Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](C3CCCCO3)[C:5]=2[O:4][CH2:3]1.C[C:19]([CH3:22])([O-:21])C.[K+].[Si:24]([O:31][CH2:32][CH2:33][CH2:34]Br)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Si:24]([O:31][CH2:32][CH2:33][CH2:34][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:4][CH:5]3[CH2:6][CH2:8][CH2:22][CH2:19][O:21]3)[C:5]=2[O:4][CH2:3][C:2]1=[O:1])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=C1COc2c(cccc2C2CCCCO2)N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)COc2c(OC3CCCCO3)cccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
3-oxo-8-(tetrahydropyran-2-yl)-3,4-dihydro-2H-1,4-benzoxazine (2.0 g) was dissolved in DMF (25 ml), and potassium t-butoxide (1.1 g) was added to the resultant solution, and the mixture was stirred at 0° C. for 15 minutes and then at room temperature for 15 minutes. The reaction solution was cooled to 0° C., and 3-(tert-butyldimethylsilyloxy)-1-bromopropane (2.1 ml) was then added to the reaction solution, and the mixture was stirred for 3 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with a saturated ammonium chloride aqueous solution and saturated brine, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=3:17) to obtain the object compound (2.55 g, yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:10])=[O:9].[H-].[Na+].[CH3:33][O:34][CH2:35]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:33][O:34][CH3:35])[C:12]1[C:13]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:9])=[O:10]
Reactant: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cn(-c2ccccc2)nc1C(=O)N1CCOCC1)S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-N-[3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-yl]benzenesulfonamide (200 mg; 0.41 mmol; 1.00 eq.) in THF (30 mL) is added NaH (24 mg; 0.61 mmol; 1.50 eq.) in a portionwise manner and the resulting mixture is stirred at room temperature for 15 minutes whereupon Chloromethyl methyl ether (82 μl; 0.81 mmol; 2.00 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 hours then quenched with sat. aq. NaHCO3. Extraction with ethyl acetate (2×), ishing with brine, drying over magnesium sulfate and concentration in vacuo gives 240 mg (quant) of the title compound as a colourless oil. 1H NMR (DMSO) δ 8.82 (s, 1H), 7.93-7.8 (m, 4H), 7.64-7.46 (m, 4H), 7.39 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 3.59-3.51 (m, 2H), 3.42 (s, 3H), 3.46-3.37 (m, 4H), 3.15-3.06 (m, 2H). MS (ESI+): 505.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][N:27]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenyl)imidazolidin-2-one (1.0 g, 2.46 mmol) and sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 1 h. tert-Butyl bromoacetate was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid (1.3 g, quant.).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (33 mg, 0.13 mmol) in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was then extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was thoroughly dried to give 2-bromoimidazo[5,1-b]thiazole (5 mg, 15%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][C:9]1[N+:18]([O-:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N+:11]([O-:20])[C:10]=1[C:21]([O:23][CH3:24])=[O:22].[OH:25]S(O)(=O)=O.[O-][Mn](=O)(=O)=O.[K+].OO.[OH2:38]>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][C:9]1[N+:18]([O-:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N+:11]([O-:20])[C:10]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:25])=[O:38]
Reactant: O
Reactant: COC(=O)c1c(CSc2ccccn2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O=S(=O)(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccn2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
Methyl 3-[(2-pyridyl)-thiomethyl]-2-quinoxalinecarboxylate-1,4-dioxide (0.03 moles) in 60 ml of acetone was cooled to 0°-5° C. and 50 ml of 2N H2SO4 was added in one portion. This was followed by the dropwise addition of a solution of KMnO4 (0.04 moles) in 150 ml of water over a 20 minute period. The mixture was stirred for about 5 minutes at which time 4 ml of 30% H2O2 was added very carefully dropwise to decolorize the purple solution. The desired product, which had precipitated, was collected by filtration and washed with water. Yield, 8.12 grams (87%); m.p. 154° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10]1N=CN(C(N2C=NC=C2)=S)C=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:25]([F:34])[C:24]=1[OH:35]>C1COCC1>[F:34][C:25]1[C:24]2[O:35][C:10]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[N:22][C:23]=2[CH:28]=[CH:27][C:26]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: c1ccc2c(c1)CCN2
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.2 %

