Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]2)=[CH:38][CH:37]=1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-(4-methylpiperazin-1-yl)benzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 532.0 (M)+
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(C)(C)C.[C:16]([Li])(C)([CH3:18])[CH3:17].CCO/C=C(/C=O)\C.FC(F)(F)C(O)=O.[OH-].[Na+]>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:16]([CH3:18])=[CH:17]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1
Reactant: [Li]C(C)(C)C
Agent: CCO/C=C(\C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2ccc(F)cc2c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
(4-Fluoro-phenyl)-carbamic acid tert-butyl ester (2.11 g, 10.0 mmol, ABCR, Karlsruhe, Germany) was added to a round bottom and purged with nitrogen. Anhydrous tetrhydrofuran (200 mL) was added to dissolve the solids and the flask placed in a dry ice/acetone bath (internal temperature −74° C. uncorrected). tert-Butyl lithium (1.7 M in pentane, 14.2 mL, 24.0 mmol) was added over 5 min causing a yellow color to develop. After the addition was complete the reaction was stirred in a −20° C. bath for 1 h. At this point, 3-ethoxymethacrolein (1.43 mL, 12.0 mmol) was added dropwise over 5 min, keeping the temperature below −19° C. The reaction was stirred at −20° C. for 2 h before slowly adding trifluoroacetic acid (14 mL) over 5 min. The red solution was stirred at room temperature for 16 h before bring to pH 12 with 1 N NaOH. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyle acetate/heptanes) gave impure desired material. This was extracted into three portions of 1 N HCl, the combined aqueous layers were brought to pH 12 with 6 N NaOH, and then extracted into two portions of ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give 6-fluoro-3-methyl-quinoline (48.0 mg) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1 H) 8.07 (dd, J=9.1, 5.4 Hz, 1 H) 7.88 (s, 1 H) 7.33-7.46 (m, 2 H) 2.53 (s, 3 H); MS (M+1): 162.1.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[C:12]([NH:14][C:15]2[NH:16][C:17](=O)[CH:18]=[CH:19][N:20]=2)[CH:11]=[N:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C(#N)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:12]2[CH:11]=[N:10][N:9]([C:2]([CH3:8])([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=2)[N:16]=1
Reactant: CCOC(=O)C(C)(C)n1cc(Nc2nccc(=O)[nH]2)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)n1cc(Nc2nccc(Cl)n2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-methyl-2-(4-((6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoate (2.0 g) obtained in Step C of Example 347 in acetonitrile (20 mL) was added phosphorus oxychloride (4.0 mL), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added 8 M aqueous sodium hydroxide solution (25 mL), and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.0 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[N:34]2[N:35]=[C:36]([C:38]([OH:40])=O)[CH:37]=[C:33]2[N:32]=[C:31]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH:30]=1.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:49]([NH:56][C:38]([C:36]1[CH:37]=[C:33]2[N:32]=[C:31]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[CH:30]=[C:29]([NH2:28])[N:34]2[N:35]=1)=[O:40])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Nc1cc(-c2ccc(Cl)c(Cl)c2)nc2cc(C(=O)O)nn12
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)nc2cc(C(=O)NCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.081 g, 0.184 mmol) was added to a suspension of 7-amino-5-(3,4-dichloro-phenyl)-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.050 g, 0.154 mmol) and benzylamine (0.034 mL, 0.308 mmol) in tetrahydrofuran (5 ml) containing triethylamine (0.064 mL, 0.462 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (5 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography to give 7-amino-5-(3,4-dichloro-phenyl)-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.026 g, 55%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[C@H:12]([OH:34])[C@@H:11]1[OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36](N1C=CN=C1)(N1C=CN=C1)=[S:37]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:11]2[C@@H:12]([O:34][C:36](=[S:37])[O:35]2)[C@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@@H]2OC(=S)O[C@H]12
Temperature: 80 °C
Yield: 81.3 %

Procedure:
To a solution of (1S,2R,3S,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol (179 mg, 0.362 mmol) in DMF (2.00 mL) under an atmosphere of nitrogen was added 1,1′-thiocarbonyldiimidazole (72.3 mg, 0.406 mmol) and the solution was heated to 80° C. for 3 h. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (158 mg, 81%). LC/MS: Rt=2.24 min, ES+ 538 (FA standard).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.O[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.CO>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:2]1
Reactant: OCC1CCOC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a solution of tetrahydrofuran-3-ylmethanol (21.89 g), methyl 4-hydroxybenzoate (33.5 g) and triphenylphosphine (64.5 g) in tetrahydrofuran (400 mL) was slowly added dropwise a solution (120 mL, 40% toluene solution) of diethyl azodicarboxylate in toluene at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and triphenylphosphine oxide was precipitated from ethyl acetate-hexane. The mixture was filtered through a glass filter to remove triphenylphosphine oxide, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=90:10 (volume ratio)→hexane:ethyl acetate=40:10] to give a colorless oil. The obtained colorless oil was dissolved in tetrahydrofuran (200 mL) and methanol (100 mL), 8N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was stirred with heating at 80° C. for 2 hr. The reaction solution was concentrated, cooled to 0° C., and neutralized with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (23 g, yield 48%) as colorless crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:12])[CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCNCC2)cc1N
Yield: 92.5 %

