Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][C:18]=1[F:30])(C(C)(C)C)(C)C.C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:30][C:18]1[CH:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]1[CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[CH:13]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cc(OCCO[Si](C)(C)C(C)(C)C)cc(Oc3ccccc3)c2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCc2cc(OCCO)cc(Oc3ccccc3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Ethyl 3-(4-{[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-phenoxybenzyl]oxy}-3-fluorophenyl)propanoate (0.43 g, 0.75 mmol) was dissolved in a solution of tetrabutylammonium fluoride in THF (3 mL, 3.00 mmol), and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (0.25 g, yield 74%) as an oily matter.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22]>>[ClH:22].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
A solution of ethyl 4-(3-piperidin-1-ylpropoxy)benzoate (D1) (1.4 g) in concentrated hydrochloric acid (15 ml) was heated under reflux for 1 h, cooled and evaporated to give the title compound (D2) (1.02 g). MS electrospray (+ion) 264 (MH+). 1H NMR δ (DMSO-d6): 10.59 (1H, s), 10.25 (1H, s), 7.90 (2H, d, J=9 Hz), 7.02 (2H, d, J=9 Hz), 4.14 (2H, t, J=6 Hz), 3.05-3.52 (4H, m), 2.91 (2H, m), 2.20 (2H, m), 1.25-1.91 (6H, m).
Reaction SMILES: Br[C:2]1[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:4]3[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=3[C:6](=[CH2:13])[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][C:12]=3[CH:2]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: C=C1c2ccccc2C=C(Br)c2ccncc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C=C1c2cnccc2C=C(N2CCN(C)CC2)c2ccccc21

Procedure:
A mixture of 5-bromo-11-methylenebenzo[5,6]cyclohepta[1,2-c]pyridine (11.0 g.), 1-methylpiperazine (7.8 ml.), potassium tert.-butoxide (8.4 g.) and tert.-butanol (150 ml.) is heated under reflux for 4 hours. The tert.-butanol is removed in vacuo and the residue is taken up in methylene chloride (600 ml.). The resulting mixture is washed with 10% NaCl solution, saturated NaCl solution, and dried (anhydrous Na2SO4). Filtration and removal of the solvent gives 10.76 g. of dark amber oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[C:10]([I:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]cc(I)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a suspension of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR, 0.48 g, 3.0 mmol) in DMF (8 mL) was added N-iodosuccinimide (0.80 g, 3.6 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and washed with ethyl acetate to give the desired product as yellow solid (0.81 g, 95%). LCMS calculated for C7H6IN4O (M+H)+: m/z=289.0; Found: 289.0.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[N:25]=[CH:26][C:27]5[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:28]=5[N:29]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C.CN(C=O)C>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[N:25]=[CH:26][C:27]5[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:28]=5[N:29]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ncc5c(n4)c(C)nn5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3ccnc(-c4ncc5c(n4)c(C)nn5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
A solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (7.7 mg, 0.012 mmol) and 5M sodium hydroxide (20 μL, 0.012 mmol) in THF (1 mL) and MeOH (0.2 mL) was stirred at 50° C. for 2 h. Reaction mixture was cooled to rt, acetic acid (15 μL) and DMF (0.3 mL) were added and reaction mixture was concentrated to ˜0.3 mL, filtered, purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) and lyophilized to give desired product. LCMS-ESI+: calc'd for C32H30ClN6O3S: 613.2 (M+H+); Found: 613.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 9.41 (s, 1H), 9.28 (s, 1H), 8.85 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.76-7.43 (m, 4H), 5.28 (s, 1H), 4.16 (s, 3H), 2.71 (s, 3H), 2.65 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[O:17][C:18]4[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=4[C:20]=3[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=1.[OH-].[K+]>C1COCC1.CO>[C:21]([C:20]1[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[O:17][C:16]=1[C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])[CH:15]=[CH:14]2)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a stirred solution of {[6-(3-benzoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.128 g, 0.293 mmol) in THF:MeOH (3:2, 10 mL) at 0° C. was added 1 N KOH (0.879 mL, 0.879 mmol) dropwise. The reaction was stirred at this temperature for 0.25 h and then warmed to room temperature for 1 h. After concentration, the residue was diluted with H2O, and this mixture was acidified to pH 1 with 2 N HCl. After stirring at room temperature for 3 h, the solid was filtered and washed with excess H2O and hexane. At this point, the compound was dried under high vacuum to afford the product (0.116 g) as a yellow solid, mp 178-181° C. Mass spectrum (−APCl, [M−H]−) m/z 421. 1HNMR (500 MHz, DMSO-d6): δ11.05-14.15 (br s, 1H), 8.17 (d, J=1.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.76-7.81 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.42-7.51 (m, 2H), 7.31-7.37 (m, 3H), 7.18-7.24 (m, 2H), and 4.77 ppm (s, 2H). Elemental Analysis for C27H18O5.0.5H2O: Calculated: C, 75.17; H, 4.44; N, 0.00 Found: C, 75.03; H, 4.34; N, 0.14
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:24])/[CH:14]([OH:23])[C:15]([CH3:22])([CH3:21])[C:16]([O:18]CC)=[O:17])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2>CCOCC.C(OCC)(=O)C>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:24])/[CH:14]([OH:23])[C:15]([CH3:21])([CH3:22])[C:16]([OH:18])=[O:17])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2
Reactant: CCOC(=O)C(C)(C)C(O)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C(O)C(C)(C)C(=O)O)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) 2,4-dimethyl-4-hexenoate with ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-3-hydroxy-4-hexenoate and the corresponding compounds of Formula I-ZA-M1 prepared as described in Part A above, there are obtained (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-3-hydroxy-4-hexenoic acid, m.p. 180°-181° C. (ether/ethyl acetate) and the corresponding compounds of Formula I-ZA-M2 (where Z2 is OH) as identified in the following table.
Reaction SMILES: [CH2:1]([C:3]1[N:13](CC2C=CC3/C(=C(\C)/C#N)/C4C=CC=CC=4CCC=3C=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].OCC1C=CC2/C(=C(\C)/C#N)/C3C=CC=CC=3CCC=2C=1>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C(/C)C#N
Agent: C/C(C#N)=C1/c2ccccc2CCc2cc(CO)ccc21
Product: CCc1nc2c(C)cc(C)nc2[nH]1
Yield: 227.7 %

