Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:34][NH2:35]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:32])[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:28][CH2:29]4)=[C:21]([CH:26]=3)[C:22]([NH:34][NH2:35])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1cc(C2CC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in ethanol (15 mL) was added hydrazine hydrate (80%, 5 mL). The resulting solution was stirred at 80° C. for 15 h. After cooling to ambient temperature, the reaction was quenched with 50 mL of water, then extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 150 mg (75%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:63]([O:67][C:68](=[O:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([NH2:76])=[C:72]([O:77][CH3:78])[CH:71]=1)([CH3:66])([CH3:65])[CH3:64]>>[C:63]([O:67][C:68](=[O:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([NH:76][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:72]([O:77][CH3:78])[CH:71]=1)([CH3:65])([CH3:66])[CH3:64]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.49 g, 2.1 mmol), then reacted with (4-amino-3-methoxy-phenyl)-acetic acid tert-butyl ester prepared in Example 158 (0.25 g, 1 mmol) to give chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid tert-butyl ester as a off white solid (Yield 0.18 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1N
Reaction time: 1 h
Yield: 112.4 %

Procedure:
4-Amino-3-methoxybenzoic acid (2.045 mmol, 0.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloro-methane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.13 g). MS (ESI) m/z 492.1 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.C1COCC1.[Li+].[OH-]>O>[NH3:13].[CH3:31][C:27]1[N:26]=[C:25]([C:17]2[C:16]([C:10]3[C:9]4[C:14](=[CH:15][C:6]([CH:5]=[CH:4][C:3]([OH:32])=[O:2])=[CH:7][CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(C=CC(=O)O)ccc23)n1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 182.8 %

Procedure:
To a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic methyl ester (0.03 g, 0.07 mmol), THF (1 mL), and H2O (0.5 mL), add LiOH (0.012 g, 0.29 mmol). Stir the reaction mixture at room temperature for 24 hours. Evaporate the solvents in vacuo. Chromatograph the residue on SCX ion-exchange resin (elute with 95% methanol/ethyl acetate, then 100% methanol, then 2M NH3 in methanol) to afford the title compound 26 mg (93%) as a yellowish solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=3)[N:7]([CH3:18])[C:6]=2[CH:19]=1.[CH3:20][O-:21].[Na+].CO>CS(C)=O>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=3)[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: C[O-]
Reactant: COc1cncc(-c2nc3ccc(F)cc3n2C)c1
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cncc(-c2nc3ccc(OC)cc3n2C)c1
Temperature: 165 °C

Procedure:
To a solution of the title compound from Example 1 Step C (0.010 g, 0.038 mmol) in dimethylsulfoxide (0.2 mL) was added a solution of sodium methoxide in methanol (25 wt %, 0.018 mL, 0.078 mmol). The reaction was heated at 165° C. for 1 hour, then cooled to room temperature and purified by flash chromatography (50% ethyl acetate in hexanes, then 100% ethyl acetate) to provide the title compound: LCMS m/z 270.25 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.55 (d, 1.5 Hz, 1 H), 8.43 J=2.7 Hz, 1H), 7.72 (d, J=8.8 Hz, 1 H), 7.66 (dd, J=2.5, 1.8 Hz, 1 H), 6.98 (dd, J=8.8, 2.3 Hz, 1 H), 6.86 (d, J=2.3 Hz, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=3[CH3:38])=[CH:11][CH:12]=2)[N:7]([CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:6]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]4[CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:12][CH:11]=3)=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: COC(=O)c1cn(CCS(C)(=O)=O)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2c(C(=O)O)cn(CCS(C)(=O)=O)c2c1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 6-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-1-(2-methanesulfonyl-ethyl)-1H-indole-3-carboxylic acid methyl ester (235 mg, 0.358 mmol), methanol (17 mL), THF (8 mL), and 5 N sodium hydroxide (1.29 mL) is heated at reflux for two days. The mixture is allowed to cool and is concentrated under reduced pressure to near dryness. Approximately 10 mL of water is added and the mixture is stirred for two hours. The mixture is filtered and the solid is washed with water and dried to provide the title compound (187 mg, 81%). LCMS (ES+): (641.0).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][C:10]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])=[O:11])[N:5]=1.C(O)(=O)C>C(O)C>[C:4]([NH:5][C:6]1[CH2:9][C:10](=[O:11])[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])[N:7]=1)(=[O:8])[CH3:3].[Cl:19][C:18]1[CH:17]=[C:16]([Cl:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[NH2:12]
Reactant: Cc1nc(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)no1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Product: Nc1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 48 %
Yield: 12 %

Procedure:
To a solution of 10 g of potassium hydroxide in 200 ml of anhydrous ethanol was added 20 g of 2-(5-methyl-1,2,4-oxadiazol-3-yl)-2',4',6'-trichloroacetanilide. The mixture was heated under reflux for 10 hours. After it cooled, the mixture was acidified with 20 ml of acetic acid and concentrated to almost dryness under reduced pressure. The residue was slurried in water, collected, and dried. The crude product was stirred with 200 ml of hexane for 15 min., and the hexane solution was separated in hot ethanol and allowed to crystallize over night. There was obtained 9.6 g (48%) of 3-acetamido-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one, mp 234°-235.5° C., and 1.5 g (12%) of 2,4,6-trichloroaniline.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C([NH:15][C:16]1[CH:40]=[CH:39][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][C:35](F)(F)F)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=1)(OC(C)(C)C)=O>ClCCl>[NH2:15][C:16]1[CH:40]=[CH:39][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:21][N:20]4[CH2:2][CH2:3][O:5][CH2:18][CH2:19]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2cc1OCC(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(N)cc3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 234.6 %

