Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15]O)[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15][Cl:20])[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-n2oc(=S)n(CO)c2=S)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(-n2oc(=S)n(CCl)c2=S)cc1

Procedure:
2-(4-Cyanophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dithione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-cyanophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dithione as the residue.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[CH3:28][C:29]1[CH:30]=[CH:31][N:32]2[C:37]=1[C:36](=[O:38])[N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([C@@H:45]([NH3+:47])[CH3:46])=[N:33]2.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([S:11][C:10]2[C:3]3[C:2]([NH:47][C@H:45]([C:34]4[N:35]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:36](=[O:38])[C:37]5=[C:29]([CH3:28])[CH:30]=[CH:31][N:32]5[N:33]=4)[CH3:46])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1cc(Sc2ccc(N)cc2)c2c(Cl)ncnc21
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3ccc(N)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 42.9 %

Procedure:
4-((4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)aniline (350 mg, 0.73 mmol) was treated with (S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (215 mg, 0.80 mmol), cesium fluoride (11 mg, 0.07 mmol), N,N-diisopropylethylamine (318 μl, 1.83 mmol) and tert-butanol (4 ml) as a solvent according to Preparation 163. The residue was purified by reverse phase using SP1® Purification System to obtain 200 mg (40% yield) of the title compound. Yield 98%.
Reaction SMILES: CN1C(=O)CCC1.Cl[C:9]1[CH:14]=[N:13][C:12]([Cl:15])=[CH:11][N:10]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:15][C:12]1[CH:11]=[N:10][C:9]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[CH:14][N:13]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To an NMP (7.5 ml) solution of 1.51 g of 2,5-dichloropyrazine were added 2.00 g of 1-(t-butoxycarbonyl)piperazine and 2.00 g of potassium carbonate, followed by 1 hour of stirring under heating at 100° C. The mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2.73 g of 2-chloro-5-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine. Using this compound, 2-chloro-5-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazine was obtained in a similar manner to Example 14 as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].[OH-].[Na+]>COCCOCCOC>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C)cc3C)c2cc1OC
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 2,4-dimethylphenol (0.267 ml) were suspended in diethylene glycol dimethyl ether (0.1 ml), and the suspension was stirred at 180° C. for 1.5 hr. The reaction solution was cooled to room temperature, and an aqueous sodium hydroxide solution was then added to the reaction solution. The mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel using acetone-chloroform to give 4-(2,4-dimethylphenoxy)-6,7-dimethoxyquinoline (127 mg, yield 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1CC#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:22][C:21]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Agent: Cl
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1C

Procedure:
2-[2-Methoxy-3-(o-tolyloxy)phenyl]acetonitrile (43.0 g) was added to a mixture of acetic acid (200 ml) and conc. hydrochloric acid (50 ml), and the mixture ws refluxed under heating for 5 hrs. The reaction mixture was evaporated, and water was added to the residue and extracted with diethyl ether. The extract was washed with water and extracted with aqueous sodium bicarbonate. The aqueous extract was washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The ether extract was dried over magnesium sulfate and evaporated. The crystalline residue (37.50 g) was recrystallized from a mixture of diisopropyl ether and n-hexane to give 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetic acid (34.5 g). mp 90°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:25]>C1(C)C=CC=CC=1>[Cl:25][C:4]1[C:3]2[C:8](=[CH:9][C:10]([I:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: O=c1[nH]cnc2cc(I)cc(Cl)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cc(I)cc2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.4 g (1.27 mmol) 5-chloro-7-iodo-3H-quinazolin-4-one, 0.5 ml (3.18 mmol) DIPEA and toluene, 0.3 ml (2.8 mmol) POCl3 is added dropwise and stirred at RT for 1 h, the heated to 90° C. for 1.5 h. After cooling to RT the solvent is evaporated giving rise to crude 4,5-dichloro-7-iodo-quinazoline.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:49])=[C:44]([CH:48]=1)[C:45](O)=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:45]([C:44]4[CH:48]=[C:40]([O:39][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:41]=[CH:42][C:43]=4[CH3:49])=[O:46])[CH2:27][CH2:28]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCc1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B4*HCl) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35]Br>CN(C=O)C>[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35][N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:19])([F:20])[F:21])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Fc1ccccc1CCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccccc1CCN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine dihydrochloride (0.173 g, 0.5 mmol), DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) in DMF (2 mL) was heated at 100° C. for 2.5 hours. The reaction was incomplete and further DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) were added. The solution was stirred at 100° C. for a further 90 minutes. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[2-(2-fluorophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.131 g, 66.4%) as a crisp foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(O)C.[CH3:8][N:9]([CH3:43])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:26][C:27](=[O:42])/[C:28](=[CH:30]/[C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)/[N:29]=3)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1>CO>[CH3:8][N:9]([CH3:43])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:29]/[C:28](/[C:27]([NH:1][CH2:2][CH2:3][OH:4])=[O:42])=[CH:30]\[C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:35][CH:36]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(OC(F)(F)F)cc4)C(=O)O3)cc2)cc1
Reactant: NCCO
Solvent: CO
Solvent: CCO
Product: CN(C)c1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(OC(F)(F)F)cc3)C(=O)NCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 63.6 %

