Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: CNN
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](c3cnn(C)c3)C[C@@H]12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5] (297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:38][NH2:39]>C(O)CC>[C:1]([NH:38][NH2:39])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NN
Temperature: 25 °C

Procedure:
17.0 Grams of docosanoic acid, 1.0 g of p-toluenesulfonic acid monohydrate and 200 ml of n-propanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 4 hours. To the resulting solution was added 12.5 g of hydrazine monohydrate, followed by continuing the refluxing with heating for 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 14.2 g of the desired product. m.p. 117° C.
Reaction SMILES: C(O)C.[OH-:4].[Na+].[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:37])[C:18]([O:28][C:29]4[CH:36]=[CH:35][C:32]([C:33]#N)=[CH:31][CH:30]=4)=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:38])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[OH2:40]>>[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:37])[C:18]([O:28][C:29]4[CH:30]=[CH:31][C:32]([C:33]([OH:40])=[O:4])=[CH:35][CH:36]=4)=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:38])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(Oc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(Oc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)cc1

Procedure:
5.0 ml of ethanol and 1.5 ml of aqueous 6 M sodium hydroxide solution were added to 93 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}benzonitrile, followed by heating under reflux for 2 days. After cooling, the reaction system was neutralized with 1 M hydrochloric acid. Water was added and the solid precipitated was collected by filtration. By crystallizing the resulting solid from ethyl acetate-hexane, 65 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}benzoic acid was obtained.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].Cl.[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH2:11])[CH3:7].C(OC(=O)C)(=O)C>C(O)=O>[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH:11][CH:1]=[O:2])[CH3:7]
Reactant: O=C[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)CNC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A hot solution of sodium formate (150 g) in formic acid (200 mL) was added to a hot solution of glycine ethyl ester hydrochloride (228.7 g; 1.64 mol) in hot formic acid (250 mL). This was allowed to stir at room temperature for 1 hour. Small portions of acetic anhydride (450 g) were added to the well-stirred suspension as an exothermic reaction ensued. The suspension was stirred overnight, the solid was filtered and the filtrate was distilled in vacuo to remove excess reagents. The residue was filtered and then distilled to give N-formylglycine ethyl ester (182 g; 85%) having a boiling point of 105°-110° C. under vacuum.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[S:10][C:9]([NH:11]C(=O)OC(C)(C)C)=[N:8][C@:7]([CH3:31])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:20]=2)[CH2:6]1)([CH3:4])[CH3:3].CO.[F:34]C(F)(F)C(O)=O>>[NH2:11][C:9]1[S:10][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][C@:7]([C:19]2[CH:24]=[CH:23][C:22]([F:34])=[C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:20]=2)([CH3:31])[N:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(-c3cncnc3)c2)C[C@@H](C(C)(C)O)S1
Solvent: CO
Product: CC(C)(O)[C@@H]1C[C@@](C)(c2ccc(F)c(-c3cncnc3)c2)N=C(N)S1
Yield: 67.5 %

Procedure:
A solution of tert-butyl (4S,6S)-6-(2-hydroxypropan-2-yl)-4-methyl-4-(3-(pyrimidin-5-yl)phenyl)-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate (221 mg, 0.50 mmol) in trifluoroacetic acid (2 mL) is stirred at room temperature for 80 min. The mixture is added directly to a MeOH-equilibrated SCX column. The column is washed with MeOH (100 mL) and the product is eluted with 7N NH3 in MeOH (100 mL). The solution is concentrated under reduced pressure. The residue is diluted with CH2Cl2 and HCl (g) is bubbled through for 5 min. The reaction mixture is concentrated to give the title compound (67.5% yield): MS (m/z): 343 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=O)[NH:17]3)[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=[S:32])[NH:17]3)[C:4]=2[CH:3]=1
Reactant: O=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Yield: 130.4 %

Procedure:
In a 250-mL flask, the (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthen]-5-one (1.483 g, 3.14 mmol) was suspended in toluene (30 mL). Lawesson's reagent (0.794 g, 1.963 mmol) was added. An air-cooled condenser was affixed, and the reaction vessel was placed in a 90° C. oil bath After 7 h, the reaction was concentrated. Without working it up, the residue was purified by chromatography (15% EtOAc/hexanes) to afford (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthene]-5-thione (1.25 g, 2.56 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3]C=1N1CCC(=O)CC1.N.C(O[C:18]([N:20]1[CH2:25][CH2:24][C:23]([C:46]#[N:47])([NH:26][C:27](=[O:45])[CH:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][CH2:21]1)=O)C.[NH2:48][C:49]1([C:61]#[N:62])[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:51][CH2:50]1>CO>[NH2:48][C:49]1([C:61]#[N:62])[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:51][CH2:50]1.[C:46]([C:23]1([NH:26][C:27]([CH:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:45])[CH2:24][CH2:25][N:20]([C:18]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:21][CH2:22]1)#[N:47]
Reactant: O=C1CCN(c2ncccn2)CC1
Reactant: CCOC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1
Agent: N
Agent: N#CC1(N)CCN(c2ncccn2)CC1
Solvent: CO
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(c2ncccn2)CC1

