Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](Cl)=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3].FC(F)(F)C(O)=[O:39].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:39])[NH:10][CH:9]=[N:8][C:7]=2[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2nc[nH]c(=O)c21
Temperature: 80 °C
Yield: 53 %

Procedure:
To a solution of 1-(5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (250 mg, 0.5 mmol) in 3 mL of dioxane was added 2 mL of water followed by 2 mL of trifluoroacetic acid. The mixture was warmed at 80° C. for 1.5 hours, cooled to room temperature and made basic with saturated sodium bicarbonate, diluted with water, and extracted with EtOAc. The combined organic layers were dried, filtered, and evaporated. The residue was purified by flash chromatography eluting with MeOH—CH2Cl2 (0-2% gradient) to provide 129 mg (53%) of the title compound as a white solid. MS m/z 484.33 (MH+).
Reaction SMILES: COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[N:32]1([C:37]([C:39]2[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=2)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28]([C:42]4[CH:41]=[CH:40][C:39]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36]5)=[O:38])=[CH:44][CH:43]=4)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)cc1)N1CCCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 475.6 %

Procedure:
1,2-dimethoxyethane (3.0 ml) and aqueous 2 N sodium carbonate solution (1.0 ml) were added to 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (176 mg, 0.54 mmol), and then 4-(pyrrolidin-1-ylcarbonyl)phenylboronic acid (142 mg, 0.065 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) were added thereto and stirred in a nitrogen atmosphere at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, and water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-200, chloroform:methanol=10:1) to obtain the entitled compound (130 mg, 57%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC(N(C)C)=O>[C:35]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(C)=O)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.7 %

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and triethylamine (13 μL, 90 μmol) in 300 μL of DMA was added acetic anhydride (6 μl, 60 μmol). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (4.8 mg, 11 μmol) as white powder. ES/MS m/z 426.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:9][O:10][CH2:11][C:12]([NH2:25])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: FC(F)Oc1ccc(C2(c3cccc(Br)c3)COCC(=S)N2)cn1
Solvent: CO
Product: NC1=NC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)COC1
Temperature: 100 °C

Procedure:
A dried pressure tube was charged under an argon atmosphere with a dispersion of 5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholine-3-thione (1.0 g) in a solution of ammonia (7M) in methanol (30 ml). The tube was sealed and heated at 100° C. for 3 hours. After cooling, the reaction mixture was evaporated to dryness and dissolved in dichloromethane, then loaded onto an SCX-cartridge. A 1:1-mixture of dichloromethane and methanol was passed through the column to remove impurities, and the aminoxazine was eluted with ammonia in methanol (2M solution). The (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a yellow foam (0.82 g, 83% of theory). MS (ISP): m/z=399 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15](O)=[O:16])=[CH2:13]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([OH:19])=[O:18])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc(N)cc1F
Solvent: CO
Product: COc1ccc(N2CC(C(=O)O)CC2=O)cc1F
Temperature: 110 °C

Procedure:
A mixture of 3-fluoro-4-methoxybenzenamine (7.5 g, 0.053 mmol) and itaconic acid (6.9 g, 0.053 mmol) was heated to 110° C. for 2 h. The yellow solid was dissolved in 100 mL of MeOH and concentrated in vacuo. The resulting solid was washed with 50% EtOAc/hexanes to give the title compound as a light yellow solid. MS (ESI pos. ion) m/z: 254.2 (M+H). Calc'd Exact Mass for C12H12FNO4: 253.23.
Reaction SMILES: O.[C:2]([NH:9][C:10](=[NH:19])[NH:11]C(OC(C)(C)C)=O)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CC(OC)(C)C>[C:5]([O:4][C:2]([NH:9][C:10]([NH2:19])=[NH:11])=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 57.5 °C

Procedure:
After addition of water (200.00 g) the resultant mixture was evaporated to yield a solid comprising the crude product together with inorganic salts and a small amount of bis-Boc-guanidine. The solids were suspended in 2-Me-THF (344.00 g), the suspension was stirred and heated to reflux and maintained at reflux for about 1 h. The suspension was then cooled to about 55-60° C. and filtered warm to remove the inorganic salts. Evaporation of the 2-MeTHF yielded a solid. This solid was re-suspended in MTBE (37.00 g) and the resultant suspension was stirred at ambient temperature for ˜1 h. The suspension was filtered, and the solid was washed with MTBE (18.5 g). The MTBE treatment was repeated again and the resultant product was air dried for several hours at ambient temperature. The product —N-(t-butyloxycarbonyl)-guanidine—was isolated as a solid.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][CH:9]1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1CCN1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1CCN1
Yield: 92.4 %

