Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:17]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[CH:13][N:25]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCCCCCNc1ccccc1
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Solvent: CCO
Product: CCCCCCCCN(C=Nc1ccc(C(=O)OCC)cc1)c1ccccc1

Procedure:
Ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (6.6 g, 0.03 mol) and N-octylaniline (6.2 g, 0.03 mol) were heated at 180° until 1.7 ml of ethanol had been collected by distillation. The resulting pale yellow oil was flash distilled to yield the desired product, bp≈235° C. (0.05 mm). ##STR15##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:14]([NH:17]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:15][S:16][C@H:11]12)=[O:8].C(Cl)Cl.CO.[H][H]>[Pd].C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O:33][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])=[C:14]([NH2:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(NC(=O)OCc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: NC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 97.8 %

Procedure:
A solution of 0.178 g. (0.26 mmole) of benzhydryl 7-(2-thienylacetamido)-3-(4-nitrobenzyloxycarbonylamino)-3-cephem-4-carboxylate in 3 ml. of methylene chloride was combined with 70 ml. of methanol and 0.178 g. of 5 percent palladium on carbon (prereduced with hydrogen at 50 psi for 15 minutes) in 30 ml. of 3A ethanol. The alcoholic mixture was reduced with hydrogen at 50 psi for 3.5 hours. The catalyst was filtered and washed with hot 3A ethanol. The filtrate and washings were combined and evaporated in vacuo to dryness. A methylene chloride solution of the residue thereby obtained was filtered through a celite filter pad. Evaporation in vacuo to dryness provided 128 mg. (97.8 percent) of the title product as a yellow froth: ir (CHCl3) 1720 cm-1 (β-lactam); nmr (CDCl3) δ3.7 (ABq, C2--H), 3.92 (s, 1, side chain CH2), 5.01 (d, 1, J=4.0 Hz, C6--H), 5.32 (q, 1, J = 4.0 Hz, and 8.0 Hz, C7 --H), and 6.3 (NH).
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](=[S:24])[NH2:23])=[CH:20][CH:19]=1>CC#N>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:23]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[S:24][C:2]=2[C:3]([O:5][CH3:6])=[O:4])=[CH:10][CH:11]=1
Reactant: COC(=O)C(Br)C(=O)c1ccc(F)cc1
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CC#N
Product: COC(=O)c1sc(-c2ccc(OC)cc2)nc1-c1ccc(F)cc1
Reaction time: 18 h
Yield: 22.2 %

Procedure:
To a stirring solution of methyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate 78 (1 equiv, 1.15 g, 4.2 mmol) in MeCN at room temperature was added 4-methoxybenzo-thioamide 77 (1 equiv, 700 mg, 4.2 mmol) and the reaction mixture was stirred for 18 h. The solvent was evaporated and the residue purified by trituration with diethyl ether to afford methyl 4-(4-fluorophenyl)-2-(4-methoxyphenyl)thiazole-5-carboxylate 79 (320 mg, 22% yield). LRMS (ESI): (calc) 343.37 (found) 344.235 (MH+)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:31][C:32]#[N:33].[Na+]>CC(O)=O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:33][C:32]1=[O:31]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccc(O)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.0 g (7.51 mmol) of the product prepared in step A in 45 ml AcOH is treated with 732 mg (11.3 mmol) sodium cyanate. The dark red solution is stirred for 2 h at rt. The resulting yellow-orange suspension is diluted with water and filtered. The orange product is washed well with water and diethyl ether to yield an orange solid. m.p. 230° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]([N:2]3[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]3)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10]
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: O=S1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCS(=O)CC4)S3)[nH]c12
Reaction time: 15 h
Yield: 58 %

Procedure:
To a solution of thiomorpholine 1-oxide hydrochloride (340 mg) and triethylamine (0.31 mL) in N,N-dimethylformamide (25 mL) were added [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (300 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 80:20, volume ratio), and the obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (354 mg, yield 58%) as colorless crystals. melting point 194-196° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+]>CO.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCOc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 14.1 %

