Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(N(CC)CC)C>[C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([O:21][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]D25 -153.8° (c=1.0, methanol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:10][C:5]=2[NH:4][C:3](=S)[CH2:2]1.[NH2:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[F:18][C:17]1[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH:2]=[C:3]4[NH:28][CH2:29][CH2:30][C:31](=[O:32])[N:4]4[C:5]=3[CH:10]=2)=[N:13][C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=S)CO4)n2)c1
Reactant: NCCC(=O)O
Product: O=C1CCNC2=COc3ccc(Nc4nc(Nc5cccc(O)c5)ncc4F)cc3N12

Procedure:
In a manner analogous to the preparation of N4-[2,4-dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-[2H-1,4-benzoxazin-3(4H)-thione-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (400 mg, 1.04 mmol) and β-alanine (500 mg) gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamine as a white solid. 1H NMR (acetone-d6): δ 2.68 (t, J=7.2 Hz, 2H), 3.71 (t, J=7.2 Hz, 2H), 4.62 (t, J=1.2 Hz, 2H), 6.42 (ddd, J=1.2 and 2.4 and 7.5 Hz, 1H), 6.98-7.08 (m, 3H), 7.38 (t, J=2.4 Hz, 1H), 7.62 (dd, J=2.4 and 8.7 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 8.12 (s, 1H), 8.16 (s, 1H), 8.52 (d, J=2.7 Hz, 1H), 8.65 (s, 1H); 19F NMR (282 MHz, acetone-d6): δ −168.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][CH2:9][C:10](=[O:12])[N:11]=1.C(O[Na])(C)=O.O=C1C(=[CH:28][C:29]2[N:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[CH:32]3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:28][C:29]2[N:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[CH:32]3)[C:10](=[O:12])[N:11]=1
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Reactant: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 45.1 %

Procedure:
To a mixture of 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (prepared as described below) AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (33.6 mg, 0.18 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. (oil bath) for 3 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-[2-(3-chloro-4-fluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile as a light brown solid (30.6 mg, 45.1%). HR-ES (+) m/e calcd for C20H11FClN5OS (M+H)+ 424.0430. found 424.0431.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:20][O:19][C:18]=3[CH:29]=2)[CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][O:19][C:18]=3[CH:29]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCc1coc2cc(OCCc3cccc(NC)n3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc3c(CCC(=O)O)coc3c2)n1
Reaction time: 16 h
Yield: 74 %

Procedure:
1N NaOH (4 ml) was added to a solution ethyl 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoate in THF (4 ml) and stirred for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was neutralized with 1N HCl (pH=6.5). The resulting precipitate was filtered, rinsed with distilled water, and dried to yield 70 mg (74%) of 3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoic acid as a white solid. NMR 1H DMSO-d6 δ: 7.54 (dd, 1H, J=7.3, 8.6 Hz), 7.34 (m, 2H), 6.99 (d, 1H, J=2.0 Hz), 6.77 (dd, 1H, J=2.0, 8.6 Hz), 6.53 (d, 1H, J=7.1 Hz), 6.37 (d, 1H, J=7.1 Hz), 6.27 (d, 1H, J=8.5 Hz), 4.19 (t, 2H, J=6.5 Hz), 3.09 (t, 2H, J=6.5 Hz), 2.94 m, 2H), 2.87 (s, 3H), 2.69 (t, 2H, J=6.5 Hz). Mass Spectrum (LCMS, ESI) calculate for C19H21N2O4 341.1 (M+H) found: 341.4.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:15][CH2:16][OH:17]>C(OCC)C.Cl>[CH3:1][O:2]/[N:3]=[C:4](/[C:5]1[O:17][CH2:16][CH2:15][O:14][N:13]=1)\[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CON=C1C(=NOCCO)Oc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
2 g of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) (II-1) (content according to HPLC analysis 96.88%, 0.0082 mol) prepared by the method of process e) are dissolved in 50 ml of diethyl ether saturated beforehand with hydrogen chloride gas at 0° C. Without further cooling, the mixture is stirred for 30 minutes, the solvent is then distilled off under reduced pressure and the residue is taken up once more in diethyl ether. Some of the product crystallizes out and is filtered off. The mother liquor is concentrated under reduced pressure and the residue is dissolved in 25 ml of diethyl ether saturated with hydrogen chloride gas at 0° C. Without further cooling, the solution is stirred for a further 30 minutes, the solvent is distilled off under reduced pressure and the residue is once more taken up in diethyl ether. A further fraction of the product crystallizes out and is likewise filtered off. In total, 1.37 g (69% of theory) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) are obtained (content according to HPLC analysis: 97.59%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][CH2:9][S:8]1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([Br:22])[S:8]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N=c1sc(Br)cn1-c1cccc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine (1.6 g) and N-bromosuccinimide (2 g) in chloroform (50 ml) was refluxed for 10 hours. After cooling, the reaction mixture was washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.9 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylpheny)-5-bromothiazoline (Compound No. 30).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].C(Cl)Cl.Cl>O>[OH:16][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Sc2cccc(O)n2)cc1