Procedure:
[step 1] (E)-2-[2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (399 mg, 69%) was obtained in the same manner as in step 1 of Example 36, using (E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propiononitrile (367 mg, 1.3 mmol) obtained in Reference Example 6 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (366 mg, 2.1 mmol) instead of 5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:19]O>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OO
Reactant: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cnc3c[n+]([O-])ccc32)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
In 15 mL of acetic acid, 483 mg (2.01 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine prepared in Step A of Example 1 was dissolved, and 2 mL of a 30% hydrogen peroxide aqueous solution was added thereto and the mixture solution was stirred at 50° C. for 14 hours. The solvent was distilled under reduced pressure, and the obtained residue was separated by a silica gel column (Si-10, a product of Kusano Co., Ltd., column 30 cm, dichloromethane:methanol=9:1) to obtain 298 mg (57%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine 5-oxide as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[I-:34].[Na+]>CC(=O)CC>[I:34][CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: [I-]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Yield: 85 %

Procedure:
A solution of Compound 3 (200 mg) and sodium iodide (200 mg) in 2-butanone (4 mL) was heated at 80° C. for 24 hours. Solvent was removed under reduced pressure and directly purified on a silica gel using 1% ethanol in dichloromethane to obtain the required product in 85% yield (200 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[H][H]>[Pd]>[F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][CH2:7][CH3:8])=[O:4]
Reactant: [H][H]
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Pd]
Product: CCCNC(=O)C(F)(F)F

