Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][CH:17]=1)[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][CH:17]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogen carbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-ethoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.47 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.18 g, 70%).
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCCO)CC1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 4-(6-hydroxyhexyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (42 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether, filtered and dried under vacuum to give the title product as a mixture of the 3R and 3S isomers (0.10 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.54-2.07 (m, 4H), 2.95 (s, 3H), 3.10-120 (m, 1H), 3.21-3.37 (m, 2H), 3.50-3.59 (m, 1H), 3.93 (s, 3H), 4.70 (m, 1H), 7.20-7.29 (m, 2H), 7.40-7.55 (m, 2H), 7.89 (s, 1H), 8.37 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[CH2:2].[C:25]([OH:28])(=[S:27])[CH3:26].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:25]([S:27][CH2:2][CH2:1][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:28])[CH3:26]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(OCc2ccc(C(=O)OC)cc2)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1ccc(COc2cccc(CCSC(C)=O)c2C(=O)OC)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 2-ethenyl-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.71 g, 2.18 mmol) in benzene (10 mL) was added thioacetic acid (1.80 mL, 25.2 mmol) followed by AIBN (37 mg, 0.23 mmol). After nitrogen was bubbled through the solution for 30 min, the solution was heated at reflux for 4 h. The reaction was allowed to cool to rt and saturated NaHCO3 (20 mL) was added. The mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (1:10 EtOAc/hexanes) to give 2-[2-(acetylthio)ethyl]-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.50 g, 60%) as a clear oil: 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.85–2.82 (m, 2H), 3.07–3.10 (m, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 5.16 (s, 2H), 6.81 (d, J =8.2 Hz, 1H), 6.92 (d, J =7.7 Hz, 1H), 7.28 (t, J=8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 8.04 (d, J=8.3 Hz, 2H).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.Cl.[NH2:14][C@@H:15]1[CH2:24][CH2:23][CH2:22][C:21]2[C:20]([C:25]3[N:29]=[C:28]([C:30]4[CH:31]=[CH:32][C:33]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([CH:37]=4)[C:35]#[N:36])[O:27][N:26]=3)=[CH:19][CH:18]=[CH:17][C:16]1=2.CCN(CC)CC.[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>C(Cl)Cl>[C:35]([C:34]1[CH:37]=[C:30]([C:28]2[O:27][N:26]=[C:25]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[CH2:22][CH2:23][CH2:24][C@H:15]4[NH:14][C:6]([N:53]3[CH2:54][CH2:55][C@@H:51]([N:50]([CH3:56])[CH3:49])[CH2:52]3)=[O:7])[N:29]=2)[CH:31]=[CH:32][C:33]=1[O:38][CH:39]([CH3:41])[CH3:40])#[N:36]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NC(=O)N3CC[C@@H](N(C)C)C3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
Prepared using General Procedure 3: To a stirring solution of CDI ((9.5 mg, 0.06 mmol) in DCM (1 mL) were added dropwise a solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl salt 3 (20 mg, 0.05 mmol) and Et3N (20.3 μL, 0.15 mmol) in DCM (1 mL). After stirring for 15 h at room temperature, this solution was added dropwise to another solution containing (R)-3-dimethylaminopyrrolidine (18.6 mg, 0.15 mmol)) in DCM (1 mL) at room temperature. The reaction was stirred at room temperature for 6.5 h. The solvent was evaporated and the pure product was isolated by preparative HPLC to afford 17.5 mg (70%) of (R)-N-((R)-5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(dimethylamino) pyrrolidine-1-carboxamide 20. LCMS-ESI (m/z) calculated for C29H34N6O3: 514.6; found 515.3 [M+H]+, tR=2.56 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.2 Hz, 1H), 8.31 (dt, J=8.7, 4.3 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 5.13 (d, J=6.9 Hz, 1H), 4.86-4.73 (m, 1H), 4.64 (d, J=8.2 Hz, 1H), 3.91 (dd, J=10.4, 7.3 Hz, 1H), 3.80-3.56 (m, 3H), 3.41 (dd, J=17.5, 8.3 Hz, 1H), 3.15 (d, J=18.0 Hz, 1H), 3.10-2.93 (m, 1H), 2.85 (s, 6H), 2.46 (m, 2H), 2.05 (dd, J=9.2, 4.8 Hz, 1H), 1.88 (m, 3H), 1.45 (dd, J=13.9, 6.1 Hz, 6H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)(=[O:20])=[O:21]
Reactant: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNS(=O)(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 105 °C
Yield: 52.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-methyl-4-(piperazin-1-yl)benzenesulfonamide (116 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (2:1, 6 mL) and dried in vacuum to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide (110 mg, 0.241 mmol, 52.8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.04 (m, 3H) 2.15-2.27 (m, 1H) 2.38 (d, J=4.80 Hz, 3H) 2.51 (d, J=4.29 Hz, 4H) 3.32 (br. s., 4H) 3.38-3.49 (m, 3H) 3.57-3.69 (m, 1H) 3.97-4.07 (m, 1H) 7.02 (d, J=1.52 Hz, 1H) 7.07 (d, J=9.09 Hz, 2H) 7.15 (q, J=4.72 Hz, 1H) 7.59 (d, J=8.84 Hz, 2H) 7.66 (d, J=1.77 Hz, 1H) 10.48 (s, 1H). [M+H] calc'd for C24H29ClN6O2, 457; found, 457.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([NH:44][C@@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37](=[O:38])[NH:44][C@@H:45]([C:49]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:50])[CH:46]([CH3:47])[CH3:48])([CH3:41])([CH3:43])[CH3:42]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 96.9 %

