Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.[OH-].[Na+].C(O)(=O)C>CO>[CH2:3]([C:2](=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:10]=1[Cl:9])[CH:1]=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC(C=O)=Cc1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 61.3 %

Procedure:
342 g of heptanal were added dropwise to a solution of 525 g of 2,4-dichlorobenzaldehyde and 12 g of NaOH in 1.5 l of methanol in the course of 6 hours. The mixture was allowed to continue reacting for 1 hour, then acidified with glacial acetic acid, and concentrated after a further 15 hours. The residue was taken up in CH2Cl2 /H2O, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 498 g of (I) of boiling point 152°-160° C./0.2 mbar.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH:13]=[CH:12][C@@H:11]1[O:17]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[OH:16][CH2:15][C@@H:14]1[C@@H:10]([OH:9])[C@@H:11]([OH:17])[CH:12]=[CH:13]1
Reactant: O=C(O[C@@H]1[C@@H](CO)C=C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1C=C[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a stirred solution of (1R,2S,5R)-5-(hydroxymethyl)cyclopent-3-ene-1,2-diyl dibenzoate (7) (7.5 g, 22.1 mmol) in methanol at room temperature under N2 atmosphere was added drop wise sodium methoxide (25% by wt in methanol) (14.3 mL, 77.66 mmol) over a period of 20 minutes. The mixture was stirred at room temperature for 2 hr and quenched drop wise with 1N HCl solution to the pH neutral. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (5% MeOH/DCM) to give triol 8 (2 g, 71%) as an oil; [α]24D +254.04° (c 1.0, MeOH); 1H NMR (500 MHz, CD3OD) δ 2.78 (d, J=5.0 Hz, 1H), 3.73 (dd, J=5.0, 11.0 Hz, 1H), 3.55 (dd, J=6.5, 10.5 Hz, 1H), 3.93 (t, 1H), 4.50 (t, 1H), 5.88-5.87 (m, 1H), 5.97 (d, J=6.0 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 53.7, 62.2, 73.2, 74.5, 132.0, 135.0; HR-MS Calcd. For (C6H10O3—H)+ 129.0630. found 129.0553.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(C(C)C)CC)(C)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: ClCCCBr
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (300 mg) in dry tetrahydrofuran (3 mL), diisopropylethylamine (0.65 mL) and 1-bromo-3-chloropropane (1.01 mL) were added and the resulting mixture was refluxed for 3 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>>[OH:23][C:20]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=3[CH:12]=2)[CH2:21][CH2:22][C:17]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Product: Cn1c(=O)oc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-3-methyl-3H-benzooxazol-2-one (prepared by methylation of 5-bromo-3H-benzooxazol-2-one from Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]([O:15]C)=[O:14])[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH3:12][O:11][C:9]([C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][O:6][C:7]=1[C:13]([OH:15])=[O:14])=[O:10]
Reactant: COC(=O)c1onc(C(C)C)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C(C)C)noc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
40 g of dimethyl 3-isopropylisoxazole-4,5-dicarboxylate are dissolved in 200 ml of methanol. A solution of 7.05 g of sodium hydroxide in 50 ml of water is added dropwise at 0° C. to this solution. It is stirred for 14 hours and allowed to warm to room temperature. The reaction selution is diluted with water and extracted twice with ethyl acetate. The alkaline solution is then acidified with conc. hydrochloric acid and extracted several times with ethyl acetate, and the organic phase is dried and concentrated.