Procedure:
A solution of 5 grams (0.023 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol and 2.72 grams (0.68 mole) of sodium hydroxide in 15 milliliters of water was heated at reflux for 21/2 hours. The resulting solution was poured over a mixture of ice and methylene chloride and the resulting mixture was vigorously stirred. The mixture was acidified by the dropwise addition of concentrated hydrochloric acid. The white crystalline solid 4-((6-hydroxy-2-pyridyl)thio)phenol product which precipitated out was recovered by filtration and washed with methylene chloride. The product was recovered in a yield of 4.35 grams (88 percent of theoretical) and melted at 234°-238° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:16][C:17]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:16][C:17]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:24][C:25]=1[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(OCC(F)(F)F)c1=O
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(OCC(F)(F)F)c(=O)n(C)c2)c1
Temperature: 70 °C
Yield: 11.8 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(2,2,2-trifluoro ethoxy)pyridin-2-one (50 mg, 0.18 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide (79 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70° C. for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (11 mg, 11%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 1H) 7.32 (m, 1H) 7.25 (d, J=2.8 Hz, 1H) 7.12 (dd, J1=2.8 Hz, J2=8.8 Hz, 1H) 6.99-6.93 (m, 2H) 6.88-6.83 (m, 1H) 6.79 (d, J=8.8 Hz, 1H) 6.47 (b.s., 1H), 4.56 (m, 2H), 3.65 (s, 3H) 3.15 (q, J=7.2 Hz, 2H) 1.42 (t, J=7.2 Hz, 3H). LCMS (M+H)+=519.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]1([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:30]#[N:31])[C:14]([CH3:29])=[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:16]=3[CH:17]([CH2:21]I)[CH2:18][CH:19]=[CH2:20])[N:12]=2)[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1.[Cu]I>[CH2:18]([CH:17]([C:16]1[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:14]([CH3:29])[C:13]([C:30]#[N:31])=[C:11]2[C:10]=1[O:9][C:8]([CH:5]1[CH2:7][CH2:6]1)=[N:12]2)[CH2:21][CH:1]=[CH2:2])[CH:19]=[CH2:20]
Reactant: C=CCC(CI)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Reactant: C=C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Copper (I) iodide (52 mg, 0.27 mmol) was suspended in tetrahydrofuran (3 ml), and under nitrogen atmosphere at −30° C., vinylmagnesium bromide (1 M tetrahydrofuran solution) (2.72 ml, 2.72 mmol) was dropwise added. The solution was stirred at the same temperature for 30 minutes, then a solution of 2-cyclopropyl-7-(l iodomethylbut-3-enyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-298)(425 mg, 0.91 mmol) dissolved in tetrahydrofuran (6 ml) was gradually added. After stirring at the same temperature for 1 hour and 20 minutes and heating up to 0° C., aqueous saturated ammonium chloride solution was added, followed by further stirring for 30 minutes. This was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=9:1, v/v) to obtain the entitled compound (243 mg, 73%) as a colorless gel.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18]=[O:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][OH:19])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: C=O
Product: CCOC(=O)c1cnc2c(SCO)cccn2c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 1.0 g of 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido[1,2-a]pyrimidine (II-1) and 325 mg of 27% formaldehyde is stirred at 100° C. for 2 hours in a nitrogen atmosphere. The reaction mixture is washed with methylene chloride and recrystallized from methylene chloride-methanol (19:1 v/v) to give 311 mg (Yield: 27.8%) of 3-ethoxycarbonyl-9-(hydroxymethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (III).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:11](=O)[CH2:12][CH:13]([CH3:17])[C:14](O)=[O:15])[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:20][NH2:21]>>[N:1]1([C:6]2[CH:7]=[C:8]([C:11]3[CH2:12][CH:13]([CH3:17])[C:14](=[O:15])[NH:20][N:21]=3)[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: CC(CC(=O)c1cc(-n2ccnc2)cs1)C(=O)O
Solvent: O
Product: CC1CC(c2cc(-n3ccnc3)cs2)=NNC1=O