Procedure:
Indoline (0.49 ml, 4.36 mmol) was dissolved in THF (20 ml). To the resulting solution was added N,N′-thiocarbonyldiimidazole (863 mg, 4.36 mmol). The resulting mixture was stirred at room temperature for 14 hours. Methyl 4-amino-2-fluoro-3-hydroxyphenylacetate (1.0 g, 5.0 mmol) was added to the reaction mixture, followed by stirring at 70° C. for 1 day. Mercuric oxide (yellow) (944 mg, 4.36 mmol) was added to the reaction mixture and the resulting mixture was heated at 70° C. for 15 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (10/1) eluate fractions, methyl (7-fluoro-2-(1-indolinyl)-6-benzoxazolyl)acetate (330 mg, 23%) was obtained as a pale brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:22]([Cl:27])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: OC1CCCC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(OC2CCCC2)c(Cl)c1

Procedure:
Starting with {(R)-4-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester and cyclopentanol using the method analogous to the one described above for example 3-1, {(R)-4-[(3-chloro-4-cyclopentyloxy-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester was obtained. MS cald. for C23H30ClN3O5S 495, obsd. (ESI+) [(M+H)+] 496.
Reaction SMILES: [CH2:1]([Cl:5])[C:2](=[CH2:4])[CH3:3].[SiH:6]([Cl:9])([CH3:8])[CH3:7]>>[Si:6]([CH2:4][CH:2]([CH2:1][Cl:5])[CH3:3])([CH3:8])([CH3:7])[Cl:9]
Reactant: C[SiH](C)Cl
Reactant: C=C(C)CCl
Product: CC(CCl)C[Si](C)(C)Cl
Yield: 42.2 %

Procedure:
In a 100 ml apparatus, there were combined 30.5 g (0.1 mol) of 92% D3D', 9.1 g (0.1 mol) of methallyl chloride, and 9.5 g (0.1 mol) of Me2SiHCl. Heat was applied to 43° C. and 0.05 ml Pt catalyst solution added, causing an exothermic reaction to 95.5° C. in 26 min, with the heat source removed. Vacuum distillation of the complete reaction yielded 7.82 g (42.3%) of Me2SiClCH2CHMeCH2Cl and 16.89 g (45.3%) of D3D'CH2CHMeCH2Cl. This example shows that neither Me2SiHCl nor D3D' is an effective promoter for reaction of the other with methallyl chloride when used at the equimolar level.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 54.9 %

Procedure:
A solution of 18.95 g (0.25 mo.) of 3-aminopropanol and 37.0 g (0.25 mol) of phthalic anhydride in 25 ml of dry toluene was refluxed for three hours using a Dean-Stark apparatus. The mixture was cooled, concentrated in vacuo, dissolved in dichloromethane and washed with water. The evaporated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 183°-184° C. (0.1 mm Hg) to give 28.18 g (55%) of a white solid; m.p. 75°-77° C.; NMR: (CDCl3) δ 1.9 (2H,q), 3.65 (5H,m), 7.6 (4H,s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][C:3]=1[Cl:13].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:12])=[CH:4][C:3]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1nc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid (Y. Hirokawa et al., Bioorg. Med. Chem. Lett., 1998, 12, 1551–1554, 500 mg, 2.47 mmol) and 1,1′-carbonyldiimidazole (440 mg, 2.71 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 45 min. A solution of 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate (529 mg, 2.47 mmol) in N,N-dimethylformamide (5 ml) was added and the resulting mixture was stirred at room temperature for 5 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate/toluene (2:1, 200 ml×3). The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:25) to give 703 mg (71%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[NH:32][C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[N:32]([CH3:1])[C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2cc1OC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2cncc(Cc3nc4c(c(=O)n(C)c(=O)n4CC(C)C)n3C)c2cc1OC
Reaction time: 8 h

Procedure:
Potassium carbonate (48 mg, 0.35 mmol) and iodomethane (0.018 ml,0.295 mmol) are added to a solution of the product of Example 10, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione (0.100 g, 0.24 mmol) in DMF (2 ml). The reaction is stirred overnight and purified by preparative HPLC to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1,7-dimethyl-3,7-dihydro-purine-2,6-dione, [MH]+ 438.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[C:6]([CH3:36])=[C:7]([C:11]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]3[C:12]=2[CH2:13][CH2:14][C@H:15]3[O:21][C:22]2[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4]>O1CCCC1.O.CO>[C:3]([C:5]1[C:6]([CH3:36])=[C:7]([C:11]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]3[C:12]=2[CH2:13][CH2:14][C@H:15]3[O:21][C:22]2[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(C#N)c5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C#N)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
LiOH×H2O (131 mg) is added to a solution of methyl 2-((3S)-6-((1R)-4-(3-cyano-2-methylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (119 mg) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The mixture is concentrated, cooled to 0° C., diluted with water and acidified with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 103 mg; LC (method 20): tR=6.30 min; Mass spectrum (ESI−): m/z=442 [M−H]−.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][C@@H:10]([CH3:14])[C:11]([OH:13])=O.C([N:19](C(C)C)CC)(C)C.N[N:26]([CH:34]=[NH:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:19]=[C:34]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[NH:35][C:11](=[O:13])[C@@H:10]([O:9][C:2]1[C:1]([CH3:15])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8])[CH3:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: Cc1cc(C)c(O[C@@H](C)C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(O[C@@H](C)C(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 137 h
Yield: 91.2 %