Procedure:
2-Aminoethanol (57 μL, 0.944 mmol) was added to a solution of ethanol (0.5 mL) containing (4Z)-2-(4-{2-[4-(dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (234 mg, 0.471 mmol) prepared in Example 23 (23c). The mixture was stirred at 60° C. for 2.5 hours, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol, 50:1, v/v) to give 167 mg of the title compound (white amorphous solid, yield: 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:14]([O:13][C:11]([C:9]1[C:10]([I:16])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][N:8]=1)=[O:12])[CH3:15]
Reactant: II
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Temperature: 25 °C

Procedure:
To a solution of 10 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 400 ml acetonitrile 13 g ammonium cerium(iv) nitrate (CAN) and 7.17 g iodine were added and the mixture was heated to reflux for 5 h. Then, after cooling to RT, 30 ml sat. sodium thiosulfate solution were added. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water and then dried over MgSO4, filtered and the solvents were removed under reduced pressure. The residue was filtered through a pad of silica gel eluting with heptane/ethyl acetate 1:1. Yield: 13 g.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].Cl>O>[C:20]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]1=[O:19])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)C1C(=O)Nc2ccccc21
Agent: Cl
Solvent: O
Product: CC(=O)N1C(=O)C(C(=O)Cc2ccccc2)c2ccccc21
Yield: 40 %

Procedure:
3-(2-Phenylacetyl)-2-oxindole was acetylated with acetic anhydride using the procedure of Example 7. When the reaction mixture was poured into a mixture of 3N hydrochloric acid and water, a solid formed. The solid was recovered by filtration and recrystallized from isopropanol to give a 40% yield of the title compound, m.p. 149°-151° C.
Reaction SMILES: [Li][CH2:2]CCC.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:16]=1)[CH:14]=O)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(N(C)C)=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:14]=[CH2:2])[CH:16]=1)([O-:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
Methyltriphenylphosphonium bromide (4.97 g, 13.9 mmol) was dissolved in dry THF (30 ml) and a solution of n-BuLi (1.6 M in hexane, 8.69 ml, 13.9 mmol) was added drop-wise. After 15 minutes, 5-nitro-2-(pyridin-2-ylmethoxy)benzaldehyde (3.0 g, 11.6 mmol) dissolved in dry DMA was added. After 1 hour, the reaction was quenched with saturated sodium bicarbonate and the mixture was extracted with ethyl acetate. After evaporation, the crude material was purified on silica gel (20% EtOAc/petroleum ether) to give 2-[(4-nitro-2-vinylphenoxy)methyl]pyridine (1.11 g, 37%); NMR Spectrum: 5.40 (s, 2H), 5.48 (d, 1H), 6.06 (d, 1H), 7.05 (dd, 1H), 7.34 (d, 1H), 7.38 (dd, 1H), 7.55 (d, 1H), 7.87 (t, 1H), 8.18 (dd, 1H), 8.37 (d, 1H), 8.60 (d, 1H); Mass Spectrum: 257 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5](=[CH:9][C:10]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:6]([OH:8])=[O:7].O.[C:17](=O)([O-])[O-].[K+].[K+]>CO.S(=O)(=O)(O)O>[NH2:15][C:4]1[CH:3]=[C:2]([F:1])[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7]
Reactant: Nc1cc(F)c(S(N)(=O)=O)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)c(F)cc1N