Procedure:
The nitroaniline derivative (10.0 g, 0.045 mol) (obtained in step 1 above) was hydrogenated using 10% Pd-C (1.5 g) in ethanol (45 mL), by an analogous procedure to that described in preparation 1 (step 4) to yield 4-(piperazin-1-yl)-1, 2-phenylenediamine (8.0 g, 93%) as a brown viscous oil. IR (Neat) 3342 cm-1 ; 1H NMR (CDCl3) δ 2.80 (brs, 5H, NH), 3.00 (m, 8H, 4×NCH2), 6.30 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 6.62 (d, J=8.0 Hz, 1H); Mass (m/z) 192 (M+.).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[Cl-].[NH4+]>C1COCC1.CCOCC.CN(P(N(C)C)(N(C)C)=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:5]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:7][CH2:8][C:4]1=[O:3]
Reactant: BrCCCCBr
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: O=C1CCCC1(CCCCBr)C(=O)OCc1ccccc1

Procedure:
In a 500 mL three-necked flask provided with magnetic stirring and a condenser, under an inert nitrogen atmosphere, sodium hydride 95% (2.2 g; 87.1 mmol; 1.25 eq.) is suspended in a mixture of anhydrous THF (115 mL) and HMPA (14.6 mL). A solution of benzyl 2-oxocyclopentanecarboxylate (15.3 g; 70.3 mmol) in 45 mL of anhydrous THF is added dropwise so as to keep the temperature below 45° C. The reaction mixture is stirred for 1 hour at ambient temperature. 1,4-Dibromobutane (12.6 mL; 105.4 mmol; 1.5 eq.) is added to the clear yellow solution. The reaction mixture is stirred again, for 14 hours, at reflux. After coming back to ambient temperature, 80 mL of saturated aqueous ammonium chloride solution are added. The mixture is poured into 500 mL of ether and the organic phase is washed five times with 100 mL of water and then with 100 mL of saturated aqueous sodium chloride solution. The organic phase is dried over MgSO4, filtered and concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][CH2:31][C:32](OC)=[O:33].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:31]([CH2:30][CH2:29][CH2:28][C:20]3[S:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[C:32]2=[O:33])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCc1nc2ccccc2s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2nc3ccccc3s2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 5-(2-benzo-thiazolyl)pentanoate (1.5 eq., prepared in Synthetic Example 23) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(benzothiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 185 to 186° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:12][N:13](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][CH2:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[C:12]#[N:13]
Reactant: COc1cc(Br)cc(CO)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COc1cc(C#N)cc(CO)c1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of 3-bromo-5-methoxy-phenyl-methanol (460 mg, 2.119 mmol, prepared according to the procedure reported by Claudi, F. et al. J. Med. Chem. 2000, 43, 599-608) in dimethylformamide (3 mL) at room temperature was added zinc cyanide (149 mg, 1.271 mmol). The reaction mixture was degassed by passing argon through for 30 min before tetrakis(triphenylphosphine)palladium (147 mg, 0.127 mmol) was added. The reaction mixture was heated at 100° C. for 12 h. It was diluted with diethyl ether and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 3-hydroxymethyl-5-methoxy-benzonitrile as white solids (269 mg, 78%).
Reaction SMILES: C(OC([O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[OH:8][CH2:9][CH:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCCCCCN1C(=O)OCC1COC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCCN1C(=O)OCC1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 1-4 (446 mg) in a mixture of 10% TFA in dichloromethane (10 mL) was stirred at room temperature for 2 h and concentrated. The residue was purified by column chromatography. Eluting with 70–100% ethyl acetate in hexanes afforded the alcohol 1-5 (264 mg). 1H NMR (400 MHz, acetone-d6): δ 4.33 (t, 1H), 4.19 (t, 1H, OH), 4.14 (dd, 1H), 4.09 (q, 2H), 3.95 (m, 1H), 3.78 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 3.16 (m, 1H), 2.29 (t, 2H), 1.70–1.55 (m, 4H), 1.45–1.30 (m, 4H), 1.21 (t, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[CH2:30](O)CCC.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:21]2[CH:22]=[CH:23][C:18]([O:24][CH2:25][CH3:26])=[CH:19][CH:20]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2ccc(C)c(Br)c2)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (1.2 g, 4.74 mmol) and oxalyl chloride (0.7 mL, 8.16 mmol) in 8 mL of CH2Cl2 was added 50 μL of DMF. The reaction mixture was stirred overnight prior to removal of the volatiles under reduced pressure using a rotary evaporator. The crude 3-bromo-4-methylbenzoyl chloride was dissolved in 10 mL of CH2Cl2 and then cooled to −5° C. prior to adding phenetole (0.63 mL, 5.0 mmol). AlCl3 (0.945 g, 7.1 mmol) was added via a solid addition funnel over 30 min. After the mixture was stirred at 5° C. for 2 h, the reaction was quenched by pouring over ice. Subsequently, the suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic layers were washed 2× with 1 M HCl, once with H2O, 2× with 1 M NaOH, and 2× with brine prior to drying over Na2SO4. Recrystallization 2× from absolute EtOH provided 1.13 g of (3-bromo-4-methylphenyl)(4-ethoxyphenyl)methanone. 1H NMR (CDCl3, 300 MHz): δ 7.93 (d, J=1.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.60 (dd, J=1.6, 8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.46 (t, J=7.0 Hz, 3H); MS ESI (m/z) 319 (M+1)+, calc. 318.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[CH:10]=[C:11]([C:18]([O:20]C)=[O:19])[C:12]3[C:17]([C:8]2=[N:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(O)C.Cl>O>[F:23][C:4]([F:3])([F:22])[C:5]1[N:9]2[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12]3[C:17]([C:8]2=[N:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1cn2c(C(F)(F)F)nnc2c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(C(F)(F)F)nnc2c2ccccc12

