Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Cl)cc(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc(O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5-chloro-2-hydroxy-3-methoxy-benzaldehyde (7 g, 37.5 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. was added a solution of BBr3 in CH2Cl2 (1 M, 93.7 mL, 93.7 mmol) and the reaction mixture was stirred overnight at room temperature. The solution was diluted with CH2Cl2 (200 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure generating the title compound (6.2 g, 36.0 mmol, 96%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.02 (s, 1H), 9.83 (s, 1H), 7.18 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 5.71 (s, 1H).
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@H:13]([N:34]2[CH:39]=[C:38]([F:40])[N:37]=[C:36]([C:41]([NH2:43])=[O:42])[C:35]2=[O:44])[O:12]1)(=O)C1C=CC=CC=1.C[O-].[Na+].Cl>CO>[OH:25][C@@H:14]1[C@H:15]([OH:16])[C@@H:11]([CH2:10][OH:9])[O:12][C@H:13]1[N:34]1[CH:39]=[C:38]([F:40])[N:37]=[C:36]([C:41]([NH2:43])=[O:42])[C:35]1=[O:44]
Reactant: NC(=O)c1nc(F)cn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1nc(F)cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
In 2.0 mL of methanol was dissolved 0.15 g of [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate. Then, 0.14 g of a 28% methanolic solution of sodium methoxide was added and stirred at an ice-cooled temperature for 20 minutes and thereafter at room temperature for 30 minutes. The reaction mixture was acidified with 0.75 mL of 1 mol/L hydrochloric acid and the solvent was removed under reduced pressure. After purifying the residue by column chromatography [eluent: chloroform:methanol=5:1], isopropanol and diethyl ether were added and the solid product was collected by filtration to obtain 40 mg of 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[OH-].[Na+]>N1C=CC=CC=1>[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1Br
Reactant: NCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cccnc1NCCCN
Yield: 48.2 %

Procedure:
A mixture of 3-methyl-2-bromopyridine (15 g), 1,3-diaminopropane (37.3 g) and pyridine (10 ml) was heated under reflux for 3 hr. After stripping, the residue was treated with 2N sodium hydroxide and the product extracted into chloroform. The extract was dried, stripped and the residue distilled at reduced pressure to give 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) bp 100° C., 0.09 mm Hg. (ii) Sodium hydride (1.11 g) was dissolved in DMSO (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) in DMSO (10 ml) added at room temperature. Methyl iodide (6.56g) in DMSO (20 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hr, water (100 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid. The pH of the acid extract was raised to 9.5 and extracted with chloroform. The pH was raised further to 14 and again extracted with chloroform. After stripping the final extract, the residue was taken back up in water and the product extracted out again with ether. After drying (K2CO3), stripping the ether extract gave 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (4.46 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (1.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.46 g) were heated together under reflux in pyridine (10 ml) for 20 hr. The mixture was stripped and the residue triturated with water (pH adjusted to 7 with 6N hydrochloric acid) until a solid (2.1 g) was obtained. This was chromatographed (silica gel, 1-3% methanol/chloroform) and crystallised from acetone/water to give 2-[3-[N-methyl-N-(3-methylpyrid-2-yl)amino]-propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.48 g (22%) mp 83°-85° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[F:16])(=O)C.O.[CH3:18][CH2:19][O:20]C(C)=O>>[Br:15][C:12]1[CH:11]=[C:10]([F:16])[C:9]([OH:8])=[C:14]([C:19](=[O:20])[CH3:18])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)Oc1ccc(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1cc(Br)cc(F)c1O
Temperature: 150 °C

