Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:6])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([Br:18])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1cccc(C(F)(F)F)c1

Procedure:
The ester 51 (0.05 mol) was dissolved in carbon tetrachloride (75 mL) and N-bromosuccinimide (0.05 mol) was added. The mixture was heated at reflux and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and filtered. The solution was concentrated to afford the title compound 52.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 1-iodo-3-nitro-benzene (9 g), piperazine-1-carboxylic acid tert-butyl ester (13.5 g) and sodium tert-butoxide (9.7 g) in dioxane (150 mL) was added tris(dibenzylideneacetone)dipalladium (2 g) and tri-o-tolylphosphine (2.2 g) and the mixture was heated at reflux for 24 hours. The solution was then cooled to room temperature, taken in Et2O and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized from diisopropyl ether to give the title compound (6 g) as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH3:14])[CH:16]=2)[NH:20][C:19]1=[O:24]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 42.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 5-methyl-2-oxindole and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 65 mg (42%) of the title compound as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[CH2:3][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To tert-butyl (3-oxocyclobutyl)carbamate (see PREPARATION 4A, STEP 1; 110 g, 0.594 mol, 1 eq) in ethanol (600 mL) was slowly added sodium borohydride (11.23 g, 0.297 mol, 0.5 eq) at 0° C. Reaction mixture was warmed to RT and stirred at this temperature for 2 h. It was quenched with water (1 L). Solvent was removed under reduced pressure. Water layer was extracted with EtOAc (3×2 L). Combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Residue was purified by column chromatography with aluminum oxide (Eluent: 20% EtOAc in hexane to 10% MeOH in DCM) to get 64 g of tert-butyl (3-hydroxycyclobutyl)carbamate as a white solid in 58% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>N1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture containing 24.9 g of 2-amino-5-chloro-2'-fluorobenzophenone and 22.1 g of 4-nitrophenylsulfonyl chloride is refluxed for 10 hours in pyridine. It is evaporated to dryness, water and ethyl acetate are then added and the ethyl acetate phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The expected product precipitates on evaporation; it is filtered off and recrystallized from a DCM/isopropyl ether mixture to give 20 g.
Reaction SMILES: [Si]([O:18][C@@H:19]([CH3:51])[C:20]([N:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[S:24][C:23]1([CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C([O-])(O)=O.[Na+]>[F:33][C:29]1[CH:28]=[C:27]([C:25]2[S:24][C@@:23]([CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:22]([C:20](=[O:21])[C@@H:19]([OH:18])[CH3:51])[N:26]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(3-((S)-2-(tert-butyldiphenylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (180 mg, 0.25 mmol) in THF (2.5 mL) was added TBAF (0.40 mL of 1M solution in THF). After stirring at room temperature for 2 hours, the volume was reduced in vacuo and the mixture was diluted with half-saturated NaHCO3 (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (95 mg, 79%) as a viscous, yellow syrup.
Reaction SMILES: [F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:41][C:42]1[NH:46][N:45]=[C:44]([NH2:47])[CH:43]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:47][C:44]2[CH:43]=[C:42]([CH3:41])[NH:46][N:45]=2)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(OC(F)(F)F)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(OC(F)(F)F)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (250 mg, 0.66 mmol) was added phosphoryl tribromide (2.3 g) and toluene (2 mL) followed by DIEA (0.232 mL, 1.33 mmol). The mixture was heated at 105° C. for 0.5 h, then allowed to cool to rt. The mixture partitioned between EtOAc and saturated aq sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (280 mg, 2.8 mmol) in DMF (5 mL) and the mixture was stirred at rt for 2 h. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amine (100 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.02 (s, 1H) 7.71 (t, J=8.10 Hz, 1H) 7.86-8.10 (m, 3H) 8.60-8.79 (m, 2H) 10.95 (s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 455 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[CH:24](=O)[CH2:25][CH3:26].[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH2:24][CH2:25][CH3:26])[C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.6 %

Procedure:
This compound was prepared according General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (11 mg, 0.03 mmol), propionaldehyde (0.3 mmol, 10 eq) and NaCNBH3 (10 equiv) in 4 mL TFA (0.03 M) stirred at rt for 12 h to afford 12 mg (100%) of (R)-3,4-dihydro-8-isopropoxy-3-methyl-4-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (12 mg, 0.030 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl and heated at 90° C. for 4 h to afford 8 mg (75%) of Compound 105 after purification by silica gel chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ11.15 (bs, 1H), 7.10 (s, 1H), 6.99 (d, J=8.8, 1H), 6.88 (d, J=8.8, 1H), 4.11 (dd, J=10.7, 3.2, 1H), 4.03 (dd, J=10.7, 2.4, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 3.14 (m, 1H), 1.64 (m, 2H), 1.21 (d, J=6.4, 3H), 0.97 (t, J=7.3, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.CC1[N:20]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CC(N)CC2