Reaction SMILES: C[Li].[CH2:3](OCC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]4[O:29][C:28]([CH3:31])([CH3:30])[C:27](=[O:32])[C:26]=4[C:33]=3[CH3:34])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C1COCC1.O>[CH3:30][C:28]1([CH3:31])[C:27]([CH3:3])([OH:32])[C:26]2[C:33]([CH3:34])=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]=2[O:29]1
Reactant: CCOCC
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A solution of methyllithium in diethyl ether (1.14 M, 5.60 mL, 6.38 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (2.00 g, 5.06 mmol) obtained in Reference Example 13 in THF (20 ml) under ice cooling and the mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from hexane to obtain 2.00 g (yield 96%) of the title compound. mp. 139–141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (660 mg, 1.4 mmol) was dissolved in anhydrous methylene chloride (10 mL) with triethylamine (0.28 mL, 1.7 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (161 μL, 1.7 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes followed by 98:2 methylene chloride:methanol to give diethyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylphosphonate (Cpd. No. 1) as a white solid. 1H NMR (CDCl3): 7.94 (m, 1H), 7.79 (m, 1H), 7.64 (m, 1H), 7.46-7.40 (m, 2H), 7.43-7.36 (m, 2H), 6.72 (s, 1H), 5.85 (s, 1H), 4.08 (m, 6H), 2.13 (m, 2H), 1.33 ppm (m, 6H). MW=580 confirmed by LC-MS, tr=11.55 min (Method A) MH+=578-582.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.976 min, m/z=805.3; 1H NMR (CDCl3) 1.50 (d, 2H), 2.06-2.19 (m, 2H), 2.26 (m, 3H), 2.83 (m, 1H), 3.53 (m, 1H), 3.71 (m, 1H), 5.64 (m, 1H), 6.94 (d, 2H), 7.14 (m, 1H), 7.24 (m, 3H), 7.28 (m, 2H), 7.56 (d, 2H), 7.67 (m, 3H), 8.59 (d, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: C1CCOC1
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Reaction time: 4 h

Procedure:
To a 2-L PAAR hydrogenation bottle was charged Pd/C (10%, 11.06 g) and part of THF (1.11 L). Solid 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole (as prepared in the previous step, 221.1 g) was added along with the rest of the THF. The bottle was connected to the PAAR shaker, cycled through vacuum/nitrogen (3×), vacuum/hydrogen (3×) and the 45 psi hydrogen was applied with shaking Over the course of 4 hrs, the pressure dropped and was recharged until 45 psi was maintained. The reaction was complete by LCMS. The catalyst was filtered using celite/glass fiber filter, and the reaction was evaporated, but not to complete dryness. Denatured EtOH (250 mL) was added, the reaction concentrated, but again not to dryness. EtOH (1050 mL) was added, the contents heated to boiling, which dissolved nearly all the material. The mixture was allowed to come to ambient temperature with stirring and the product precipitated. After coming to ambient temperature, the suspension was chilled in a refrigerator for 3 hrs, and the product was filtered, and washed with ice-cold EtOH (250 mL) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.79-8.04 (m, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=6.8 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 4.00 (s, 4H), 2.74-3.03 (m, 1H), 2.09 (br. s., 2H), 1.66-1.96 (m, 6H). 13C NMR (101 MHz, CHLOROFORM-d): 136.4, 126.8, 121.9, 119.3, 111.1, 108.9, 77.2, 64.3, 35.1, 34.1, 31.0.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[F:20][C:19]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: OC1CN2CCC1CC2
Reactant: Fc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1OC1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A solution of 1.78 g (14 mmol) of 3-quinuclidinol in 20 ml of dry N,N-dimethylformamide (DMF) was added dropwise under nitrogen to a suspension of 0.6 g (15 mmol) of sodium hydride in 20 ml of dry DMF. The mixture was stirred for 15 min at 70° C., and a solution of 3.8 ml (30 mmol) of 2-fluoro-(trifluoromethyl)benzene in 8 ml of dry DMF was added dropwise. The mixture was stirred for another 1.5 h, after which the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude compound was purified by column chromatography on silica using methanol-dichloromethane (2:8) as eluent to give 3.0 g (59% yield) of 3-[2-(trifluoromethyl)phenoxy]-1-azabicyclo[2.2.2 ]octane, which was converted into the oxalate salt by treatment with oxalic acid and recrystallization from methanol. m.p. 174° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.[CH3:15][C:16](=O)[C:17](=O)[CH3:18]>O>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[C:17]([CH3:18])[C:16]([CH3:15])=[N:1]1
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Reactant: CC(=O)C(C)=O
Solvent: O
Product: Cc1nc2ccc3nc(O)c(O)nc3c2nc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 10 ml water was at 50° C. added a solution of 0,45 g (5,2 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50° for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,4 g (64%) 2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d : 7.27 (lH,d), 6,93 (lH,d), 2.07 (6H,s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C@H:26]12[CH2:32][C@H:29]([NH:30][CH2:31]1)[CH2:28][O:27]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:30]3[CH2:31][C@@H:26]4[CH2:32][C@H:29]3[CH2:28][O:27]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C[C@@H]4C[C@H]3CO4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate. Light yellow solid. MS (m/e): 353.1 ([{37Cl}M+H]+, 36%), 351.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH3:36])[NH:11][C:12](=[O:35])[C@H:13]([CH:23]([C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[C:24]([F:27])([CH3:26])[CH3:25])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH3:36])[NH:11][C:12](=[O:35])[C@H:13]([CH:23]([C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[C:24]([F:27])([CH3:25])[CH3:26])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](N)C(=O)C([C@@H](C(=O)N[C@@H](C)C(=O)OCc1ccccc1)N(C)C(=O)OC(C)(C)C)C(C)(C)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C(=O)[C@@H](N)C(C)C)C(C)(C)F