Procedure:
AlCl3 (5.0 g, 38 mmol) was added in portions to 4-bromo-2-fluorophenyl acetate (5.8 g, 25 mmol). The mixture was heated at 150° C. for 3 h and then brought to ambient temperature. Water (ice-cold) was slowly added and then EtOAc. The resulting mixture was vigorously stirred and then the phases were separated and the water phase extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness to give the title compound (5.3 g). MS m/z (rel. intensity, 70 eV) 233 (M+, 55), 232 (M+, 56), 218 (98), 217 (bp), 161 (10).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl>[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54]([N:13]2[CH2:14][CH2:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:29])([F:31])[F:30])[C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[C@@H:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:12]2)(=[O:56])=[O:55])=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A 20 mL vial was charged with tert-butyl (3R)-3-((phenylsulfonyl)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.038 g, 0.065 mmol), TFA (0.50 mL, 6.5 mmol, Sigma-Aldrich, St. Louis, Mo.) and DCM (1 mL). The mixture was stirred at rt for 10 min. The volatile was removed and the residue was taken into DCM (1 mL). TEA (0.10 mL, 0.78 mmol) was added and the mixture was stirred at rt for 5 min. At this time, 6-chloropyridine-3-sulfonyl chloride (0.016 g, 0.073 mmol, Organic Process Research & Development 2009, 13, 875) was added and the mixture was stirred at rt for 10 min. The reaction mixture was directly purified by column chromatography (10 g of silica, 0 to 50% EtOAc in hexanes) to afford 2-(4-((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.026 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:23]=2[O:22][CH2:21][CH2:20]1>>[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:17][CH3:18])[C:14]5[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:16])[CH2:31][CH2:30]3)[C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Product: CCC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine.
Reaction SMILES: [C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:15]2[C:21]([NH2:23])=O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(#N)C.C(OCC)(=O)C>[C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:15]2[C:21]#[N:23])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)COS(=O)(=O)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrroli dine-2-carboxamide (872 mg) was dissolved in acetonitrile (16 mL), followed by triethylamine (1.05 mL). While this mixture was cooled in a salt-ice bath, trifluoroacetic anhydride (0.53 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour, followed by the addition of water (16 mL) and extraction with ethyl acetate (2×60 mL). The ethyl acetate extracts were combined, washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=1:1) to give (2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrrolidine-2-carbonitrile as a white crystal (789 mg, 96% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH:10](Br)[CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15](C(OCCCC)=O)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>ClCCl>[N:15]1[N:14]2[CH:10]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:26])[CH2:11][CH2:12][C:13]2=[CH:17][CH:16]=1
Reactant: CCCCOC(=O)n1ccc(CCC(Br)C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1CCc2ccnn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 16.9 g (40.0 mmol) of text-butyl 3-[4-(benzyloxy)-3-bromo-4-oxobutyl]-1H-pyrazole-1-carboxylate from step E in 50 mL of dichlormethane was added 50 mL of TFA. The resulting mixture was stirred for 2 h at ambient temperature then all volatiles were evaporated in vacuo. The residue was then diluted with 50 mL of toluene and evaporated again in vacuo to remove all residual TFA. The crude material was then dissolved in 125 mL of anhydrous acetone and 14.0 g (100 mmol) of solid potassium carbonate was slowly added over 15 min followed by 1.2 g (8.0 mmol) of sodium iodide. The resulting mixture was then heated at reflux for 16 h, cooled to room temperature and evaporated to dryness in vacuo. The residue was diluted with 100 mL of a saturated, aqueous ammonium chloride solution and then extracted with ethyl acetate (3×100 mL). The combined organics layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 10-80% EtOAc in hexanes gradient to afford the title compound as a clear gum 6.2 g (64% yield). LC-MS: m/z (ES) 243 (MH)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([N:10]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:11]1)=[O:9]>C(OCC)(=O)C>[F:20][C:16]1[CH:17]=[CH:18][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:14]([CH:12]2[CH2:11][N:10]([C:8](=[O:9])[C:7]([F:6])([F:21])[F:22])[CH2:13]2)[CH:15]=1
Reactant: O=C(N1CC(c2cccc(F)c2)C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C(N1CC(c2cc(F)ccc2S(=O)(=O)Cl)C1)C(F)(F)F

Procedure:
Chlorosulphonic acid (5 mL) was added to 2,2,2-trifluoro-1-[3-(3-fluorophenyl)azetidin-1-yl]ethanone (Intermediate 90, 1.15 g) with stirring and ice cooling. The mixture was stirred for 1 hour then poured carefully onto a mixture of ice and ethyl acetate. The organic layer was washed with water and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give 4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzenesulfonyl chloride (0.910 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=O)[CH3:12])[CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:10]=[CH:9][N:8]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccn1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cc(OCC(F)(F)F)ccn1
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (60 mg, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone (120 mg, 0.53 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:19][CH3:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[ClH:31]>O1CCOCC1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:31].[ClH:31].[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[N:8]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:6]=[C:5]3[NH:19][CH3:20])[CH:25]=[CH:24][CH:23]=1
Reactant: CNc1nc(-c2cccnc2)nc2c(C)cc(Br)cc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1nc(-c2cccnc2)nc2c(C)cc(-c3cccc(F)c3)cc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
6-Bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (340 mg, 1.03 mmol), 3-fluorobenzeneboronic acid (217 mg, 1.55 mmol), K2PO4 (658 mg, 3.10 mmol) and Pd(PPh3)4 (59.7 mg, 0.052 mmol) were dissolved in the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere. After the reaction was completed, water was added to the mixture and stirred for 30 minutes. The resulting precipitate was collected by filtration and purified by column chromatography on NH-silica gel (eluted with THF) to give a yellow powder. The solid was suspended in ethanol and 5N HCl (1 mL) was added to the mixture. The mixture was sonicated for 10 min and the resulting precipitate was collected by filtration and dried to give 304 mg of 6-(3-fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4 amine dihydrochloride as a yellow powder in 71% yield.
Reaction SMILES: [P:1]([O:13][CH2:14]Cl)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I-:16].[Na+].CC(C)=O>C(#N)C>[P:1]([O:13][CH2:14][I:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCI)OC(C)(C)C