Procedure:
This product is produced from 4-(imidazol-1-yl)-thiophen-2-aldehyde which is reacted with methacrylo nitrile to yield 4-[4-(imidazol-1-yl)-thien-2-yl]-2-methyl-4-oxo-butyric acid nitrile. This compound is hydrolized to 4-[4-(imidazol-1-yl)-thien-2-yl]-2-methyl-4-oxo-butyric acid and which is subjected to reaction with hydrazine hydrate to yield 4.5-dihydro-6-[4-(imidazol-1-yl)-thien-2-yl]-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][O:26][CH2:27][CH3:28])[N:19]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:10][C:9]=2[N:8]=1.ON1C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>O>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:25][O:26][CH2:27][CH3:28])[N:19]([CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])[C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:29][CH2:30][C:31]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:32])=[CH:10][C:9]=2[N:8]=1
Reactant: C1COCCN1
Reactant: CCOCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
A 20-ml glass vial was charged with anhydrous DMF (1 mL), 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (165 mg, 0.43 mmol), N-(3-dimethylaminopropyl)-N″-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol, 1.3 eq), 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol, 1.3 eq), and morpholine (110 mg, 1.29 mmol, 3.0 eq). The reaction was maintained at ambient temperature overnight. The reaction mixture was poured into water (10 mL), and the resulting mixture was extracted with dichloromethane (3×10 mL). The chloroform fractions were combined and concentrated, and the residue was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1-[4-amino-2-(ethoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 118-119° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])O)#[N:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:19][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:1]#[N:2]
Reactant: COC(=O)c1cc(C(O)C#N)ccc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(Cl)C#N)ccc1OC

Procedure:
To a suspension of methyl 5-(1-cyano-1-hydroxymethyl)-2-methoxybenzoate (2.15 g) in chloroform (40 ml) were added thionyl chloride (2.0 ml) and DMF (2 drops), and the mixture was refluxed for 30 minutes under heat. After cooling, the reaction mixture was washed with water, aqueous solution of sodium hydrogencarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure to obtain 2.37 g of aimed compound as an oily product.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl[C:26]1N=C(Cl)C2C(=CC=CC=2)[N:27]=1.COC1C=C(NC)C=CC=1OC>Cl.CC(O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:27][CH3:26])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CNc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CC(C)O
Product: CNc1nc(N(C)c2ccc(OC)c(OC)c2)c2ccccc2n1

Procedure:
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride: A mixture of 2,4-dichloro-quinazoline (88 wt %, 758 mg, 3.4 mmol), (3,4-dimethoxy-phenyl)-methyl-amine (502 mg, 3.00 mmol) and 2 drops of concd HCl in i-PrOH (11 mL) was reacted for 16 h then the product was collected on a Büchner funnel, washed with i-PrOH and dried. The title compound was obtained as a pale yellow solid (792 mg; 72%). 1H NMR (CDCl3) δ 8.65 (m, 1H), 7.75 (m, 1H), 7.18 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.90 (m, 1H), 6.85-6.78 (m, 2H), 3.99 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H); LC-MS (ESI+; 330 ([M+H]+)).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:19]2=[C:25]([C:28]([NH2:30])=O)[N:26]=[CH:27][N:18]2[C:17]2[CH:31]=[CH:32][S:33][C:16]1=2>O1CCOCC1.N1C=CC=CC=1>[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:19]2=[C:25]([C:28]#[N:30])[N:26]=[CH:27][N:18]2[C:17]2[CH:31]=[CH:32][S:33][C:16]1=2
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 80.7 %

