Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][C:34]([F:41])=[N:35][C:36]=2[NH2:40])C1C=CC=CC=1.N.[NH4+].[Cl-].[C@@H]1(N2C=NC3C2=NC=NC=3N)OC[C@@H](O)[C@@H](O)[C@@H]1O>O.C(Cl)(Cl)Cl.CO>[C@@H:10]1([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][C:34]([F:41])=[N:35][C:36]=3[NH2:40])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: N
Agent: Nc1ncnc2c1ncn2[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2-fluoroadenine (II, 1.7 g, 3 mmol) was suspended in liquid NH3 (75 ml) with stirring and Na (410 mg, 18 g-atoms) was added in small portions. When a purple color persisted for a few minutes after the addition of Na, the mixture was neutralized with NH4Cl (920 mg, 18 mmol). The NH3 was evaporated in a stream of dry N2, and the residue was triturated with Et2O (75 ml). The insoluble solid that formed was collected by filtration and washed with H2O (three 3-ml portions) before it was recrystallized from H2O (65 ml) giving the crude produce (479 mg), which was shown by TLC (4:1 CHCl3 -MeOH) to be primarily a mixture of I and 9-β-D-arabinosyladenine. A solution of the crude product in H2O (1 ml/mg) was percolated through an ion-exchange column [10 g of Amberlite (CG50, 100-200 Mexh)/mmol of nucleoside] at a rate not exceeding 0.5 ml/min, and the column was eluted with H2O until elution of I was complete. The fractions containing homogeneous I were combined and evaporated to dryness. The residue was recrystallized from H2O; yield 290 mg (34%), mp 265°-267° (Mel-Temp).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][CH2:12][O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15]>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:17]([NH:16][C:14](=[O:15])[O:13][CH2:12][CH3:11])=[S:18])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1N
Reactant: CCOC(=O)N=C=S
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1nc(Cl)ncc1OC
Temperature: 15 °C

Procedure:
2-Chloro-5-methoxypyrimidin-4-amine (1) (6.4 g, 0.040 mol) was suspended in ethyl acetate (100 mL) and heated to near reflux. Ethyl isothiocyanatidocarbonate (8.9 g, 1.7 eq) was added all at once, and the mixture was maintained at reflux for 10 hours. The resulting slurry was cooled to 15° C., and the solid product was isolated by filtration and the cake washed with fresh ethyl acetate to afford the title compound in several crops as a solid (7.8 g, 67%): mp 182° C.; 1H NMR (DMSO-d6): δ 11.97 (s, 1H), 11.72 (s, 1H), 8.50 (s, 1H), 4.22 (q, 2H), 3.72 (s, 3H), 1.17 (t, 3H); 13C NMR (DMSO-d6): δ 177.82, 153.58, 150.00, 149.01, 144.26, 142.63, 62.76, 57.56, 14.44; Mass spec (accurate mass): Calcd for C9H11ClN4O3S: 290.024039; found, 290.0241.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:37]=2)[NH:32]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:43][CH2:44][N:45]([C:21]([C:20]4[CH:24]=[CH:25][C:17]([O:16][C:13]5[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]6[CH:26]=[CH:27][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=6)=[CH:11][CH:12]=5)=[CH:18][CH:19]=4)=[O:23])[CH2:46][CH2:47]3)[CH:37]=2)[NH:32]1
Reactant: O=C(O)c1ccc(Oc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cn2)cc1
Reactant: O=C1CCc2cc(CN3CCNCC3)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(CN3CCN(C(=O)c4ccc(Oc5ccc(NC(=O)c6ccc(C(F)(F)F)cc6)cn5)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)-piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:10]1[CH:43]=[CH:42][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C>[CH2:3]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([O-:32])=[O:31])=[CH:40][CH:41]=2)=[CH:42][CH:43]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Na+:2]
Reactant: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 68.6 %

Procedure:
Ethanol (6 ml) and a solution of 1N sodium hydroxide in ethanol (0.536 ml) were added to (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoic acid (330 mg, 0.596 mmol) and the mixture was concentrated. To the residue was added diisopropylether to give the object compound as a solid. 212 mg (yield: 68.6%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=1)[C:10]#N.O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=[C:25]([CH3:26])[CH:10]=1
Reactant: C=C(C)C=O
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1F
Product: Cc1cc(-c2ccc(F)cc2F)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(2,4-difluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 32%), melting at 170-172° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[CH:7]3[CH3:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:27]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[CH:7]3[CH3:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(O)c([N+](=O)[O-])cc3N21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c([N+](=O)[O-])cc3N21
Temperature: 70 °C
Yield: 52.8 %