Procedure:
The title compound was prepared by halogen exchange reaction of di-tert-butyl chloromethyl phosphate (Intermediate 1) with sodium iodide in suitable solvent such as dry acetone or acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)CCO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)C1(C(=O)OCCC(C)C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-methylbutanol accord-ing to the procedure of Example 1 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.90 (d, 12H), 1.35 (d, 2H), 1.55-1.80 (m, 6H), 2.70-2.85 (m, 1H), 3.45-3.55 (m, 3H), 4.30 (t, 4H), 5.45 (bd, 1H), 5.65 (bs, 1H), 6.70-6.80 (m, 1 H), 6.80-6.90 (m, 3H), 7.25-7.35 (m, 3H), 7.43 (s, 1H), 8.74 (bs, 1H), 10.08 (bs, 1H); IR (KBr): 3303 cm-1 (--OH), 1765 cm-1 (C=O); MS (ES) m/z 562.4 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C30H40ClNO7 ·HCl: C, 60.20; H, 6.74; N, 2.34; Cl, 11.85. Found: C, 59.98; H, 7.04; N, 2.24; Cl, 12.09.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)O
Product: CCN(CC)C(=O)CCCCCCNC(=O)OC(C)(C)C

Procedure:
Prepare by a method similar to Example 70 using 7-(t-butoxycarbonyl)amino-heptanoic acid and diethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[C:26]([F:34])[CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:35]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:35])(=[O:32])=[O:31])=[C:26]([F:34])[CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1F
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1F

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 125 mg, 31%). mp 224-226° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 2H) 7.75 (m, 4H), 7.9 (t, 1H); 8.4 (s, 1H). MS (DCI/NH3) m/z 492 (M+H)+, 509 (M+NH4)+. Anal. calc. for C22H13F4N3O4S: C, 53.77; H, 2.67; N, 8.55. Found, C,; 53.33; H, 2.84; N, 8.22
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C#N)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 1H-indole-5-carbonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:23][C:24](C)([O-])[CH3:25].[K+].C(Br)C=C.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:25][CH:24]=[CH2:23])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 0.7 g (2.2 mmole) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml of dry dimethyl formamide which was cooled to 0° C. After stirring for 15 minutes, 1.0 ml (11 mmole) of allyl bromide was added and the mixture was allowed to warm to room temperature. Water was added and the mixture was extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a yellow oil. Crystallization from a mixture of ether and petroleum ether gave a tan solid (mp 100°-102° C.). Recrystallization from a mixture of ether and petroleum ether gave colorless prisms, mp 104°-106° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[CH2:1]([N:8]([C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:21])([CH3:22])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)O)n1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
To a suspension of 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid resin (0.15 g) synthesized in Example 461-6 in acetonitrile (1.5 ml) were added triethylamine (0.16 ml) and 2-chloro-3-nitropyridine (0.089 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the mixture, washed three times with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried. Trifluoroacetic acid (2.0 mL) was added to the obtained resin, and the mixture was left standing at room temperature for 2 hr. Then the resin was removed by filtration from the reaction mixture, and the filtrate was concentrated by blowing a nitrogen gas, vacuum dried, and purified by preparative HPLC to give the title compound (1.5 mg) as a pale-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:28][C:29]([C:32]([F:35])([F:33])[F:34])=[N:30][N:31]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.69(1H,bs), 9.53(1H,s), 8.91(1H,s), 8.65(1H,dd), 8.11(1H,d), 7.64(2H,d), 7.45(5H,m), 7.15(2H,d), 5.19(2H,s); m/z (M+1+) 464.