Procedure:
A mixture of 3-hydroxy-4-ethoxybenzaldehyde (0.350 g, 2.5 mmol), 3,4,5-trimethoxyacetophenone (0.443 mg, 2.5 mmol) and 50% w/v of aqueous sodium hydroxide (3.37 ml, 0.042 mol) in methanol (5 ml) at room temperature for 18 h. An orange solid was isolated by filtration, dissolved in ethyl acetate which was subsequently dried over MgSO4 and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) yielded 0.126 g (16.7%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 4H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.75 (s, 1H), 4.2 (q, 2H), 3.95 (s×2, 9H), 1.5 (t, 3H). 13C-NMR (CDCl3) δ 190.0, 153.1, 150.0, 146.0, 133.7, 128.4. Mass Spectrum m/e (M+1) 359. Anal. Calcd. for C20H22O6: C, 67.03; H, 6.19. Found C, 66.74; H, 6.33.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C@H:19]([CH2:22][OH:23])[O:18][C:17]=2[CH:24]=1.O>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:19]2[O:18][C:17]3[CH:24]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][CH2:20]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccc(Cl)cc2O1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(Cl)cc3O2)cc1
Reaction time: 4 h

Procedure:
4-Toluenesulphonyl chloride (5.9 g) was added to a solution of (S)-7-chloro-1,4-benzodioxan-2-ylmethanol (6.0 g; prepared by the method described above) in pyridine (40 ml) and the mixture stirred for 4 hours. More 4-toluenesulphonyl chloride (250 mg) was added, stirring continued for 2 hours, then further 4-toluenesulphonyl chloride (250 mg) was added and stirring continued for 1 hour. The mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined extracts were washed with hydrochloric acid (2M; 2×200 ml), saturated aqueous sodium bicarbonate solution (2×200 ml) and brine (200 ml), then dried over magnesium sulphate. The solvent was removed in vacuo and the residue recrystallised from ether to give (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (7.00 g) m.p. 90-91° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21].C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[C:20]=[S:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NCCCc1cc(F)cc(F)c1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(F)cc(CCCN=C=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of 3-(3,5-difluorophenyl)propylamine (0.0327 mol) and triethylamine (0.072 mol) in tetrahydrofuran (20 ml) was added dropwise to a solution of thiophosgene (0.0392 mol) in tetrahydrofuran at 0°. The reaction was stirred 2 hours at room temperature then ethyl ether was added and the mixture filtered. The filtrate was concentrated and distilled (Kugelrohr) to yield 3.8 g (55%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][N+:7]([O-])=[O:8].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]1[CH2:13][CH:12]([C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[O:8][N:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCC1=NOC(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 105 g of 4-nitrobutyric acid methyl ester (Bruson U.S. Pat. No. 2,342,119), 64 g of t-butyl acrylate, 1 ml triethyl amine in 200 ml of toluene is stirred and treated dropwise with 137 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphenyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on elution with hexane:ethyl-acetate; 75:25) to yield 4,5-dihydro 5-(t-butoxycarbonyl)-3-isoxazolepropanoic acid methyl ester as a colorless oil. NMR (CDCl3) and 4.87 (t, J=9 Hz, 1H), 3.70 (s, 3H), 3.20 (d, J=9 Hz, 2HO, 2.67 (s, 4H), 1.47 (s, 9H). IR (cm-1) 2970, 1740, 1600, 1556, 1445, 1396, 1373, 1340, 1300, 1262, 1230.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].CC(C)([O-])C.[K+].Cl[CH2:19]/[CH:20]=[CH:21]\[CH2:22]Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:22][CH:21]=[CH:20][CH2:19]1)=[O:11])[CH3:2]
Reactant: ClC/C=C\CCl