Procedure:
To a solution of 7-hydroxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.2 g, 0.72 mmol) and K2CO3 (0.30 g, 2.16 mmol) in DMF (10 mL) was added benzyl bromide (0.37 g, 2.16 mmol) dropwise. The solution was heated at 70° C. for 14 h. The reaction mixture was cooled to ambient temperature and brine (30 mL) was added. The aqueous phase was extracted with EtOAc (3×15 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give 7-benzyloxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.140 g, 53%) as yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.08 (s, 1H), 7.62 (s, 1H), 7.49 (m, 2H), 7.44 (m, 2H), 7.39 (m, 1H), 6.81 (s, 1H), 5.23 (s, 2H), 4.70 (m, 3H), 1.56 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([CH3:18])[N:7]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>C(O)C>[CH3:38][N:37]([CH3:39])[C:34]1[CH:35]=[CH:36][C:31]([C:29](=[N:5][NH:4][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[C:8]([CH3:18])[N:7]=2)[CH3:28])=[CH:32][CH:33]=1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(N(C)C)cc1
Yield: 17.9 %

Procedure:
To a solution of 4-hydrazino-2-methyl-6-phenylpyrimidine trihydrochloride (300 mg, 0.97 mmol) and diisopropylethylamine (0.17 mL, 0.97 mmol) in ethanol (10 mL) was added 4-dimethylaminoacetophenone (158 mg, 0.97 mmol). The resultant reaction mixture was heated at reflux overnight. The reaction mixture was diluted with dIH2O and the pH was adjusted to 1-2 and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 and was extracted with ethyl acetate. The combined extracts were concentrated in vacuo and the residue crystallized from ethyl acetate:hexanes. 60 mg (18%) of the title compound was isolated as a yellow solid. HPLC Purity: 98%.
Reaction SMILES: [SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][SH:7].[C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)(=[O:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)=[O:11]
Reactant: SCCOCCS
Reactant: C=CC(=O)OCC1CO1
Product: O=C(CCSCCOCCSCCC(=O)OCC1CO1)OCC1CO1

Procedure:
2-mercaptoethyl ether, 18.3 g (0.13 mole), was reacted with glycidyl acrylate, 34 g (0.26 mole), at 25°-35° C., to give diglycidyl 4,10-dithia-7-oxatridecanedioate according to the following reaction: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)c(F)c1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1F

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-2,4-difluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.79 (d, J=8.7 Hz, 1 H), 7.51 (d, J=8.7 Hz, 1 H), 7.25-7.14 (m, 1 H), 7.08-6.99 (m, 1 H), 6.96-6.85 (m, 1 H), 4.67 (t, J=4.9 Hz, 2 H), 4.28 (t, J=4.9 Hz, 2 H), 2.89 (t, J=7.3 Hz, 2 H), 1.73-1.57 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); MS (ES) m/z 375 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.[CH:18]1([O:22][CH2:23][C@H:24]([OH:35])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)=[O:26])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([O:22][CH2:23][C@H:24]([O:35][C:2]2[C:3]3[CH:10]=[N:9][N:8]([C:11]4[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)=[O:26])[CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC2CCC2)nc1
Reactant: Cc1nccnc1-n1ncc2c(Cl)ncnc21
Product: Cc1ccc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2nccnc2C)nc1

Procedure:
Prepared using an analogous procedure to that described for Example 106 using 4-Chloro-1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate I4) with (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate U1).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]([O:9][CH3:10])([O:7][CH3:8])[CH2:4]1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH:2]([C:3]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]([O:7][CH3:8])([O:9][CH3:10])[CH2:4]1)=[O:1]
Reactant: COC1(OC)CC(CO)(C(=O)OC(C)C)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC1(OC)CC(C=O)(C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of isopropyl 1-(hydroxymethyl)-3,3-dimethoxycyclobutanecarboxylate (2.3 g, 9.90 mmol) in DCM (45 mL) was added iodosobenzene diacetate (4.78 g, 14.85 mmol) and TEMPO (0.155 g, 0.990 mmol) and the mixture was stirred at RT for 8 h. The reaction mass was diluted with DCM (25 mL), washed with and a 10% aq. solution of NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 5% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 304A as a pale yellow liquid (1.3 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 4.96 (s, 1H), 3.04 (d, J=7.18 Hz, 6H), 2.59-2.66 (m, 2H), 2.47 (m, 2H), 1.20 (d, J=6.42 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=[O:28])=[CH:21][C:20]=1[NH:29][C:30](=[O:46])[CH2:31][CH:32]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:39][C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:28])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:21][C:20]=1[NH:29][C:30](=[O:46])[CH2:31][CH:32]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:39][C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(CCC=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: Br[Mg]CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
0.18 ml of a 1M solution of cyclohexylmethylmagnesium bromide in diethyl ether was added to 2 ml of tetrahydrofuran, and the mixture was cooled to -78° C. 2 ml of a tetrahydrofuran solution containing 50 mg (0.12 mmol) of N-[2-t-butyl-5-(3-oxopropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 19) was then added dropwise to this solution, over a period of 5 minutes. The mixture was then stirred for 40 minutes at this temperature, after which the temperature was allowed to return gradually to 0° C. The reaction was then stopped by the addition of a saturated aqueous solution of ammonium chloride. Diethyl ether was added, which caused the title compound to be distributed between the organic solvent and water. The organic layer was separated and washed with water, after which the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel. Elution with a 100:15 by volume mixture of methylene chloride and ethyl acetate afforded 41 mg (yield 67%) of the title compound as crystals, melting at 145°-146° C. (after recrystallization from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[N:26]1([C:15]([C:14]2[CH:18]=[CH:19][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=3)=[N:12][CH:13]=2)=[O:17])[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.4 %