Procedure:
Following general amide formation method 1, 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 0.123 mmol, 1.0 eq) was combined with BOC-D-Valine (26.7 mg, 0.123 mmol, 1.0 eq) which gave ((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (82 mg) in 92% yield. HRMS m/z, (M+H)+: 688.3961.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O:32][C:33](=O)[CH:34]([C:36](Cl)=[O:37])[CH3:35])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:33](=[O:32])[C:34]([CH3:35])=[C:36]([OH:37])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)Cl
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(O)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH2:17]N1C=NN=C1.CC(C)([O-])C.[K+].O>CS(C)=O.C(O)(=O)C>[NH2:17][C:9]1[C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Nn1cnnc1
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)c(N)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 4-methyl-3,5-dinitrobenzamide (6) (15.1 kg) in dimethyl sulfoxide (95.6 kg) is added to a solution of 4-amino-1,2,4-triazole (21.6 kg) and potassium tert-butoxide (21.7 kg) in dimethyl sulfoxide (144.5 kg) at a rate to maintain a temperature of about 20° C. The mixture is allowed to stir for about 30 minutes, whereupon additional amounts of 4-amino-1,2,4-triazole (5.5 kg) and potassium tert-butoxide (3.7 kg) are added. The mixture is allowed to stir for about 1 hour at about 20° C., and then the mixture is added, over a period of about 30 minutes, to a cold (about 5° C.) solution of water (347 kg) and acetic acid (15 kg), allowing the temperature to rise to about 25° C. The vessel containing the initial reaction mixture is then rinsed with water (87 kg) and the rinse solution is also added to the acetic acid solution. The resulting mixture is cooled to about 5° C. and held at this temperature for about 30 minutes, whereupon the mixture is filtered and the solids obtained are washed with water (82 kg). The solids are then dried in a vacuum tray dryer for about 19 hours, at a temperature of about 50° C. and a vacuum of about 15 torr, to provide 2-amino-4-methyl-3,5-dinitrobenzamide (7) (13.6 kg, 84% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:13][NH:14][NH2:15]>C(O)C>[OH:6][C:5]1[N:14]([CH3:13])[N:15]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1O