Procedure:
In Reaction Scheme 4, 6-amino-4-methoxypyrazolo[3,4-d]pyrimidine was converted to the iodo derivative (14) which was treated with 1-chloro-1,2-dideoxy-3,5-di-O-toluoylribofuranose to yield the nucleoside (15). Compound (15) was treated with NaOMe/MeOH to hydrolyze the toluoyl groups and yield the unblocked nucleoside (16). Treatment of (16) with aqueous sodium hydroxide gave (17) which could be converted to the trifluoro-N-prop-2-ynyl acetamide derivative (18). Compound (18) was reduced with hydrogen and a Pd catalyst to yield the trifluoro-N-propylacetamide derivative (19). The 4-amino group of compound (19) was protected by treatment with N,N-dimethylformamide dimethylacetal to give compound (20) which was converted to DMTr derivative (21) and then to the phosphoramidite derivative (22).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=3[C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[F:24][C:22]([F:23])([F:25])[C:19]1[CH:20]=[CH:21][C:14]2[O:13][C:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=3)(=[O:10])=[O:11])=[C:16]([CH3:17])[C:15]=2[CH:18]=1
Reactant: COc1ccc(S(=O)(=O)c2oc3ccc(C(F)(F)F)cc3c2C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)c2ccc(=O)[nH]n2)oc2ccc(C(F)(F)F)cc12
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-pyridazine (1.34 mmol, 500 mg), conc. HCl (2 mL), and dioxane (4 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue. The resulting white solid was collected and air dried to obtain the desired product: 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one (56%, 270 mg); mp 244° C.-245° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)COCCO.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.O>[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Solvent: O
Solvent: OCCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)cc(N[C@H]2CCN(Cc3ccccc3)C2)n1
Temperature: 140 °C
Yield: 24.4 %

Procedure:
A mixture of 2-chloro-6-methyl-4-trifluoromethylpyridine (0.196 g), (S)-1-benzyl-3-aminopyrrolidine (0.529 g), diethylene glycol (4 mL), and N,N-diisopropylethylamine (0.52 mL) was heated at 140° C. for 2 h using a microwave reaction apparatus. After completion of the reaction, water and ethyl acetate were added to the reaction solution, the mixture was extracted with ethyl acetate, washed with saturated brine, and then dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and then the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (silica gel, hexane/ethyl acetate=5:1-2:1) to obtain (S)-N-(1-benzylpyrrolidin-3-yl)-6-methyl-4-trifluoromethylpyridin-2-amine (0.082 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]1=[O:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:8][CH:2]([NH:1][C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[O:36])[C:3]1=[O:26])[CH3:25]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2F)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(RS)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 253°-254° C.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4](O)=[O:5].C[CH2:18][N:19]=[C:20]=NCCCN(C)C.Cl.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CNC>O1CCOCC1>[CH2:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:5])[N:19]([CH3:20])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CNC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (0° C.) solution of Z-Beta-Ala-OH (1.784 g, 8.0 mmol) in dioxane (20 ml) is added EDCI.HCl (2.145 g, 11.2 mmol), hydroxybenzotriazole (1.08 g, 8.0 mmol) and triethylamine (1.56 ml, 11.2 mmol). After stirring at 0° C. for 30 minutes, dimethylamine (0.397 g, 8.8 mmol) is added and stirring continued for a further hour. The reaction mixture was allowed to warm to room temperature and the solvent is removed in vacuo. Initial purification of the crude residue is carried out by flash chromatography of silica eluting with ethyl acetate. The combined organic factions are washed with water (3×20 ml), brine (1×50 ml) and dried over MgSO4. The solvent is removed in vacuo to yield the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)Nc2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 80 %

