Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:12]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:12])[C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1ncccc1Cl
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1c(Cl)ccc[n+]1[O-]

Procedure:
To a stirring solution of 3-chloro-2-pyridinesulfonamide (2.5 g, 13.0 mmol) in 35 mL of trifluoroacetic acid was added 30% H2O2 (1.2 g, 35.1 mmol). The solution was concentrated to ~15 mL, diluted with ethyl acetate, washed twice with brine, dried and concentrated. The resulting solid was flash chromatographed with EtOAc to afford the desired product, m.p. 195°-197° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 83188.9 %

Procedure:
To a stirred solution of ethyl (2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (15) (7.75 g, 0.0185 mmol) in THF (100 mL) and EtOH (100 mL) was slowly added 1 N NaOH (93 mL) solution at RT. The reaction mixture was heated to 70° C. and stirred at that temperature for 4.5 h. Reaction mixture was cooled to room temperature and then poured into 20% aqueous HCl (350 mL). The product was separated out as an off-white solid. The suspension was filtered and the filtered solid was dried to afford 6.01 g (83%) of compound 16 as an off-white solid. mp 219-220° C. 1H NMR (300 MHz, DMSO-d6): δ 0.89 (s, 6H), 0.90 (s, 6H), 1.27 (s, 2H), 1.91 (s, 2H), 1.94 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.68 (d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 9.31 (s, 1H), 12.35 (s, 1H). LRMS (ESI): m/z 389 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1F
Temperature: 120 °C
Yield: 25.6 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 90 mg, 0.261 mmol), 3-Fluoro-4-methoxyphenylboronic acid (89 mg, 0.522 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 21 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.5 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 120° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (55-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (29 mg, 26%). 1H NMR (DMSO-d6) δ: 11.18 (s, 1H), 7.82-8.28 (m, 5H), 7.61 (d, 2H), 7.43 (t, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 1H), 3.97 (s, 3H), 2.42 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 435.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:5][N:6]1[C:10](C)=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8](C)=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:48][C:46]1[CH:45]=[C:4]([CH:3]=[C:2]([F:1])[CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl) methanesulfonamide (210 mg, 0.3 mmol) was hydrolyzed by lithium hydroxide (34.2 mg, 0.91 mmol), THF/Methanol/water (4/6/1 mL) to afford 1.6 mg of the titled compound after purification by preparative TLC (SiO2-1000 micron) eluted by 3% MeOH in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 8.9 (b, 1H), 8.5 (s, 1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.0 (m, 1H), 6.85 (m, 1H), 6.78-6.7 (m, 3H), 5.29 (s, 2H), 3.93 (s, 3H), 2.98 (s, 3H), 2.51 (s, 3H), 2.17 (s, 3H). MS: m/z=538.1 (M+1), HPLC: 86.27% in method B.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:15]2[N:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2cc3cccnc3c(N[C@H]3CCNC3)n2)[nH]1

Procedure:
A mixture of (S)-tert-butyl 3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (80 mg, 0.201 mmol) in DCM (3 mL) was treated with TFA (1.5 mL) for 2 hours. The solvent was removed in vacuo to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Br>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:4](=[O:15])[N:3]1[CH2:18][O:19][CH3:20]
Reactant: COCBr
Reactant: Cn1[nH]c(=O)n(-c2ccc(Cl)cc2)c1=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Reaction time: 0.5 h

Procedure:
To 1-methyl-4-(4-chlorophenyl)-1,2,4-triazolidin-3-one-5-thione (5 g) in 200 ml dry DMF was added 0.91 g sodium hydride. After stirring for 30 minutes, bromomethyl methyl ether (2.63 g) was added dropwise, then heated to reflux for 30 minutes, and stirred overnight at room temperature. The solvent was stripped and the residue was dissolved in methylene chloride, washed with water, and chromatographed on a silica gel column (200 g) by elution with methylene chloride, followed by 2.5% methanol in methylene chloride. Yield: 4.8 g.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=1)[OH:25]
Reactant: COc1cccc(C=O)c1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)c2nc3c(cc2C)CCCCC3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 m,) in toluene (20 ml) at -20°, under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl 5-H-cyclohepta[b]pyridine (6 g, 0.025 m) in toluene (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a cooled solution (-20° C.) of 3-methoxybenzaldehyde (3.7 g) in toluene (30 ml) and allowed to warm up to room temperature. Water was added and the organic phase separated and treated with 2N hydrochloric acid. A precipitate formed and this was collected by filtration and treated with sodium carbonate solution, then chloroform. The organic phase was washed with water, dried (MgO4) and evaporated. Trituration with diethyl ether gave 1-(6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-(3-methoxyphenyl)methanol (4.42 g, 59%) m.p. 104°-6° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[C:14]([O:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[C:14]([O:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: COc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1C(C)C
Temperature: 140 °C
Yield: 36.2 %