Procedure:
A suspension of 18.8 g (68.0 mmol) of 1-benzyl-2-[(t-butoxycarbonylamino)methyl]azetidine, 8.2 g (137 mmol) of acetic acid, 1.0 g of 20% palladium on carbon and 200 ml of tetrahydrofuran was shaken in a hydrogen atmosphere at pressures of 48.3-51.7 psi and temperatures of 21.5°-27° for 16 hours. The catalyst was removed by filtration and the solvent was removed. in vacuo to give 11.7 g (92%) of the title compound as a colorless viscous oil which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:20](F)=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1>O>[F:12][C:13]1[C:14]([C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(F)c1nc(F)ccc1F
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)c1nc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added dropwise at room temperature to the 3,6-difluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature for 6 hours, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture ( 1/10) as eluent to give 0.39 g (48% yield, 99% GC purity, 98% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,6-difluoropicolinate: 70 eV EIMS (GC) m/z=160 (41%), 142 (100%), 115 (43%), 114 (66%), 64 (31%), 43 (51%). 1H NMR (400 MHz, CDCl3) δ 7.69 to 7.63 (m, 1H), 7.16 to 7.12 (m), 5.33 (hept, J=6.3 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 161.41 (d, J=6.3 Hz), 158.80 (d, J=1.2 Hz), 158.26 (d, J=4.3 Hz), 156.41 (d, J=1.2 Hz), 155.62 (d, J=4.4 Hz), 134.05 (t, J=13.5 Hz), 131.06 (dd, J=23.9, 8.3 Hz), 114.86 (dd, J=41.7, 5.9 Hz), 70.34 (s), 21.71 (s). 19F NMR (376 MHz, CDCl3) δ −69.40 (d, J=26.9 Hz), −122.76 (d, J=27.4 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][CH:14]([CH3:18])[CH2:15][CH:16]=O.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:16][CH2:15][CH:14]([CH3:18])[CH3:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C)CC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 0.414 ml of 3-methylbutyraldehyde (3.75 mmol) were dissolved in 7.5 ml methanol at rt and then refluxed for 1.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and the reaction mixture was then refluxed for 1.5 h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 458 mg light yellow oil (78%). MS (ISP) 234.3 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:26])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:11][C:10](=[O:26])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1O
Yield: 113.1 %

Procedure:
Twenty percent Pd/C (50 mg) was added to a solution of 3-benzyloxy-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example 1, 0.21 g, 0.6 mmol) in 100 mL of THF and 100 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 4.5 hours, filtered, and concentrated to afford 0.18 g of the title compound as a solid, mp >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
The mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (130 mg, 0.32 mmol), tert-butyl 4-aminobenzoate (185 mg, 0.96 mmol), EDC (122 mg, 0.64 mmol) and DMAP (78 mg, 0.64 mmol) in 10 mL of DMF was stirred at room temperature for 2 hours. Excess of DMF was removed under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate, washed with brine (2×10 mL), dried over anhydrous sodium sulfate. The crude residue was purified by silica gel chromatography (200-300 mesh, eluting with ethyl acetate) to give tert-butyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoate (130 mg, 70%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.76 (s, 1H), 10.18 (s, 1H), 9.41 (s, 1H), 8.97 (s, 1H), 8.62 (d, 1H, J=8.1 Hz), 8.10 (d, 1H, J=7.8 Hz), 7.95 (s, 4H), 7.85 (s, 1H), 7.71 (t, 1H, J=7.7 Hz), 7.54 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.75 (s, 3H), 1.57 (s, 3H). LC-MS: 584 [M+H]+, tR=1.78 min. HPLC: 98.03% at 214 nm, 98.38% at 254 nm, tR=7.05 min.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>CO>[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCCO)C(=O)C1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
700 mg (2.13 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(6-hydroxyhexylthio)-2-cyclopentenone, 1020 mg (10 mmoles) of acetic anhydride and 1580 mg (20 mmoles) of pyridine were mixed, and stirred at room temperature for 2 hours. After the reaction, methanol was added. The solvent was removed to give 795 mg of 4-t-butyldimethylsilyloxy-2-(6-acetoxyhexylthio)-2-cyclopentenone as a nearly pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[OH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:30][CH2:31][CH:27]([OH:26])[CH2:28]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: OC1CCNC1
Product: CCOc1ccc(S(=O)(=O)N2CCC(O)C2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and, 70 mg (0.784 mmol) of 3-hydroxypyrrolidine, 13 mg (11.1% of theory) of 2-[2-ethoxy-5-(3-hydroxy-pyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2]triazin-4-one are obtained.
Reaction SMILES: OC(C)COC1C=CC([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[CH:12][CH:11]=[CH:16][N:15]=2)=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCc1ccc(-c2ncc(-c3ccc(OCC(C)O)cc3)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(-c2ncccn2)cc1
Reaction time: 2 h