Procedure:
A reaction flask, containing 7.2 g (0.0307 molecule) of 4-fluoro-5-sulphamylanthranilic acid (6) in 125 ml of methanol and 10 ml of concentrated sulphuric acid, was attached to a Soxhlet apparatus, containing molecular sieves 4A, immersed in methanol (25 ml). After 48 hours' reflux, the solution was poured into cold water (500 ml), containing 25 g of potassium carbonate. The solid, which separated out, was recovered on a filter and dried in vacuo at 80°; yield: 5.6 g (73.7%); m.p.: 209°-211°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].CCO.[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:12]/[OH:13]
Reactant: NO
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc(F)cc1F
Temperature: 0 °C
Yield: 49.7 %

Procedure:
2,4-Difluorobenzaldehyde (2.27 g, 16.0 mmol) and hydroxylamine hydrochloride (6.67 g, 96.0 mmol) were added to EtOH (25 mL) and water (25 mL) along with about 40 g of ice. The mixture was stirred and 50% aqueous NaOH (7.68 g, 96 mmol) was added dropwise. The mixture was stirred at ambient temperature for about 15 min then the solid was collected by filtration, washed with water (10 mL) and dried to give the title compound (1.25 g, 50%): 1H NMR (DMSO-d6) δ 11.58 (d, 1H), 8.18 (s, 1H), 7.78 (m, 1H), 7.33 (m, 1H), 7.14 (m, 1H).
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21](O)=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>ClCCl>[CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21]([Cl:28])=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)O)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)Cl)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) amino]propionic acid (190 mg, 0.49 mmol) prepared in Example 29 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.17 mL, 4 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. Then, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino]propionic chloride. And then, the compound was dissolved in THF (2 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.34 g, 10 equi.) and NaHCO3 (0.49 g, 12 equi.) was dissolved in THF/H2O (1 mL/1 mL) and cooled down to 0° C. Acid chloride THF solution was slowly added to hydroxyamine solution at 0° C., and the solvent was removed after 1 hour. Then, the product was extracted with ethylacetate (5 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino] propion amide (190 mg, 97%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:10]([C:9]([F:8])([F:40])[F:41])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g, 22.5 mmol) followed by titanium isopropoxide (5.98 mL, 20.1 mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (5.24 g, 16.1 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was and stir the solution for 4 h. Dilute the reaction with methanol (40 mL) and slowly add sodium borohydride (0.912 g, 24.1 mmol) over 15 min to the reaction and stir at room temperature for 3.5 h. Quench the reaction with addition of 2 N NaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate/ethanol (4:1, 3×100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N HCl, and brine (50 mL each), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford isopropyl-5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (22.6 mL, 241 mmol) dropwise to a suspension of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in dichloromethane (64 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (100 mL) and wash with 2 N hydrochloric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (7.60 g, 79%, 2 steps): ESI MS 595 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+]>C(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccsc1
Temperature: 0 °C
Reaction time: 1.3 h
Yield: 72.2 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, thiophene-3-carbaldehyde (3 g, 26.78 mmol) in ethanol (50 mL) was reacted with nitro methane (1.45 mL, 26.78 mmol) and 10N NaOH (3.5 mL, 28.11 mmol). The resulting mixture was stirred at 0° C. for 1.30 hours to afford 3 g of the product (72.28% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([NH2:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([C:21](Cl)=[O:22])[CH2:19][CH3:20]>>[C:21]([NH:17][C:15]([CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:16])(=[O:22])[CH2:18][CH2:19][CH3:20]
Reactant: NC(=O)C1c2ccccc2Oc2ccccc21
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NC(=O)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 222° C. and MS: m/e=295 (M4) was prepared in accordance with the general method of example 39 from 9H-xanthene-9-carboxylic acid amide and propanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: NCCCN1CCCC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCCC1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (70 mg, 0.19 mmol), (prepared as described in Example 278), and 1-(3-aminopropyl)pyrrolidine (74 mg, 0.58 mmol) in DMF (5 ml) was heated to 60° C. overnight. The solvents were removed in vacuo and the residue purified by column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-(pyrrolidin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (64 mg, 68%).