Reactant: CCOC(=O)Cc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cccs2)CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a solution of thiophen-2-yl acetic acid ethyl ester (1) (980 mg, 5.76 mmol) in 10 ml of THF at -20° C. was added a 1M solution of potassium t-butoxide in THF (5.76 ml, 5.76 mM) over 15 minutes. After 30 minutes at -20° C., cis-1,4-dichlorobut-2-ene (0.610 ml, 5.76 mmol) was added dropwise and the reaction was warmed to room temperature. After 20 minutes the reaction was recooled to -20° C. and treated with potassium t-butoxide in THF (5.76 ml, 5.76 mM). The reaction was allowed to warm to room temperature, then was heated at 50° C. for 30 minutes and quenched with saturated ammonium chloride solution. The solvents were removed in vacuo and the residue taken up in EtOAc and washed with water. The organic layer was washed with saturated sodium chloride and dried over MgSO4 to yield the title compound (2) (450 mg) after chromatography on silica gel using 5% EtOAc in hexanes as the eluant.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:8]
Reactant: COC(CCCC(C)O)OC
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: COC(CCCC(C)OCc1ccccc1)OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
5-benzyloxyhexanal dimethyl acetal: a sodium hydride dispersion (7.2 g of 50% dispersion, 150 mmol, 1.2 equivalents) was washed with hexane (3×50 ml), suspended in DMF (250 ml) and cooled to 5° C. before adding the 5-hydroxyhexanal dimethyl acetal (20.28 g, 125.0 mmol) prepared in (b) in DMF solution (20 ml); the suspension being allowed to warm then up to 20° C. over 1 hour. After 30 minutes benzyl bromide (25.6 g, 150 mmol) was added at 5°-10° C. over 15 minutes and the resulting thick slurry quenched after 30 minutes by the careful addition of water (200 ml). Pentane (250 ml) was added and the layers separated, the aqueous phase was extracted with pentane (3×100 ml) and the combined pentane layers washed with water (2×100 ml) and brine (150 ml) dried (MgSO4) and concentrated. Distillation gave pure 5-benzyloxyhexanal dimethyl acetal (101°-102° C. at 0.05 mm Hg, 122.4 mmol, 98%)
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:3]=1.Br[CH2:32][CH:33]=[CH2:34].C([O-])([O-])=O.[K+].[K+].[N+](C(C)(C)C)(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[O-]S(O)(=O)=O>C(Cl)Cl.O>[CH2:34]([O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][CH:21]=3)[N:16]=2)=[N:5]1)[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: C=CCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
A solution of 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 140 mg, 0.33 mmol) in DCM (5 mL), was added to a mixture of 3-bromoprop-1-ene (60 mg, 0.5 mmol), K2CO3 (138 mg, 1.0 mmol) and t—Bu4NHSO4 (113 mg, 0.33 mmol) in H2O (5 mL). The mixture was stirred at RT for 16 h, then diluted with H2O (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel chromatography (Petroleum ether:EtOAc=5:1 to 2:1) to give the title compound (140 mg, 91%) as a white solid. MS (ES+) C22H18F3N5O3 requires: 457. found: 458 [M+H]+.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:22]3[O:21][C:20]4[C:15](=[CH:16][C:17]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][N:29]5C(=O)C6=CC=CC=C6C5=O)=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])C(=O)C2=CC=CC=C12.C1(=O)N(CCCC([Cl:57])=O)C(=O)C2=CC=CC=C12.C1C2CC3C(=CC=CC=3)OC=2C=CC=1.[ClH:78]>C(O)(=O)C>[ClH:57].[ClH:78].[NH2:29][CH2:28][CH2:27][CH2:26][C:25]([C:17]1[CH:18]=[CH:19][C:20]2[O:21][C:22]3[C:13](=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH2:5])=[CH:24][CH:23]=3)[CH2:14][C:15]=2[CH:16]=1)=[O:40]
Reactant: O=C(CCCN1C(=O)c2ccccc2C1=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN3C(=O)c4ccccc4C3=O)ccc1O2
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: c1ccc2c(c1)Cc1ccccc1O2
Solvent: CC(=O)O
Product: NCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN)ccc1O2