Procedure:
To a solution of 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 777 μmol) in NMP (2.6 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (672 mg, 2.33 mmol) in four portions approximately every 12 h and heated to 140° C. in the periods between additions. After a total of 48 h, the mixture was cooled then diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (2×), concentrated in vacuo and purified by chromatography (silica, 0 to 4% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (141 mg, 281 μmol, 36%) as light brown solid. MS (EI/CI) m/z: 502.3 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:21][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCl
Reactant: O=C(/C=C/c1cccnc1)NCC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C(O)CNC(=O)/C=C/c2cccnc2)c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 51.3 %

Procedure:
(E)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-3-(3-pyridyl)-2-propenoic acid amide (5.68 g, 20 mmol) and ethyl chloroacetate (5.2 ml, 48 mmol) were dissolved in dimethylformamide (60 ml) and potassium carbonate (8.28 g, 60 mmol) was added and stirred at 50° C. for 7 hours. After allowing to cool, insoluble materials were filtered out and water was added to the filtrate, extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:hexane:methanol=20:2:1) and dried under reduced pressure to yield the titled compound (3.80 g, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.F[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1N1CCOCC1)[NH2:38]>>[CH2:2]1[C:35]2[C:41](=[CH:40][CH:39]=[C:37]([NH:38][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-fluoro-4-(4-morpholinyl)aniline by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (t, 4H, J=4.5 Hz), 3.76 (t, 4H, J=4.5 Hz), 6.61 (d, 1H, J=5.2 Hz), 6.96 (t, 1H, J=9.4 Hz), 7.17 (t, 1H, J=6.8 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.37 (d, 2H, J=7.9 Hz), 7.48-7.55 (m, 2H), 7.63 (t, 1H, J=8.3 Hz), 7.73 (d, 1H, J=15.5 Hz), 7.85 (d, 1H, J=8.8 Hz), 8.06 (s, 1H), 8.32 (d, 1H, J=5.2 Hz), 8.47 (d, 1H, J=8.0 Hz), 8.90 (d, 1H, J=6.9 Hz), 9.63 (s, 1H), 10.97 (s, 1H); ESIMS (M+H)+=622.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[OH:17].[OH-].[K+]>C(O)C>[C:11]1([C:9]2[CH:8]=[CH:7][C:6]3[O:17][C:1](=[S:3])[NH:4][C:5]=3[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C=S
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbon disulfide (7.7 mL) was added to a mixture of 2-amino-4-phenylphenol (1.0 g, 5.4 mmol), potassium hydroxide (0.36 g, 6.5 mmol) and ethanol (11.7 mL). The flask was fitted with a reflux condenser and the resulting mixture was placed in an oil bath at 60° C. for 16 h. After cooling to RT, the mixture was concentrated and ethyl acetate (20 mL) and 1 M hydrochloric acid (10 mL) were added to the residue. The layers were partitioned and the organic layer was washed successively with 1 M HCl, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford 1.20 g (98%) which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 13.98 (s, 1H), 7.64-7.62 (m, 2H), 7.58-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.33 (m, 2H); 13C (d6-DMSO, 400 MHz) δ 181.2, 148.4, 140.1, 138.5, 132.7, 129.7, 128.3, 127.7, 123.4, 111.0, 109.1; MS (Cl) m/z 228.1 (M+1); HPLC retention time=3.09 min.
Reaction SMILES: NN.[C:3]([O:7][C:8](=[O:44])[NH:9][C@H:10]([CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]2)=[CH:17][CH:16]=1)([CH3:6])([CH3:5])[CH3:4].C(OCC)C>C1COCC1.C(O)C>[C:3]([O:7][C:8](=[O:44])[NH:9][C@H:10]([CH2:32][NH2:33])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]2)=[CH:17][CH:16]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 45 °C

