbonylbenzyloxy)-phenyl]pentanoate, 31 g of potassium hydroxide in 40 ml of water and 250 ml of 95% of ethanol was heated under reflux overnight. The solution was concentrated and the residue was dissolved in water, cooled and acidified with cold conc hydrochloric acid. The mixture was extracted with ether, and the extract was dried over anhydrous sodium sulfate, filtered and evaporated. Trituration with hexane afforded 8.9 g (72%) of product, mp 104°-106°. Recrystallization from acetonitrile gave an analytical sample, mp 115°-117.5°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[F:22])(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:37][C:38]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[O:41]>N1C=CC=CC=1.CN(C=O)C>[C:40]([C:39]1[C:38]2[N:37]=[C:1]([C:4]3[CH:9]=[CH:8][C:7]([CH:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=3[F:22])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)(=[O:41])[NH2:42]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)c(F)c1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 50D (1.48 g) in pyridine (5 mL) and DMF (5 mL) was added CDI (0.856 g). The solution was stirred at 45° C. for 2 hours, treated with 2,3-diaminobenzamide dihydrochloride (1.08 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (30 mL), and this solution was heated at 80° C. for 3 hours and concentrated. The concentrate was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 0-15% methanol in 2:1 ethyl acetate/hexane.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>C(O)(=O)C>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[O:7][CH:2]([F:1])[C:3]([F:4])([F:5])[F:6])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(OC(F)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(OC(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g (0.10 moles) 3-tetrafluoroethoxytoluene is placed in 25 ml glacial acetic acid and nitrated at 5° C. with a mixture of 30 ml concentrated nitric acid and 35 ml concentrated sulfuric acid. The solution turns yellow as the nitrating acid is added dropwise. When the addition is terminated the cooling bath is removed and the solution is agitated for 31/2 hours at room temperature. The solution is then poured onto ice, the precipitated oil separated and the aqueous solution is extracted with ethyl acetate. After drying over sodium sulfate and distilling the solvent, a yellow oil remains in quantitative yield, which according to the NMR spectrum, involves the 4-nitro-3-tetrafluoroethoxytoluene.