Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].I[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: ICC1CCOCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl(4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25-1.45 (3H, m), 1.55-1.65 (2H, m), 1.70-1.80 (1H, m), 2.05-2.15 (1H, m), 3.25-3.35 (2H, m), 3.79 (1H, t), 3.90-3.95 (2H, m), 4.10-4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP-HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1.ClC(Cl)C>[CH3:23][O:24][CH2:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])=[O:27]
Reactant: COCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)s1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)OCCCS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-hydroxypropane sulfonyl)thiophene-2-sulfonamide (1.2 g, 4.2 mmol) in 75 ml of THF was added 0.4 ml of pyridine and 0.5 g of methoxyacetyl chloride. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oily residue was dissolved in ethyl acetate and the ethyl acetate was washed with water and then brine. After drying over sodium sulfate the ethyl acetate was concentrated under vacuum, giving an oily residue. A crystalline product was obtained by dissolving the oil in hot dichloroethane and then cooling to 0° C. The yield was 0.8 g. m.p. 93°-95° C. 1H-NMR, δ (DMSO, d6) 8.00 (2H, s); 7.80 (1H, d, J=3); 7.63 (1H, d, J=3); 4.12 (2H, t, J=6); 4.00 (2H, s); 3.55 (2H, m); 3.27 (3H, s); 1.91 (2H, m).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O[C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.O>C(Cl)(Cl)Cl>[N:1]([C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])([CH3:8])[CH3:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COc1ccc(C(C)(C)O)cc1C(N)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)COc1ccc(C(C)(C)N=[N+]=[N-])cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of NaN3 (3.96 g, 60.9 mmol) in a solution of 5-(1-Hydroxy-1-methylethyl)-2-(2-methylpropyloxy)benzamide (5.1 g, 20.3 mmol) in CHCl3 (160 mL) at 0° C. under N2 was slowly added TFA (7.8 mL, 101 mmol). The reaction mixture was stirred overnight while slowly warming to rt. The thick slurry was then poured into H2O (100 mL). The layers were separated, and the organic layer was washed with additional H2O (100 mL) and brine (100 mL). The aqueous washes were reextracted with EtOAc, and the combined extracts were dried over MgSO4 and concentrated. The material was purified by flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc produced product that was still contaminated with TFA. The product was dissolved in EtOAc and washed with half-saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous washes were reextracted once with EtOAc, and the combined extracts were dried over MgSO4 and concentrated to 5.23 g (93%) of azide as a white solid which was used without further purification.
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]([CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=[O:11])=O)(C)(C)C.F[C:36](F)(F)C(O)=O>>[C:6]([NH:8][CH:9]([CH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=[O:11])(=[O:5])[CH3:36]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)cc(COC(=O)C(NC(=O)OC(C)(C)C)C2c3ccccc3-c3ccccc32)c1
Product: CC(=O)NC(C(=O)OCc1cc(C)cc(C)c1)C1c2ccccc2-c2ccccc21