Procedure:
4-Amino-4-cyano-1-pyrimidin-2-yl-piperidine was prepared according to the procedure from Example 7, step a, starting with 1-(pyrimidin-2-yl)-4-piperidone with the exception that a 2 M ammonia in methanol solution replaced the 5 M ammonia in methanol solution. (b) The title compound was prepared starting from N-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and 4-amino-4-cyano-1-pyrimidin-2-yl-piperidine according to the procedure from Example 2, step b, except that the compound was purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 30% acetonitrile in water to 100% acetonitrile. MS, m/z 469=M+1.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:16]([O:15][C:7]([CH:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14])[CH3:17]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
123.4 g of potassium tert-butoxide were added in portions, at a temperature of 15° C., to a solution of 160.1 g of diethyl malonate in one litre of dimethylformamide. The reaction mixture was stirred for 30 minutes and a solution of 207.7 g of phenethyl bromide in 200 ml of dimethylformamide was then added dropwise at room temperature. The reaction mixture was subsequently heated at 60° C. for one hour and then allowed to cool down once again. The dimethylformamide was evaporated off under reduced pressure and the remaining residue was taken up in a mixture of methyl tert-butyl ether and water. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The crude product, which remained as an oily residue, was purified by distillation under reduced pressure. 202.5 g of ethyl 2-ethoxycarbonyl-4-phenylbutanoate were obtained, b.p.1.5 =148°-153° C.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C1COCC1>[CH2:38]([O:45][N:46]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCC(=NOCc1ccccc1)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Yield: 51.9 %

Procedure:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (1.0 g, 2.96 mmol) (Example 1) and carbonyldimidazole (0.51 g, 3.11 mmol) were stirred for 18 hours at room temperature under nitrogen. A slurry of O-Benzylhydroxylamine (0.57 g, 3.55 mmol) and triethylamine (0.49 mL, 3.55 mol) in THF (5 mL) was added in one portion and the resulting mixture refluxed for 18 hours, filtered, and washed with THF (50 mL). The filtrate was concentrated and columned on silica gel eluting with 50% ethyl acetate in hexanes to give 4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.68 g, %C,H,N found: 76.01, 6.89, 6.26).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40](Cl)=[O:41])[CH3:35].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40]([N:13]1[CH:12]=[C:11]2[C:15]([C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([NH:17][C:18]([C:20]3[N:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:19])[C:9]([CH3:16])=[CH:10]2)=[N:14]1)=[O:41])[CH3:35]
Reactant: CCOC(=O)CSC(=O)Cl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(=O)n1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In a vial, 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropyl amide (0.200 g, 0.427 mmol) was suspended in chloroform (1 ml), then a solution of (chlorocarbonylthio)-acetic acid ethyl ester (0.086 g, 0.471 mmol) in chloroform (1 ml) was added, followed by triethylamine (0.065 ml). The reaction mixture became a clear solution that was stirred for 1 hour at a temperature of 20° C. The reaction mixture was concentrated and the residue was purified by flash chromatography over silica gel using a 50% ethyl acetate-50% cyclohexane mixture. The desired compound was isolated as a yellow solid showing the physical properties reported in the corresponding table (P.41.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.C(OC(=O)C)(=O)C.[CH:20](=O)[C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([CH:24]=[O:25])[CH:22]=1>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](/[CH:1]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Yield: 52 %

Procedure:
Starting with 6.56 g of 2-methyl-7-chloroquinoline, 10.4 ml of acetic anhydride and 4.95 g of isophthalaldehyde in 100 ml of xylene and using the procedure of Preparation Il, there was obtained 5.64 g of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([S:4]([OH:7])(=[O:6])=[O:5])[CH2:2][CH3:3].BrCCCS([O-])(=O)=O.[Na+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]1[C:23]([OH:25])=[O:24]>[OH-].[Na+]>[C:23]([CH:18]1[CH2:19][N:20]([CH2:3][CH2:2][CH2:1][S:4]([OH:7])(=[O:6])=[O:5])[CH2:21][CH2:22][NH:17]1)([OH:25])=[O:24]
Reactant: CCCS(=O)(=O)O
Reactant: O=C(O)C1CNCCN1
Agent: O=S(=O)([O-])CCCBr
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(CCCS(=O)(=O)O)CCN1

Procedure:
Synthesis of 3-(±)-2-carboxypiperazin-4-yl)-propane-1-sulphonic acid. (CPS) ##STR9## Sodium 3-bromo-propane-1-sulphonate (2.25 g, 0.01 mole) was added to a solution of piperazine-2-carboxylic acid (1.3 g, 0.01 mole) in aqueous sodium hydroxide (0.9 g NaOH/30 ml H2O). The resulting solution was maintained at 60°-65° for 12 h. The product, 3((±)-2-carboxypiperazin-4-yl)-propane-1-sulphonic acid, was isolated by passage of the reaction mixture through Dowex-AG-1-acetate resin. Evaporation of the column filtrate and aqueous washings and recrystallization of the crude product from a 50% aqueous ethanol solution yielded 3-((±)-2-carboxy-piperazin-4-yl)-propane-1-sulphonic acid (500 mg) as a white crystalline solid, m.p. 190°-191°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Yield: 92.8 %