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A solution of 1.75 g (0.0033 mole) of Boc-4-fluoro-3(R,S)-L-Valyl-N-Methyl-L-Leucyl-L-Alanine benzyl ester in 17 ml of dry methylene chloride was stirred and cooled at -10° C. as 17 ml of trifluoroacetic acid, which was previously cooled at the same temperature, was added. The reaction was stirred and kept at -5° C. for 16 hours, then poured carefully with stirring into a mixture of 21 g of sodium bicarbonate, ice, and 100 ml of methylene chloride. After 5 minutes the organic layer was separated and washed with 3×30 ml of saturated sodium bicarbonate solution. The methylene chloride layer was dried over magnesium sulfate, and evaporated in vacuo to give 1.38 g of a stiff oil as the product. The yield was 99% of theory and the FAB m.s. showed a molecular ion peak at 424.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C[O:30][C:31]1[C:32](=O)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1>C(O)CCC>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:37]3[C:31](=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:3][CH2:2]2)[N:16]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: COc1cccccc1=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4cccccc4=O)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (2.48 g, prepared as described by T. H. Althuis and H.-J. Hess, J. Med. Chem., cited above), triethylamine (2.3 g) in butanol (190 ml) was stirred at room temperature for 2 hr and 2-methoxy-2,4,6-cycloheptatrien-1-one (2.06 g) was added. The mixture was refluxed for 48 hr, evaporated and chromatographed through silica gel using dichloromethane-methanol (9:1). The appropriate fractions were evaporated to give 1.73 g of the title compound. The latter material was stirred for 2 hr in a solution of hydrogen chloride in methanol and evaporated. The residue was crystallized from dichloromethane-methanol to give the title compound as the hydrochloride salt (0.835 g): mp 220°-224° C.; uv max (MeOH) 246 (ε=51740) and 343 nm (ε=25525); nmr(DMSO-d6) δ 3.55 (m, 4H), 3.85 (s, 6H), 4.05 (m, 4H), 7.0 (m, 5H), 7.75 (s, 1H) and 7.85 (s, 1H); and Anal. Calcd for C21H23N5O3.HCl: C, 58.66% H, 5.63% N, 16.29% and Found: C, 57.62% H, 5.50% N, 16.38% H2O, 1.86%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:28]=[CH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:36]OS(OC)(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:36][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:28]=[CH:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:16][N:17]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc([N+](=O)[O-])c3)cc21
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1

Procedure:
To (3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine (434 mg, 0.89 mmol) in THF (5 mL) cooled to −5° C. under an atmosphere of argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed by LiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction was quenched with saturated NH4Cl(aq) (2 mL), then extracted 3×20 mL EtOAc. The pooled organic material was washed with brine (10 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with hexane:EtOAc 9:1) gave methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine, as an oil (367 mg, 82%): TLC (Hexane:EtOAc 7:3) Rf sm 0.29, Rf p 0.39 (ethyl acetate:hexane 3:7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J=8.67 Hz) 7.77 (t, 1H, J=2.25 Hz), 7.72 (dd, 1H, J=0.79, 2.09 Hz), 7.60, (d, 2H, J=7.22 Hz), 7.26–7.54 (m, 7H), 7.19 (dd, 1H, J=0.78, 2.41 Hz) 7.07 (dd, 1H, J=1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J=8.10 Hz), 3.48 (s, 3H), 0.92 (t, 2H, J=8.10 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2, 126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0, 66.8, 41.1, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 501. Found 510.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([OH:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1>>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1
Reactant: CCOC(=O)CCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 7-bromoheptanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.19 (t, 2H), 1.66 (m, 2H), 1.54-1.40 (m, 4H), 1.31 (m, 2H); MS (ESI): 480.9.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].COCCOC.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:36].[Na+]>O>[F:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=1[I:36]
Reactant: [I-]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a stirred solution of 66.15C (1.00 g, 3.6 mmol) in DME (10.00 mL, 96 mmol) at 23° C. was added sulfuric acid (0.19 mL, 3.6 mmol) in water (8 mL), followed by dropwise addition of a solution of sodium nitrite (0.38 g, 5.4 mmol) in water (2 mL) at 0° C. over 30 minutes. The reaction was then stirred for 20 minutes. To the mixture was added a solution of sodium iodide (3.0 g, 20 mmol) in water (7 mL) at 0° C. The resulting mixture was then stirred for 1 hour. The reaction was quenched with sodium thiosulfate and extracted three times with diethyl ether. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-40% EtOAc in hexanes) to yield a colorless solid 66.15D (0.820 g, 58% yield).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[S:10][C:9]([CH:11]=[CH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>CO>[CH3:1][O:15][C:14](=[O:16])[C:13](=[O:17])[CH:12]=[CH:11][C:9]1[S:10][C:6]([Br:5])=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)s1
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)s1
Yield: 89.5 %

Procedure:
Acetyl chloride (23.0 mL, 325.6 mmol) was slowly added at 0° C. to methanol (100.0 mL) under stirring. A solution of 4-(5-bromo-thiophen-2-yl)-2-oxo-3-butenoic acid (25.0 g, 95.8 mmol) prepared in Step 1 in methanol (25.0 mL) was added at 0° C. to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 3 hours, and then filtered at room temperature to give 23.6 g of the titled compound as a yellow solid.