Procedure:
To a stirred solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.10 g, 0.40 mmol) in anhydrous tetrahydrofuran (5 mL), triethylamine (0.17 mL, 0.12 g, 1.22 mmol) and phenyl isocyanate (0.07 mL, 0.072 g, 0.61 mmol) were added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 25 h and then diluted with ethyl ether (20 mL). The white precipitate obtained was collected by filtration, washed with ethyl ether (3×6 mL) and dried under the reduced pressure to afford the title compound as a white solid in 80% yield (0.119 g); m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.00 (s, 1H), 8.47 (t, J=5.7 Hz, 1H), 7.46-7.17 (m, 10H), 7.03-6.98 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.2, 140.0, 129.4, 129.2, 128.7, 127.7, 127.1, 123.3, 119.1, 118.6, 43.0, 39.1; MS (ES+) m/z 367.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:24][NH:23][C:10](=[O:11])[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2ccccn2)=C1c1ccc(Cl)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
A mixture of 0.67 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-pyridyl)-2(5H)-fu ranone, 0.25 g of hydrazine monohydrate and 8 ml of 1-butanol was stirred for 5 hours on an oil bath of 110° C. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The resultant solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 0.32 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)-2H-pyridazin-3-one.
Reaction SMILES: OO.[CH3:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH3:13])=[C:8]([CH3:14])[N:7]=1.CC[O:17]CC>C(O)(=O)C>[CH3:3][S:4]([CH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH3:13])=[C:8]([CH3:14])[N:7]=1)=[O:17]
Reactant: CCOCC
Reactant: CSCc1nc(C)c(C)c(O)n1
Agent: OO
Solvent: CC(=O)O
Product: Cc1nc(CS(C)=O)nc(O)c1C
Reaction time: 3 h
Yield: 85 %

Procedure:
6.8 g (0.1 mol) of 50% strength hydrogen peroxide were added to a mixture of 18.4 g (0.1 mol) of 2-methylthiomethyl-4-hydroxy-5,6-dimethylpyrimidine in 100 ml of glacial acetic acid at 10° C. The mixture was subsequently stirred for 3 hours, without cooling, about 300 ml of ether were added and the product which had precipitated was filtered off. 17 g (85% of theory) of 2-methysulphinylmethyl-4-hydroxy-5,6-dimethylpyrimidine were thus obtained in the form of a grey powder with a melting point of 112° C. ##STR7##
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(C#CCCCOc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCc1cccc(CCCCCOc2ccccc2)c1
Yield: 100.3 %

Procedure:
This compound was prepared in a manner analogous to that used for the para isomer (Example 6). Thus 1.856 g of 3-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml of CH3OH was treated with 333 mg 5% palladium on charcoal and 30 PSI hydrogen for 1.25 hours. The product mixture was filtered in the customary manner through celite and the filtrate was evaporated in vacuo to yield 1.89 g of the 3-(5-Phenoxypent-1-yl)benzyl alcohol in the form of a tan solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][NH2:9])=O)=[CH:2]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:21]=[C:20]3[N:9]([C:18]([SH:19])=[N:17][C:15]4[CH:16]=[CH:11][CH:12]=[CH:13][C:14]=43)[N:8]=2)=[CH:2]1
Reactant: NNC(=O)c1ccoc1
Reactant: N#Cc1ccc(Cl)cc1N=C=S
Product: Sc1nc2ccccc2c2nc(-c3ccoc3)nn12

Procedure:
As in Example 39, 3-furoic acid hydrazide is reacted with 5-chloro-2-cyanophenyl isothiocyanate to produce 2-(3-furyl)-5-mercapto-[1,2,4]triazolo[1,5-c]quinazoline, mp>300°, which is converted to the 5-methylthio compound and thence to 9-chloro-2-(3-furyl)-5-imino-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline, purified as the methanesulphonate salt, mp 290°-292°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5](/[C:10](=[CH:12]/[C:13](=[O:15])[CH3:14])/[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([CH:10]([CH2:12][C:13](=[O:15])[CH3:14])[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)/C=C(\C)c1cc(Cl)c(N)cc1C#N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)CC(C)c1cc(Cl)c(N)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.5 %

Procedure:
(E)-5-amino-4-chloro-2-(4-oxopent-2-en-2-yl)benzonitrile (120 mg, 0.51 mmol) and Pd(OH)2 on carbon (10% w/w, 10 mg) was suspended in MeOH (3 mL). Acetic acid (0.06 mL) was then added and the reaction was stirred at room temperature under a balloon of H2 for 48 h. The reaction was then filtered through a pad of Celite, washing with EtOAc. The eluent was then concentrated in vacuo and the material was purified on ISCO (0-80% EtOAc/Hexane) to give 5-amino-4-chloro-2-(4-oxopentan-2-yl)benzonitrile (73 mg) as a white solid.