Procedure:
A mixture of 5 g of 5-[4-(2-hydroxypropyloxy)phenyl]-2-(4-nonylphenyl)pyrimidine, 2.6 g of S-2-butyloxypropanic acid, 4 g of dicyclohexylcarbodiimide, 0.3 g of dimethylaminopyridine and 60 ml of dichloromethane was stirred for two hours. After the obtained crystals were filtered off, toluene was added to the filtrate. The mixture was washed with an alkali solution and then with water. The solvent was distilled away. 4 g of S-5-{4-[2-butyloxypropionyloxy)propyloxy]phenyl}-2-(4-nonylphenyl)pyrimidine was obtained by recrystallization from a mixed solution of ethanol and ethyl acetate. Its melting point was 98.0° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:30])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[CH:1]1([N:6]2[C:10]3=[N:11][C:25]([C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][N:18]([CH3:17])[CH3:30])[CH:23]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CN(C)CCOc1cccc(C=O)c1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCCN(C)C)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.50 g, 15.74 mmol), 3-[2-(dimethylamino)ethoxy]benzaldehyde (3.95 g) and xylenes (10 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, the solvent was stripped, and the residue was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford, as an oil, 1-cyclopentyl-3-ethyl-6-[3-[2-(dimethylamino)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one labelled as [Example 23 (b)]. The free base was treated with ethanolic HCl to afford the product as the hydrochloride salt [labelled as Example 23 (c)].
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O>CN(C=O)C>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (13.4 g, 30.98 mmol, 1.00 equiv) in anhydrous DMF (100 mL) followed by potassium phthalimide (7.5 g, 40.49 mmol, 1.31 equiv). The resulting solution was heated to 100° C. and stirred for 3 h. The reaction progress was monitored by LCMS. The DMF was removed under vacuum to afford a brown oil residue. To the residue was added 200 mL water and the mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of solvent, The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:3). The solvent was removed from fractions containing phthalimide and the residue was washed with 20% ethyl acetate/petroleum ether to yield 10.1 g (78%) of tert-butyl 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:9]([CH2:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1)=[N+:10]=[N-:11]
Reactant: Cc1nnc(CCl)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(CN=[N+]=[N-])o1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
A solution of 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (R. Rufenacht, Helv. Chim. Acta, 55, 1979, 1972) (2.00 g, 15.09 mmol) in N,N-dimethylformamide (75 ml) was treated at 22° C. with sodium azide (3.0 g, 46.1 mmol) and the resulting mixture was stirred for 18 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by chromatography of the residue on silica gel (elution toluene-ethyl acetate 0-10%) gave 1.78 g (84% yield) of the title azide as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.60 (3H, s, CH3), 4.55 (2H, s, CH2). MS (ESI+) m/e 140 [M+H+].
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C>>[CH2:14]([O:13][CH:4]1[CH2:5][CH:6]2[CH2:7][CH:8]1[CH:9]=[CH:10]2)[CH2:15][CH2:16][CH3:17]
Reactant: C=COCCCC
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: CCCCOC1CC2C=CC1C2

Procedure:
Dicyclopentadiene was heated with butyl vinyl ether to form the Diels-Alder product of 5-butoxy-2-norbornene. The product was then purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:12]([O:14]CCO)=[O:13])[NH:10][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Reaction time: 16 h

Procedure:
2-Hydroxyethyl 4-(4-chlorophenoxy)pyrrole-2-carboxylate (400 mg.) was dissolved in 10 ml. of acetone and 10 ml. of 1 N sodium hydroxide and left to stand at room temperature for approximately 16 hours. Acetone was evaporated in vacuo, the aqueous residue was acidified with conc. hydrochloric acid and crystalline product (320 mg.) recovered by filtration. Recrystallization from ether/hexane of 400 mg. of product prepared in this manner affored purified 4-(4-chlorophenoxy)pyrrole-2-carboxylic acid (234 mg., m.p. 188°-190° C., m/e 237).