Procedure:
4.44 ml (31.9 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 8.98 g (31.1 mmol) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxamide in 50 ml of dioxan and 5.4 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 220 ml of ice-water. The resulting precipitate was filtered off. After drying at 70°/10 Torr there were obtained 6.78 g (80%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carbonitrile as a white powder of m.p. 249°-251°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:18]=[C:17]([CH3:19])[C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:5]1([O:4][C:2](=[O:3])[NH:16][C:15]2[C:17]([CH3:19])=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(Cl)cc(C)c1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.56 g of phenyl chloroformate in 20 ml of toluene was added to a cold solution of 2.47 g of 4-chloro-2,6-dimethylaniline and 2.4 ml of N,N-dimethylaniline in 80 ml of toluene. The resulting mixture was stirred at room temperature for 11/2 hours and then diluted with water The organic layer was washed with 3N hydrochloric acid, brine, dried, and evaporated. The residual solid was crystallized from ethylacetate:hexane to yield phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate, mp 158°-160° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[C:10]([CH3:37])[N:11]([CH2:14][C:15]2[S:30][C:18]3[N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:17]=3[C:16]=2[C:31]([N:33]([O:35]C)[CH3:34])=[O:32])[C:12]=1[Cl:13].CN(C)C=O>ClCCl>[Cl:7][C:8]1[N:9]=[C:10]([CH3:37])[N:11]([CH2:14][C:15]2[S:30][C:18]3[N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:17]=3[C:16]=2[C:31]([N:33]([OH:35])[CH3:34])=[O:32])[C:12]=1[Cl:13]
Reactant: CON(C)C(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N(C)O)c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.1 62 ml) was added to a stirred solution of the product of example 1 part d) (415 mg) and dimethylformamide (0.01 ml) in dichloromethane (4 ml). After 1 h the solution was evaporated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (3 ml) and 1 ml of the solution was added to a stirred solution of N-methylhydroxylamine hydrochloride (129 mg) in saturated aqueous sodium bicarbonate solution (2 ml). After 1 h, the mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). Organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound (129 mg).
Reaction SMILES: [C:1]([C@H:6]1[O:10][C@H:9](C(=O)C)[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]([C@H:6]1[O:10][C@@H:9]([O:23][C:21](=[O:22])[CH3:17])[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1OC[C@@H](C(C)=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1OC[C@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% meta-chloroperbenzoic acid (mCPBA) (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resultant suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-Hexanes) to give the title compound (11% yield) which displayed the following spectral characteristics; 1H NMR (CDCl3):δ 1.31 (t, 3H, J=7.2 Hz), 2.07 (s, 1H), 4.15 (d of d, 1H, J=4.5, 9.1 Hz), 4.21-4.29 (m, 3H), 5.42 (s, 1H), 6.39 (d of d, 1H, J=2.4, 4.5 Hz); 13C NMR (CDCl3):δ 14.05, 20.97, 29.69, 71.34, 94.04, 99.80, 167.19, 170.11.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>CO>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[O:2]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCc2ccccc21
Solvent: CO
Product: O=C1OC(=Cc2ccncc2)c2ccccc21

Procedure:
In accordance with the procedure described in Lombardino, J.O.C. Vol. 32, pp. 1988-1992 (1967), a solution of isobenzofuran-1-one (13.4 g, 0.1 mol) and 4-pyridine carboxaldehyde (10.7 g, 0.1 mol) in 100 ml dry methanol are refluxed for 2 hours. The solvent is evaporated, and the product, 3-(4-pyridylmethylene)-isobenzofuran-1-one, is used in the next step without further purification.