Procedure:
3,5-Dimethylbenzyl N-t-butoxycarbonyl-2-(9-fluorenyl)glycinate (Example 9d, 0.5g) was dissolved in trifluoroacetic acid (10ml) for 40 minutes then evaporated in vacuo. To a solution of the residue in pyridine (10ml) was added acetic anhydride (1ml) for 16h. The solvent was removed in vacuo and the residue crystallised from diethyl ether/petroleum ether bp 60°-80° C. to give the title compound mp 162°-164° C. Found: C, 78.19; H,. 6.26; N, 3.45. C26H25NO3 requires C,. 78.17; H, 6.30; N, 3.50%. m/z (CI+)=400 (M+H), (CI-)=398 (M-H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:26]([O:22][CH:18]1[CH2:19][CH2:20][CH2:21][N:15]([S:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13])[CH2:16][CH2:17]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(O)CC2)c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a mixture of methyl 4-bromo-3-(4-hydroxyazepan-1-yl)sulfonyl-benzoate (1.00 g, 2.55 mmol, 1.00 Eq) in DMF (15 mL), was added NaH (153.00 mg, 3.82 mmol, 1.50 Eq) in portions at 0° C. under N2. The mixture was stirred at 25° C. for 30 min. Then bromomethylbenzene (654.19 mg, 3.82 mmol, 1.50 Eq) was added and stirred at 25° C. for 16 hours. TLC showed the reaction was completed. The mixture was poured into NH4Cl aqueous and extracted with EA. The combined organic phase was washed with saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (eluting with PE/EA=10/1, 2/1) to afford methyl 3-(4-benzyloxyazepan-1-yl)Sulfonyl-4-bromo-benzoate (550.00 mg, 1.14 mmol, 44.71% yield) as white solid. LCMS: 482/484 [M+1].
Reaction SMILES: [CH:1]1([C:4]([O:8][Si](C)(C)C)([CH3:7])[C:5]#[N:6])[CH2:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:13]([O:8][C:4]([CH3:7])([CH:1]1[CH2:3][CH2:2]1)[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: CC(C#N)(O[Si](C)(C)C)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)OC(C)(C#N)C1CC1
Yield: 87.5 %

Procedure:
To a well stirred and ice-cooled solution of 2-cyclopropyl-2-trimethylsilanyloxy-propionitrile (188.5 g, 1.03 mol) in acetonitrile (1000 mL) was added acetic anhydride (194 mL, 2.06 mol) and scandium trifluoromethanesulfonate (5 g, 10.3 mmol). The temperature rose to ˜10° C. and stirring was continued for 15′ at room temperature. The solvent was evaporated in vacuo and the residue was distilled to yield 138 g of the title compound as colorless liquid, bp: 84–86° C./6 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:21]#[N:22])=[CH:11][C:12]2[N:13]([C:15]([N+:18]([O-])=O)=[CH:16][N:17]=2)[CH:14]=1.[OH2:23].[OH2:24].[Sn](Cl)Cl>CCO>[NH2:22][CH2:21][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][N:13]2[C:15]([NH:18][C:9]([CH:3]3[CH2:4][CH2:5][O:24][CH2:7][CH2:2]3)=[O:23])=[CH:16][N:17]=[C:12]2[CH:11]=1
Reactant: N#Cc1cc2ncc([N+](=O)[O-])n2cc1-c1ccc(Cl)cc1Cl
Reactant: O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: NCc1cc2ncc(NC(=O)C3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of the previously obtained 6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile and Tin(II) chloride dihydrate (3.61 g, 15.7 mmol) in absolute EtOH (10 mL) was refluxed for 10 min, then cooled to RT and concentrated under vacuum. The residue was suspended into a 2M NaOH solution in water (100 mL) and extracted with DCM (4×50 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH—NH3 99:1→95:5) to yield the title compound (517 mg, 1.71 mmol, 28% for 2 steps). HPLC: AtRet=1.34; TLC: RF 0.47 (DCM/7N NH3 in MeOH 95:5).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N+:4]=1[O-:10]>>[OH:10][N:4]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]1=[O:2]
Reactant: [O-][n+]1ccc(O)cc1O
Agent: Cl
Product: O=c1cc(O)ccn1O
Yield: 30 %

Procedure:
2,4-Dimethoxypyrid-1-oxide is refluxed together with 20% w/v HCl for 13 hours. On cooling the solution 2,4-dihydroxypyridine-1-oxide is obtained as an orange-white solid (0.42 g, 30%), δ(d6DMSO+trace of D2O), 6.08 (s, 1H), 6.12 (q, 1H), 7.88 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:30]([NH:38][CH:39]4[CH2:41][CH2:40]4)[N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([F:29])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:30]([NH:38][CH:39]4[CH2:40][CH2:41]4)[N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([F:29])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4c(NC4CC4)c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4c(NC4CC4)c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.4 %