Procedure:
Hydrazine (2.2 ml of a 1M solution in THF, 2.2 mmol) is added to a solution of [(S)-5-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester (0.16 g, 0.28 mmol) in ethanol (5 ml), and the resulting colourless solution is heated at 45° C. overnight. The reaction is allowed to cool to room temperature, and diethyl ether (30 ml) is added and the resulting white suspension cooled at 0° C. for 30 minutes. The white solid is removed by filtration, and the solvent removed in vacuo to yield {(S)-1-Aminomethyl-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-3,3-dimethyl-pentyl}-carbamic acid tert-butyl ester as a colourless oil; [M+H]+ 451.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][O:21][C:22](=[O:29])[C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)[CH:3]=1)([CH3:25])[C:22]([O:21][CH3:20])=[O:29]
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reactant: COC(=O)C(C)(C)N=C=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a solution of 4-(3-amino-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (4) (50 mg, 0.195 mmol) in dry DCM (10 ml) was added 2-isocyanato-2-methyl-propionic acid methyl ester (60 mg, 0.428 mmol). The resulting solution was stirred for 2 days, washed with water (3×10 ml), dried over sodium sulphate and concentrated in vacuo to yield a semi-crystalline solid (44 mg).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41]1([P:47](Cl)(=[O:55])[O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([P:47](=[O:55])([O:32][C:30]([CH3:31])=[C:16]([N:13]2[C:12](=[O:33])[CH:11]3[CH:14]2[S:15][C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]3)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=P(Cl)(Oc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OP(=O)(Oc1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0° C. was added triethylamine (1.6 ml.) followed by phenyl phenylphosphonochloridate (2.91 g). After stirring for 3 hours at 20° C., the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1% hydrochloric acid and then water, dried with magnesium sulphate and evapoated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silica)Rf 0.64 (ethyl acetate). NMR δCDCl3 2.60 (m, 3H), 3.70-4.67 (m, 2H), 5.15 (s, 2H), 5.57-5.87 (m, 2H) and 6.6-8.17 (m, 19H).
Reaction SMILES: [N:1]#[N:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C@@H:12]([CH3:14])[OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[N:1]#[N:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([NH:17][O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C@@H:12]([CH3:14])[O:13][S:27]([CH3:26])(=[O:29])=[O:28])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: N#N
Solvent: c1ccncc1
Product: C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
N2 -(t Butyloxycarbonyl)-N-(Phenylmethoxy)-L-threonineamide (244 g) was dissolved in 1.2 liters of pyridine and the solution was cooled to 0° C. With stirring 120 grams of methanesulfonyl chloride was added dropwise at 0°-5° C. After 2.5 hours, the reaction mixture was poured into a mixture of 1500 ml of 2N hydrochloric acid and ice and concentrated HCl was added to adjust the pH of the mixture to 4. The title compound crystallized, and, after stirring for 1 hour, was filtered off, washed with water and petroleum ether. After drying at room temperature the yield was 356.4 grams, which contained a considerable amount of water, melting point 128°-130° C. dec.
Reaction SMILES: [C:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][C:14]([CH2:16][C:17](=O)[CH3:18])=[O:15]>O1CCCC1>[NH:7]([C:8]1[C:16]([C:14](=[O:15])[CH3:13])=[C:17]([CH3:18])[NH:10][N:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)CCl
Reactant: NNC(=S)Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1c(Nc2ccccc2)n[nH]c1C
Reaction time: 12 h

Procedure:
50 g of 4-phenylthiosemicarbazide is suspended in 300 ml of tetrahydrofuran and 0.5 ml of concentrated HCL is added. Then 40.4 g of 3-chloroacetyl acetone is allowed to run in all at once and the whole is cooled with an ice-bath. After 12 hours' stirring, the precipitate formed is suction filtered, washed with acetone and then boiled in a water/acetone mixture (1:1). This hot solution is filtered off from the sulfur and neutralized with aqueous ammonia solution. The product is then suction filtered and recrystallized from acetone; m.p. 246°-247° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:11]2[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Cl)cc1
Product: Clc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-chlorophenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[O:24]=[CH:25][C:26](OCC)=O.[H-].[Na+]>O1CCOCC1.C(OCC)(=O)C.O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][N:10]1[C:25](=[O:24])[CH:26]=[N:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[N:4][C:3]1=2
Reactant: COc1ccc(N)c(NCC2OCCO2)n1
Reactant: CCOC(=O)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(=O)n(CC3OCCO3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.20 g of 3-amino-2-(1,3-dioxolan-2-ylmethyl)amino-6-methoxypyridine in 2 mL of dioxane, 0.22 g of a 45 to 50% toluene solution of ethyl oxoacetate was added, and the mixture was stirred at room temperature for 2 hours and then left overnight. Thereto was added 36 mg of 60% sodium hydride, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 50:50 to obtain 36 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-methoxypyrido (2,3-b)pyrazin-3(4H)-one as a light brown solid.