Procedure:
6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid (100 mg, 356 μmol, Eq: 1.00) was suspended in dichloromethane. Oxalyl chloride (67.8 mg, 46.8 μl, 534 μmol, Eq: 1.5) was added followed by a drop of DMF (10 μl) and the reaction mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated. The acid chloride was used as is for the next step. It was dissolved in dichloromethane (10 ml). To that was added azetidine (20.3 mg, 24.0 μl, 356 μmol, Eq: 1.00) followed by DIEA (230 mg, 311 μl, 1.78 mmol, Eq: 5) and the reaction was stirred over night at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated sodium carbonate solution, washed with brine, dried over sodium sulfate, filtered and concentrated to give a light brown solid (145 mg) which was triturated with DCM/Hex/EtOAc to give the desired product as a yellow solid (56 mg). (M+H)+=320.0 m/e
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([NH2:28])=[S:27])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:28]=[C:26]([NH:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[S:27][CH:2]=1)[CH3:9]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 56 mg (0.33 mmol) ethyl 4-chloroacetoacetate and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with diethyl ether yielding 115 mg (98%) {2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester as an off-white solid. MS ISP (m/e): 373.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.68 (s, 1H), 9.26 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.46 (d, 1H), 7.22 n(d, 1H), 6.79 (s, 1H), 4.09 (q, 2H), 3.83 (s, 3H), 3.67 (s, 2H), 2.33 (s, 3H), 1.19 (t, 3H).
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>C(OCC)C.C1COCC1>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Agent: N#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Equip a 250-mL round bottom flask with an ice bath, a magnetic stirrer, and a N2 atmosphere. Add 3-aminopyridine (15 g, 159 mmol), THF (60 mL), diethylether (60 mL), triethylamine (17.7 g, 24.4 mL, 175 mmol). Cool the mixture to 0° C. and add trimethylacetyl chloride (21.0 g, 14.9 mL, 175 mmol) slowly via syringe. Mix overnight while warming to RT. Add water (100 mL), transfer to a separatory funnel, and extract and discard the lower aqueous layer. Dry the organic layer over Na2SO4, filter, and concentrate via a rotovap to a colorless oil that solidifies on cooling. Dry under high vacuum for 2.5 h to give the title compound as a tan solid 21.56 g (76%). MS (ES) m/z 179 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH2:14][OH:15]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[CH:14]=[O:15]
Reactant: CNC(=O)CCc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CNC(=O)CCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
MnO2 (10.6 g, 110 mmol) was added to a sol. of 3-(4-chloro-3-hydroxymethyl-phenyl)-N-methyl-propionamide (2.50 g, 11.0 mmol) in CH3CN (223 mL). The mixture was stirred for 1 h at rt. The mixture was filtered over celite and washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure, and the residue was dried under high vacuum to yield the crude title compound (2.30 g, 93%) that was used without further purification. LC-MS: tR=0.76 min; ES+: 267.30.
Reaction SMILES: [C:1]1([C:7]([C:28]2NN=[N:30][N:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>CCOCC.CO>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[C:1]1([C:7]([C:28]2[O:35][C:33]([CH3:34])=[N:30][N:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C2CCN(CCC(c3ccccc3)(c3ccccc3)c3nnn[nH]3)CC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1nnc(C(CCN2CCC(c3ccccc3)CC2)(c2ccccc2)c2ccccc2)o1

Procedure:
2.0 Parts of 5-[1,1-diphenyl-3-(4-phenylpiperidino)propyl]-1H-tetrazole hemimethanolate, 6.21 parts of acetic anhydride and 20 parts by volume of pyridine are heated together to reflux for 1 hour and 20 minutes. The mixture is then cooled and stripped in vacuum. The resulting residue is taken up in ether. The ether solution is washed with sodium hydroxide, dried over sodium sulfate and then stripped in vacuum to give a gum. 1.74 Parts of this gum dissolved in 6 parts by volume of methanol and 0.35 part of oxalic acid dissolved in 4 parts by volume of methanol are mixed together. This solution is diluted with ether to just below the point of cloudiness. The crystals which form are filtered off and dried in vacuum to provide 5-[1,1-diphenyl-3-(4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole oxalate, melting at 180° - 190° C., having the following formula ##STR9##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2CCCCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(cyclohexyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aminomethylcyclohexane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([OH:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1Cc2ccc(Cl)cc2NC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2ccc(Cl)cc2NC1=O

Procedure:
7-chloro-1,2,3,4-tetrahydro-2-oxo-3-quinoline carboxylic acid, ethyl ester (1.35 g) was dissolved into a solution of potassium hydroxide (0.76 g) in ethyl alcohol (15 ml) at room temperature under stirring. A solid soon separated and was recovered by filtration after 2 hours. The solid was dissolved into cold water and hydrochloric acid was added until precipitation of a white solid took place. The title acid was recovered by filtration and after drying 1.0 g were obtained. M.p. 158°-160° C.