Procedure:
Into a flask in which substrates, that is, 300 mg of 7-methoxy-2-tetralone and 309.4 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 24 hours with stirring. After the reaction is completed, 7-methoxy-2-aminotetralin thus produced in the reaction mixture was analyzed by HPLC with the conditions described below. This showed that 7-methoxy-2-aminotetralin was produced with a conversion rate of 85%, and it had a (S) configuration and optical purity of 96.7% e.e.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]([Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=[CH2:25].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:22][C:4]12[CH2:25][CH:24]([CH2:23][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:7]([C:8]([O:10][CH3:11])=[O:9])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]1[C:18]([O:20][CH3:21])=[O:19])[C:2]([CH3:1])=[N:3]2
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C(C)=NC1(C)CC2C[Si](C)(C)C
Reaction time: 4 h

Procedure:
To 1.0 g (3.3 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) [B. Loev. et al., J. Med. Chem., 17, 956 (1974)] in 50 ml chloroform cooled in an ice-bath to 0°-5° there was added 7.5 g (66 mmol) commercially obtained allyltrimethylsilane (2) followed by 1.41 g (10 mmol) boron trifluoride etherate added dropwise via syringe. The reaction mixture was then stirred for 4 hours at 0°-10° and quenched by addition of saturated aqueous NaHCO3 solution. After the addition of 50 ml Et2O, the organic phase was separated, washed with brine and dried. Solvent removal left an oil that was purified by column chromatograhy on silica gel eluting with 7% isopropanol/hexane to give pure 3 as of oil, which crystallized after standing, mp. 152°-155°, formula: C23H33NO4Si; m.w., 415.606. mmr (CDCl3) δ 0.78(9H, s), 0.27(1H, dd), 0.47(1H, dd), 0.83(1H, dd), 1.57(3H, s), 2.46(1H, dd), 2.55(3H, s), 2.60(1H, dd), 2.76(1H, m), 3.58(3H, s), 3.74(1H, d), 3.79(3H, s), 7.16(2H, dd), 7.30(3H, m).
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:14]=[CH:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=O)[C:6]=2[CH:5]=1)[CH3:3].P(Cl)(Cl)([Cl:17])=O>C(N(CC)CC)C>[Cl:17][C:11]1[C:6]2[CH:5]=[C:4]([N:2]([CH3:3])[CH3:1])[N:14]=[CH:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CN(C)c1cc2c(=O)[nH]cnc2cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
6-(N,N-Dimethylamino)-pyrido[3,4-d]pyrimidin-4-one (12 g) was carefully treated with phosphorus oxychloride (42 ml) and triethylamine (18 ml) at room temperature under N2. After 1 hour at room temperature and 1 hour at 50° C., the mixture was concentrated in vacuo, azeotroping with toluene, then taken up in ethyl acetate, washed with sodium bicarbonate solution, dried and concentrated in vacuo to give the title compound (10.34 g); δH CDCl3 9.13(1H,s), 8.74(1H,s), 6.69(1H,s), 3.25(6H,s).
Reaction SMILES: [H-].[Na+].[C:3]12[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8][C:7](=[O:14])[O:6][C:4]2=[O:5].I[CH2:16][CH3:17]>CN(C)C=O>[CH2:16]([N:8]1[C:7](=[O:14])[O:6][C:4](=[O:5])[C:3]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:9]12)[CH3:17]
Reactant: CCI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Sodium hydride (28 g of a 55% oil dispersion) was added in portions to a stirred, cooled (4° C.) solution of isatoic anhydride (100 g) and iodoethane (104 g) in anhydrous dimethylformamide (600 ml). The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (1 l) and water (500 ml). The organic layer was separated, washed with brine (2×100 ml), dried (sodium sulphate) then evaporated to give a semi-solid which was triturated with diethyl ether to afford N-ethyl isatoic anhydride as a tan powder (70 g). N-Ethyl isatoic anhydride (64 g), glycine (27 g) and glacial acetic acid (500 ml) were heated at reflux for 4 hours. The solvent was evaporated and the residue was partitioned between dichloromethane (1.5 l) and saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with 1M sodium hydroxide (200 ml), dried (magnesium sulphate), evaporated then the residue triturated with diethyl ether to afford the title compound as a beige solid (53 g). mp 169°-170° C. (ethyl acetate). Rf 0.50 in dichloromethane/methanol (9:1) on silica plates. 1H NMR (360 MHz, CDCl3) δ1.21 (3H, t, J=7 Hz), 3.73-3.83 (3H, m), 4.13-4.22 (1H, m), 6.97 (1H, broad s), 7.26-7.36 (2H, m), 7.56 (1H, ddd, J1 =2 Hz, J2 =J3 =8 Hz), 7.89 (1H, dd, J1 =2 Hz, J2 =8 Hz). Found: C, 64.25; H, 5.92; N, 13.67. C11H12N2O2 requires C, 64.69; H, 5.92; N, 13.72%.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15](=O)[NH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>>[Cl:38][C:15]1[C:16]2[NH:20][C:19]3[N:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=3[C:17]=2[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[CH:13][N:14]=1
Reactant: CCS(=O)(=O)c1cccc(-c2c[nH]c(=O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Yield: 69 %