Procedure:
A solution of potassium hydroxide (2.8 g., 0.05 mol.) and 3-trifluoromethyl-6-methoxycarbonyl-s-triazolo-[3,4-a]-isoquinoline (14.8 g., 0.05 mol.) was allowed to reflux in 280 ml. of ethanol for 12 hours. Removal of the solvent provided a residue which was dissolved in water andfiltered. The aqueous filtrate was neutralized with 2N hydrochloric acid and the product, 9.7 g. (70%) was collected by filtration; m.p. 290°C. (dec.).
Reaction SMILES: NC1C=CC=CC=1.Cl[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[CH:16]=[N:17][C:10]=12.C(Cl)(Cl)Cl.CO>O>[N:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:9]=2)[NH:15][CH:16]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ccnc32)[C@H](O)[C@@H]1O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Nc1ccccc1
Product: c1cnc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Aniline (1.6 g, 17.5 mMol) and 1.0 g (3.5 mMol) 7-chloro-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine were suspended in 100 mL water and heated at 100° C. oil bath for two days. The oil bath temperature was raised to 130° C. and the reaction was continued for two days, when 2 equivalents of aniline were added. On the tenth day of heating, 5 equivalents of aniline were added and the reaction continued for six hours more. The mixture was concentrated in vacuo to give a dark oil. Chromatography twice on silica gel using CHCl3 /CH3OH (9:1) gave nearly pure 7-anilino-3-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine. This was crystallized in two batches from methanol. Total yield was 0.307 g, 18%; m.p. 186°-187° C. The NMR, UV and HPLC retention time were identical to the product prepared enzymatically.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH3:8])[CH3:2].[NH3:12]>>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][CH2:6][CH:7]([NH2:12])[CH3:8])[CH2:10][CH3:11]
Reactant: CCN(CC)CCCC(C)=O
Reactant: N
Product: CCN(CC)CCCC(C)N

Procedure:
Novoldiamine is presently prepared by a complex synthesis. The compound is prepared commercially from 2-diethylaminoethanol and ethyl acetoacetate. The alcohol is reacted with thionyl chloride to form 2-chlorotriethylamine (A) while the acetoacetate is reacted with sodium ethoxide to provide the sodium derivative of ethyl acetoacetate (B). The initially formed compounds A and B are then condensed to yield an intermediate ester which must be hydrolyzed and then decarboxylated to provide 5-diethylamino-2-pentanone (C). This product (C) is hydrogenated in the presence of ammonia to produce the subject novoldiamine product. Other modes of preparation are known (See U.S. Pat. No. 2,365,825), but are not practiced due to the complexity of the synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of the product from Example 10A (3.0 g, 8.44 mmol), 4-aminothiophenol (1.06 g, 8.44 mmol) and cesium carbonate (5.5 g, 17.0 mmol) in N,N-dimethylformamide (15 mL) was heated to 90° C. for 4 hours. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution acidified to pH 5 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as an orange solid (3.6 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:17][C:18]1[N:26]([C:27]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([O:36][CH3:37])=[CH:21][C:20]=2[C:19]=1[CH2:38][C:39](O)=[O:40].O>C(Cl)Cl>[CH:5]([C:4]1[CH:3]=[C:2]([O:1][C:39](=[O:40])[CH2:38][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([O:36][CH3:37])[CH:21]=3)[N:26]([C:27](=[O:28])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:17])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)Oc1cccc(C=O)c1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 3-hydroxybenzaldehyde (g 8.30) and triethylamine (g 0.824) in methylene chloride (200 ml), cooling at a temperature in the range −5° C.-0° C. indomethacin in the form of the corresponding acylchloride (g 16.50) is added under stirring. It is still maintained under stirring for 15 minutes, then water (100 ml) is added and the phases are separated. The aqueous phase is recovered and extracted with methylene chloride (300 ml). The organic phases are joined together, washed with a 5% Na2CO3 solution, the organic phase is anhydrified with sodium sulphate obtaining the expected compound.