Procedure:
To ethyl 4,4,4-trifluoroacetoacetate (18 mL, Aldrich) in ethanol (200 mL) was added methyl hydrazine (6.6 mL) in ethanol (50 mL). The mixture was refluxed for 16 h and concentrated in vacuo leaving a white solid. Recrystallization from EtOAc/toluene (50:50) gave pure 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2.O.[OH-].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A solution of boron tribromide (32.5 ml, 341 mmol) in methylene choride (60 ml) was added in portions to a solution of 5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. After stirring for 15 minutes at −30° C., the mixture was warmed up to ambient temperature and stirred for 1 hour. Methylene chloride (300 ml) was added in portions and the mixture was cooled to 0° C. Water was added in portions and the mixture was adjusted to pH6 with 4N sodium hydroxide. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:27])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].Cl.[NH2:29]O.[C:31]([O-:34])(=O)[CH3:32].[Na+]>C(O)C.O>[CH3:32][C:31]1[O:34][N:29]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)[N:2]=1
Reactant: NO
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)no1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
53 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of ethanol containing 20% of water. 19 mg of hydroxylamine hydrochloride and 17 mg of sodium acetate were added thereto, followed by heating under reflux for 24 hours. Further, 19 mg of hydroxylamine hydrochloride and 17 mg of sodium acetate were added thereto, followed by heating under reflux for 36 hours. After cooling to room temperature, the mixture was evaporated, and the resulting crystals were washed with water, dried, and 50 mg of amidoxime compound was collected by filtration. 20 mg of the product was dissolved in 4 ml of toluene. 16 mg of acetic anhydride was added thereto, followed by heating under reflux for 96 hours. After cooling to room temperature, the mixture was neutralized with potassium carbonate under ice-cooling. After extracting with ethyl acetate, the extract was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 4 mg of the title compound.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35]CC2C=CC=CC=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][OH:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCO)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride by hydrogenation over palladium/charcoal (10%) at 5 bar hydrogen pressure and at ambient temperature. Yield: 61% of theory, C26H28N6O2 (456.6) Rf value: 0.70 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution=9:1) ##EQU122##
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:4]2=[CH:3][CH:2]=1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14]>C(O)C.CO.C(N)CCC>[C:10]1([CH:11]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC[N+](=O)[O-]
Solvent: CO
Solvent: CCCCN
Solvent: CCO
Product: CC(=Cc1cccc2ccccc12)[N+](=O)[O-]
Yield: 89.9 %

Procedure:
A solution of 1-naphthylaldehyde (624.8 g, 4.0 mol), nitroethane (300.0 g, 4 mol) and n-butylamine (14.8 g, 0.20 mol) was refluxed in ethanol (400 mL) for 24 hours. The mixture was cooled, diluted with methanol (200 mL), and filtered to give 767 g (90% yield) of 1-naphthyl-2-nitropropene. Upon standing, an additional 60 g (97% total yield) of 1-naphthyl-2-nitropropene crystallized from solution.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH:19]3[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][C:4]=1[F:29].CO>CC(C)=O.C(Cl)Cl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([NH2:2])=[C:4]([F:29])[CH:5]=3)=[CH:10][N:11]([CH:19]3[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Nc1ccc(-c2cn(C3CCC4(CC3)OCCO4)c3ncnc(N)c23)cc1F
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Yield: 77328568 %

Procedure:
5M HCl (300 mL) was added slowly to a solution of 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (18.49 g, 48.28 nmol) in acetone (800 mL) at 0° C. the resulting dark orange-brown solution was heated at 60° C. for 4 h. (t.l.c. analysis using 10% MeOH in CH2Cl2). The acetone was removed under reduced pressure and the acidic layer was basified to approx. pH 8 using sat. aq. Na2CO3. The resulting precipitate was collect by filtration and scrupulously dried to afford 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a light brown solid (12.67 g, 77%). A second crop was also obtained from the mother liquor on standing (2.01 g, 12%), 1H NMR (400 MHz, d6-DMSO) 2.27(2H, m), 2.30 (4H, br d), 2.73(2H, m), 5.14(1H, m), 5.20(2H, brs), 6.05(2H, brs), 6.85 (1H, t), 6.97(1H, dd), 7.06(1H, dd), 7.35(1H, s) and 8.12(1H, s) and m/z 340.1(MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[H-].[Na+]>CC(N(C)C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: c1ccc(CCCCc2ccccc2OCCN2CCOCC2)cc1
Yield: 76.5 %

Procedure:
Following a procedure similar to that described in Example 2, 340 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 330 mg of 4-(2-chloroethyl)morpholine hydrochloride and 140 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 2, was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 390 mg (yield 76%) of the title compound as a colorless oil.