Procedure:
720 mg (1.3 mmol) Crude {1-[4-(9-fluoro-4-cyclopropylamino-3-phenyl-pyrimido[1,2-b]indazol-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, described in step 2, were dissolved in 36 mL dioxane. After dropwise addition of 36 mL of a 4 M hydrogen chloride in dioxane the reaction mixture was stirred for five hours at room temperature. The reaction mixture was evaporated to dryness. Saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried. After evaporation of the solvent the residue was purified by HPLC to yield 44.3 mg of the desired compound which was 90% pure.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1)=O.[I-].[CH:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(-c2c(C)cccc2C=O)c1
Agent: [I-]
Product: COC(=O)c1cccc(-c2c(C)cccc2CC(C)C)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 217 from methyl 2′-formyl-6′-methylbiphenyl-3-carboxylate and isopropyltriphenylphosphonium iodide. colorless oil (yield 45%).
Reaction SMILES: [Cl:1][C:2]1[C:3](OC2C=CC=CC=2)=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[C:8]#[N:9].[NH:23]1[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]1>O>[Cl:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]2)=[N:4][C:5]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:6][C:7]=1[C:8]#[N:9]
Reactant: O=S1CCNCC1
Reactant: N#Cc1nc(N2CCNCC2)nc(Oc2ccccc2)c1Cl
Solvent: O
Product: N#Cc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1Cl

Procedure:
0.3 gm (0.001 mol) of 5-chloro-6-cyano-4-phenoxy-2-piperazino-pyrimidine [m.p. 126°-128°C, obtained from 6-cyano-2,5-dichloro-4-phenoxy-pyrimidine and piperazine in acetone/dioxane (1:1) while cooling] were heated with 2.3 gm (0.02 mol) of thiomorpholine-1-oxide at about 140°C for 90 minutes. The dark colored molten mass was taken up in a small quantity of water, and the precipitated raw reaction product was purified on a silicagel column [eluant: methanol/concentrated ammonia (8:1)]. After reprecipitation from 0.2 N hydrochloric acid with ammonia, 5-chloro-6-cyano-2-piperazino-4-(1-oxido-thiomorpholino)-pyrimidine, m.p. 206°-208°C, was obtained.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][CH:36]([F:41])[O:34][C:10]1[CH:9]=[C:8]([N:4]2[CH:5]=[C:6]([F:7])[C:2]([F:1])=[CH:3]2)[CH:13]=[CH:12][C:11]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OC(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 75.4 %