Procedure:
To a solution of (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (300 mg, 1.019 mmol) in ethanol (15 mL) was added a suspension of 10% palladium-on-carbon (200 mg) in ethanol under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon for 2 h at room temperature then was filtered through a pad of Celite. The filtrate was concentrated to afford (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (250 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH:11]([CH3:13])[OH:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]([OH:12])[CH3:13])[O:9][C:3]=2[CH:4]=1
Reactant: CC(O)C(=O)O
Reactant: Cc1ccc(N)c(O)c1
Product: Cc1ccc2nc(C(C)O)oc2c1
Yield: 92 %

Procedure:
2-Amino-5-methylphenol as the starting material was reacted with lactic acid in the same manner as in Reference Example 1 (4) ii) to obtain 6-methyl-2-(1-hydroxyethyl)-benzoxazole (yield, 92%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C1([CH:20]=[CH:21][C:22]([OH:24])=[O:23])C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC1C=CN=CC=1.Cl>>[C:22]([O:24][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)(=[O:23])[CH:21]=[CH2:20]
Reactant: O=C(O)C=Cc1cccc2c1Nc1ccccc1S2
Reactant: C1=COCC1
Agent: C=Cc1ccncc1
Agent: Cl
Product: C=CC(=O)OC1CCCO1
Temperature: 25 °C

Procedure:
To a 100 mL 3-neck round bottom flask equipped with a stir bar, condenser, and addition funnel was added 39 mL of dihydrofuran (FW 70.09, d=0.927), and 0.18 g of phenothiazine Acrylic acid (19 mL, FW 72.06, d=1.05) was added dropwise slowly with stirring. A mild exotherm (55° C.) occurred. After cooling to room temperature, 0.415 g of poly(4-vinylpyridine hydrochloride) was added and the reaction was stirred overnight. The acid catalyst was then filtered off and 0.2 g each of calcium hydride and potassium carbonate was added to the filtrate. After removal of excess dihydrofuran on a rotovap, 10 mg of DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate) was added and the slurry was vacuum distilled at 200 mtorr at 26° C. to give 26.0 g of 2-tetrahydrofuranyl acrylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33]>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.[Cu]I.C(OCC)(=O)C.O>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: C#CCCO
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C

Procedure:
To 3-(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C53) (0.50 g, 1.4 mmol) in a 25 mL vial equipped with a stir bar and cap with septa was added bis(triphenylphosphine)palladium(II) chloride (0.019 g, 0.027 mmol), copper(I) iodide (0.0026 g, 0.014 mmol) and triethylamine (8.5 mL) followed by but-3-yn-1-ol (0.12 mL, 1.6 mmol). The reaction was heated to 60° C. overnight. The reaction was stopped and cooled to room temperature. The reaction mixture was treated with 50% ethyl acetate/water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-50% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided a solid which was dried overnight at 50° C. in vacuo to afford the title compound as a tan solid. It was calculated based on 1H NMR to be mixed with the starting butynol (8%), (0.38 g, 71%): 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.20-8.11 (m, 2H), 7.94-7.88 (m, 2H), 7.83-7.76 (m, 2H), 7.56-7.50 (m, 2H), 3.85 (q, J=6.3 Hz, 2H), 2.74 (t, J=6.2 Hz, 2H), 1.83 (t, J=6.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −62.51; ESIMS m/z 358 ([M+H]+).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[O:30][CH:27]([CH3:29])[CH3:28])=[CH:13][CH:14]=1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (7 mg, 0.3 mmol) was dissolved in isopropanol (1 ml) and to it was added 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.07 mmol). After stirring at room temperature overnight, the reaction mixture was evaporated to dryness and extracted into ethyl acetate from saturated aqueous NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness. The crude residue was purified on a TLC preparative plate using 4% methanol/methylene chloride as the solvent to yield title compound 1A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 1A-1 (8 mg, 26%): +ESI MS (M+1) 433.4; 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.49–7.45 (3H), 7.34 (d, J=9.1 Hz, 2H), 5.73 (septuplet, J=6.2 Hz, 1H), 1.48 (d, J=6.2 Hz, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]([CH2:27]C(Cl)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:31]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:17]([N:47]2[CH2:48][CH2:49][N:44]([CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:45][CH2:46]2)=[O:19])[N:8]([C:6](=[O:7])[CH2:27][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12]1)[CH3:16]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)COc1ccccc1
Product: CCON=C1C[C@@H](C(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 1-benzhydrylpiperazine the title compound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=541.2.