Procedure:
2,7-Bis(4-phthalimidobutyryl)xanthene, prepared from 4-phthalimidobutyryl chloride and xanthene by the method of S. S. Cheng et al., J. Med. Chem. 9, 945 (1966), is treated with 700 ml. of hot glacial acetic acid after which 200 ml. of concentrated hydrochloric acid is added gradually with stirring. The mixture is heated to reflux for 24 hours with a constant stream of HCl gas passing through the mixture The reaction mixture is stirred and refluxed for an additional 24 hours, cooled, and the product worked up in the usual manner.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][CH:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:28][C:26]1([CH3:29])[C:25]([CH3:30])([CH3:31])[O:24][B:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][NH:14][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:22][CH:21]=2)[O:27]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(c2ccc(CCNS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a 0° C. solution of tert-butyl(methylsulfonyl){2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (from the previous step, assumed 19.7 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0° C. and brought to pH 10.5 with a 4N aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to provide the title compound as an off-white solid. Yield: 2.5 g, 7.7 mmol, 39% over two steps. LCMS m/z 326.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 12H), 2.84 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 3.42 (dt, J=6.6, 6.6 Hz, 2H), 4.18 (br t, J=6 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38]([O-:40])=[O:39])[N:33]=[CH:32]2>C(O)(C)C>[CH3:18][O:17][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:38]([O:40][C:11]([CH3:6])([CH3:2])[CH3:10])=[O:39])[N:33]=[CH:32]4)=[N:3][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:5]2)=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: Nc1ccc2c(cnn2C(=O)[O-])c1
Reactant: COCCOc1cc2c(Cl)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Solvent: CC(C)O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Temperature: 95 °C
Yield: 149.2 %

Procedure:
A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline (0.500 g, 1.28 mmol) and 5-amino-1H-indazole-1-carboxylate (0.314 g, 1.34 mmol) in iso-propanol (30 mL) was heated at 95° C. for 30 minutes and at 95° C. for 8 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et2O, triturated with CH2Cl2 and EtOAc and dried in vacuo to give tert-Butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.560 g, 0.955 mmol, 71%). MS 587 (M+1). HPLC retention time 7.21 mins.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Br:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23]>>[Br:17][C:18]1[CH:19]=[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cc(Br)c(Cl)s3)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)phenyl}acetamide (63 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (11.7 mg) with purity >80%: MS (pos) m/z 491.9, 493.9.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CC1(N2CCCC2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=231.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and phenyllithium.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH2:14][CH:9]3[CH:10]([CH3:13])[CH2:11][CH2:12][NH:8]3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1Cc1c[nH]c2cc(F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCNC1Cc1c[nH]c2cc(F)ccc12
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To solution containing 66 (0.89 g, 0.0024 mol) in DCM (20 mL) at 0° C. was added TFA (4 mL). After 2 h, TLC analysis revealed complete consumption of 66 [10% MeOH/DCM, Rf(66)=0.7, Rf(67)=0.3]. The reaction mixture was concentrated in vacuo, diluted with DCM, washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.6 g (86%) of 67 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ9.0 (br s, 1H), 7.6-7.35 (m, 1H), 7.1-6.7 (m, 3H), 4.2 (br m, 1H), 3.2-2.5 (m, 5H), 2.1-1.2 (m, 3H), 1.05 (d, J=6.74 Hz, 3H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([O:20]C)[C:14]4=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Br.C(O)(=O)C>CCOCC>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]4=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]ccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Yield: 76.7 %

Procedure:
Cyclopropyl-{4-[2-(4-fluorophenyl)-8-methoxyimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine (Example #A.10.1, 0.156 g, 0.414 mmol) was treated with a 4 M solution of hydrogen bromide in acetic acid (3 mL, 12 mmol) at ambient temperature. After about 45 min the mixture was treated with Et2O and filtered, washing the solid successively with Et2O, saturated aqueous NaHCO3 and Et2O. The solid was then dried in the oven for about 16 h to yield the product as white solid (0.115 g, 77%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 361.4 (M−H)−.