Procedure:
A mixture of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), sodium chlorodifluoroacetate (152 mg), potassium carbonate (104 mg), DMF (2.5 mL) and water (0.5 mL) was heated under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (193 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][CH2:67]O)=[CH:62][CH:61]=1>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:67][CH2:66][C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCc1ccncc1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCc4ccncc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(4-pyridyl)ethanol (104 mg, 0.84 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), in methylene chloride and the mixture stirred for 30 minutes at ambient temperature. The solvent was removed by evaporation. The residue was suspended in ether and the ether then decanted. The resulting crude oil was purified by column chromatography eluting with methylene chloride/methanol (90/10) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline (300 mg, 90%). 1H NMR Spectrum: (DMSOd6) 2.18(s, 3H); 3.16(t, 2H); 3.84(s, 3H); 3.92(s, 3H); 4.44(t, 2H); 7.24(s, 1H); 7.29(d, 1H); 7.40(d, 2H); 7.79(s, 1H); 8.35(s, 1H); 8.49(d, 2H); 9.51(s, 1H) MS-ESI: 501 [MNa]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:31])=[C:18]([NH:22][S:23]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[F:31][C:17]1[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:39]3[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]3)[N:7]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[NH:22][S:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(NC3CCN(S(C)(=O)=O)CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1,3-thiazole-2-sulfonamide (70 mg, 0.141 mmol) and 1-(methylsulfonyl)-4-piperidinamine (126 mg, 0.706 mmol) the title compound was obtained as an off-white solid (43 mg, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (d, J=1.6 Hz, 1H), 8.08 (d, J=4.3 Hz, 1H), 7.71-8.02 (m, 2H), 7.39-7.49 (m, 1H), 7.25 (d, J=7.7 Hz, 1H), 6.95-7.23 (m, 2H), 5.90-6.23 (m, 1H), 3.64-3.94 (m, 1H), 3.37-3.64 (m, 3H), 3.24 (br. s., 0H), 2.65-2.93 (m, 5H), 1.79-2.00 (m, 2H), 1.39-1.59 (m, 2H), 1.24-1.40 (m, 6H). MS (ESI): 638.1 [M+H]+.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]2[NH:27][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([CH:11]=[C:12]3[C:37]([CH3:38])=[C:36]([CH:39]=[CH2:40])[C:14](=[CH:15][C:16]4[C:29]([CH3:30])=[C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:18](=[CH:19]2)[N:17]=4)[NH:13]3)[C:8]([CH:41]=[CH2:42])=[C:7]1[CH3:43].[OH-].[K+].C1N(CCS(O)(=O)=O)CCOC1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[Na].[Hg].[Hg].C(O)C>[CH3:2][C:3]1[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]2[NH:27][C:4]=1[CH2:5][C:6]1[NH:10][C:9]([CH2:11][C:12]3[NH:13][C:14]([CH2:15][C:16]4[NH:17][C:18]([CH2:19]2)=[C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:29]=4[CH3:30])=[C:36]([CH:39]=[CH2:40])[C:37]=3[CH3:38])=[C:8]([CH:41]=[CH2:42])[C:7]=1[CH3:43]
Reactant: C=CC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5C=C)C(C)=C4CCC(=O)O)c(CCC(=O)O)c3C
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)CCN1CCOCC1
Agent: [Hg]
Solvent: CCO
Product: C=Cc1c2[nH]c(c1C)Cc1[nH]c(c(CCC(=O)O)c1C)Cc1[nH]c(c(C)c1CCC(=O)O)Cc1[nH]c(c(C)c1C=C)C2
Reaction time: 0.08 h

Procedure:
The powder of sodium amalgam was prpared as follows. Into a round flask of 500 ml volume, 13 g of mercury and 0.5 g of thin-layer metal sodium were added, and equilibrated with nitrogen gas for 5 minutes, and it was shaked for 5 minutesthen. 8.4 g of protoporphyrin IX was dissolved into 10 mM KOH containing 15 ml of 20% ethanol, incubated at 4° C. To 4 ml of the protoporphyrin IX solution, equal amount of reaction mixture (0.1 M MES, 50 mM ascorbic acid) was added, and 16 mg of sodium amalgam freshly prepared was added, and shaken vigorously under nitrogen gas in a dark. The reaction mixture was filtered with a three-layer glass filter in a dark, and diluted 2.5 times with 0.1 M MES (pH4.5), and divided into 1 ml each in a light-shielded test tube and stored at −80° C.
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:39][OH:40])([CH3:38])[C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O1CCCC1>[OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:39][OH:40])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C(C)(CO)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CO)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
Dissolve 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneacetic acid, ethyl ester (200 mg, 0.37 mmol) in methanol (8 mL) and tetrahydrofuran (12 mL). Add 1.6 mL (1.6 mmol) of a 1 molar solution of aqueous sodium hydroxide. After 4 hours, cool the solution to room temperature and add 10% hydrochloric acid (ca. 1 mL) dropwise until pH is 5-6. Concentrate the solution and purify by flash chromatography (50 g of silica gel, methanol/chloroform gradient elution) to give the title compound (127 mg, 66%). Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step J:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCCCCCCCCCCCCCCN1CCC(CN)CC1
Product: CCCCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 52.9 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-pentadecylpiperidine (0.650 g, 2.0 mmol) according to procedure used for Example 2 to give 0.298 g of the title compound as a white solid (mp-69-71° C., Et2O).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=[CH:26][CH:27]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COc1cccc(CCN)c1
Product: CCc1cc(-c2cncc(C(=O)NCCc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(3-methoxy-phenyl)-ethyl-amine to afford the title compound. MS: m/e=392 (M+H).