Procedure:
(2S)-2-(Mesityloxy)propionic acid (5.6 g; 27 mmol), diisopropylethylamine (17.3 g; 133 mmol), tert-butyl amino(imino)methylcarbamate (4.3 g; 27 mmol), and 1-hydroxybenzotriazole monohydrate (4.1 g; 27 mmol) were dissolved in N,N-dimethylformamide (80 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (10.2 g; 27 mmol) was added, and the mixture was stirred for 137 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed sequentially with 10% aqueous citric acid solution, brine, and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure, to give 8.6 g of the title compound (yield 91%) as an oil.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=O)([CH3:3])[CH3:2].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)(=[O:21])[CH3:20]>>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=[CH:20][C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)=[O:21])([CH3:2])[CH3:3]
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Reactant: CC(C)c1c(C=O)sc2cc(C(F)(F)F)ccc12
Product: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C

Procedure:
The titled compound was prepared from the above-mentioned 3-isopropyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (215 mg, 0.790 mmol) and methyl 3-(4-acetyl-2-methylphenyl)-acrylate (172 mg, 0.788 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (259 mg, yield 69%).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]#[N:33]>C(#N)C>[F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:11][C:5]2[N:6]([CH2:31][C:32]#[N:33])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: N#CCCl
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Temperature: 5 °C
Yield: 37.4 %

Procedure:
A suspension of 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (2 g) and potassium carbonate (1.05 g) in acetonitrile (30 ml) is refluxed for 30 minutes. The resulting solution is cooled to a temperature of 5° C. To the solution is added dropwise chloroacetonitrile (0.72 g), and thereafter the solution is refluxed for 3 hours. The solvent is distilled off, and the residue is admixed with water and subjected to an extraction operation with the aid of dichloromethane. The dichloromethane layer is separated off, washed with water, and dried over sodium sulfate. The solution is concentrated to precipitate a crystalline product, which is then recrystallized in a solvent consisting of acetonitrile and water. As an end product, 2-[7-fluoro-4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.84 g) is obtained. mp. 216°-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][CH2:13][C:14](OC)(OC)OC>>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][C:14]([CH2:13][Cl:12])=[N:1]2)=[CH:7][CH:8]=1
Reactant: COC(CCl)(OC)OC
Reactant: NC(=O)c1ccc(Br)cc1N
Product: O=c1[nH]c(CCl)nc2cc(Br)ccc12

Procedure:
Reflux a solution of 2-amino-4-bromobenzamide (27 g, 0.13 mol; see Joshi and Chaudhari, (1987) Indian J. Chem., Sect. B, 26B(6):602-4) in 2-chloro-1,1,1-trimethoxyethane (50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 28 g of 7-bromo-2-chloromethyl-3H-quinazolin-4-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:1]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:8][C:9]2=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)Cc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 130.2 %

Procedure:
Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.15. 1H NMR (400 MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>NC1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: Nc1ccccc1
Solvent: O
Product: Nc1cccc2c(N)cccc12
Temperature: 20 °C
Yield: 55.2 %

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 8 g of water-moist, 5% strength catalyst of palladium on activated charcoal, corresponding to 2.8 g of dry catalyst. Hydrogenation was performed at a temperature of about 100° C. and an initial hydrogen pressure of about 10 bars. As soon as the hydrogen pressure dropped to 5 bars, the hydrogen supply was stepped up until the original value of 10 bars was reattained. After 104 minutes the hydrogen uptake was finished and the reaction over. The catalyst was separated off at about 70° C. by filtration and the filtrate cooled to 20° C. whereupon 1,5-diamino naphthalene crystallized out. The crystallate was then filtered off and washed twice with 50 ml of methanol; 24 g of 1,5-diamino naphthalene were obtained with a m.p. of 189°-190° C.