Procedure:
Compound 31 (50 mg, 0.136 mmol) stirred in POCl3 (2 mL) with dimethylaniline (0.1 mL) at 108° C. under nitrogen for 16 h. The solution was concentrated and dissolved in CH2Cl2. Ice and saturated NaHCO3 solution were added, and organics were extracted (2×) with CH2Cl2, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (3% MeOH/CH2Cl2) gave 36 mg (69%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4/CDCl3): δ 8.46 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.89 (t, 1H, J=8.0 Hz), 7.84 (s, 1H), 7.76 (s, 1H), 3.28 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C19H16ClN3O2S, 386, 388; found 386, 388.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Si:23]([O:4][CH2:3][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:1])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: NC(CO)c1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(N)c1ccc(I)cc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a mixture of the compound (4.70 g) obtained in step (3) above, 4-dimethylaminopyridine (48.2 mg), triethylamine (4.40 mL) and chloroform (63.2 mL), a solution of tert-butyldimethylchlorosilane (2.38 g) in chloroform (31.6 mL) was added dropwise under cooling with ice and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for three days. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were then added. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to give the titled compound as a pale yellow oil (4.68 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:31]4[S:32][C:28]([CH3:27])=[CH:29][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: Cc1cncs1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and 5-methylthiazole.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1cnc(Cl)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)cn1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (600 mg), 2-chloro-5-methyl-pyrazine (100 mg), and cesium carbonate (300 mg) in N,N-dimethylformamide (10 mL) is stirred for 3 days at 80° C. After cooling to room temperature ethyl acetate and water are added. The organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 7:3) to give the title compound. LC (method 1): tR=1.08 min; Mass spectrum (ESI+): m/z=404 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:7](O)[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH:21]=[CH:22][C:4]=2[O:3]1>O1CCOCC1>[CH3:1][C:2]1([CH3:30])[CH:7]=[C:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[C:20]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Solvent: C1COCCO1
Product: CC1(C)C=C(N2Cc3ccccc3C2=O)c2cc(S(=O)(=O)C(F)(F)F)ccc2O1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
200 mg of soda talc (Merck Catalog No. 1567) were added to a solution of 200 mg of trans-3,4-dihydro-2,2-dimethyl-4-(1-oxoisoindolin-2-yl)-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared as described in Preparation 13) in 6 ml of dioxane, and the resulting mixture was stirred for 30 minutes whilst heating it on an oil bath kept at 140° C. The reaction mixture was cooled and then freed from insoluble materials by filtration. The solvent was then removed by distillation under reduced pressure. The residue was dissolved in 20 ml of methylene chloride, and the resulting solution was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The solution was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The oily residue thus obtained was recrystallized from ethyl acetate, to afford 81 mg of the title compound, melting at 110°-115° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][Cl:19])=[CH:9][C:10]=2[O:12][CH:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23]2[O:28][CH2:29][O:30][C:22]=12>>[Cl:19][CH2:18][CH2:17][O:16][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[C:23]4[O:28][CH2:29][O:30][C:22]=34)=[N:3][CH:4]=[N:5]2)=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=1
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: CC(C)Oc1cc(OCCCl)cc2ncnc(Cl)c12
Product: CC(C)Oc1cc(OCCCl)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2-chloroethoxy)-5-isopropoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 86% yield; NMR Spectrum: (CDCl3) 1.55 (d, 6H), 3.9 (t, 2H), 4.4 (t, 2H), 4.9 (m, 1H), 6.2 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.65 (s, 1H); Mass Spectrum: M+H+ 437 and 439.