Procedure:
Trifluoroacetic acid (20.0 ml, 260 mmol) was added to a suspension of 4-(4-(N-Boc-amino)anilino)-6-methoxy-7-(2,2,2-trifluoroethoxy)quinazoline (7.50 g, 11.7 mmol) in dichloromethane (80 ml) and the reaction stirred for 45 minutes at ambient temperature. The solvents were removed in vacuo, the residue was suspended in water (50 ml) and saturated aqueous sodium bicarbonate solution was added. The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic layers were washed with brine (100 ml) and evaporated in vacuo. Drying of the solid in vacuo yielded 4-(4-aminoanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (5.62 g, 100% yield) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27]1.[C:39](=O)([O-:41])[O-:40].[Na+].[Na+].[I-].[K+]>C(O)CCC>[C:39]([OH:41])(=[O:40])[C:29]([OH:30])=[O:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(CCCl)CN1Cc1ccccc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)C(=O)O
Product: O=C1OC(CCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)CN1Cc1ccccc1
Yield: 150.9 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 9.1 g (0.03 mole) of α,α-bis-(p-fluorophenyl)-4-piperidinemethanol, 7.2 g (0.03 mole) of 5-(2-chloroethyl)-3-benzyl-2-oxazolidinone, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 175 ml of 1-butanol gave a gum as residue. The gum was converted to the oxalate salt and the solid was recrystallized from 2-methoxyethanol-water to yield 13.5 g (75%) of white solid, m.p. 234°-235° C., with decomposition.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: BrBr
Reactant: Oc1ccc2cnccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc2cnccc2c1Br
Yield: 88.4 %

Procedure:
7.9 mL (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of compound 7 in 250 mL of chloroform at room temperature. After stirring for 2 h ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCO3 solution was added carefully. The precipitate was filtered and washed with NaHCO3 solution until the filtrate had a pH of 8. Drying gave 23.78 g (88%) of compound 9 as an off-white solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)(O)[O-].[Na+].O>C(O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)N[C@H](CS)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 9.28 g (56.9 mmol) of (S)-N-acetyl-cysteine, 7.43 mL (70.5 mmol) of 1-fluoro-2-nitrobenzene and 13.66 g (163 mmol) of sodium bicarbonate was refluxed in 136 mL of ethanol and 41 mL of water for 3 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was dissolved in 136 mL of water and extracted with ether. The water solution was then acidified to pH=1with 12N hydrochloric acid (HCl). The resulting yellow precipitate was filtered to yield 13.6 g (84%) of product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]([F:32])=[CH:9][C:8]=1[F:33].[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]([F:32])=[CH:9][C:8]=1[F:33])=[N+:35]=[N-:36]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 10 h
Yield: 66.8 %

Procedure:
489 mg (1.02 mmol) of the above 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 20 mL of dimethylformamide under argon atmosphere, 332 mg (5.10 mmol) of sodium azide was added and the mixture was stirred at 70° C. for 10 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 332 mg of 5-(4-azidobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (18.6 g, 164 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)benzonitrile (20 g, 136 mmol) and triethylamine (20.6 g, 204 mmol) in DCM (200 mL) at 0° C. The reaction mixture was stirred at rt until the reaction was complete (as indicated by tlc). Water (200 mL) was added and the organic layer was separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.CN(C=O)C.C(N(CC)C(C)C)(C)C.Br[CH2:34][C:35]([NH2:37])=[O:36]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH2:34][C:35]([NH2:37])=[O:36])[CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Br)cn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Br)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.6 %

Procedure:
To a 250 mL round-bottomed flask was added N-(5-bromopyridin-2-yl)-4-methylbenzenesulfonamide (10.0 g, 31 mmol), DMF (60 mL), N,N-diisopropylethylamine (6.4 mL, 37 mmol) and 2-bromoacetamide (5.1 g, 37 mmol, Aldrich, St. Louis, Mo.). The mixture was stirred at 25° C. for 1 day. The mixture was poured into water (600 mL) and the solution was stirred for 1 h. The solution was filtered and the filtercake was washed with water and then dried in vacuo to afford the title compound as a white solid (10.2 g, 87%). MS (ESI, positive ion) m/z: 384 (M(79Br)+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[O:11])=[CH:8][C:7]=1[NH:22][C:23]1[C:24]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[N:29][C:25]=2[N:26]=[CH:27][N:28]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:39]([O:43][C:44](=[O:45])[NH:46][CH2:47][C:48](=[O:49])[NH:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:4]([O:5][C:6]2[CH:21]=[CH:20][C:9]([C:10](=[O:11])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[CH:8][C:7]=2[NH:22][C:23]2[C:24]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[N:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:3]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(N)c3)ncnc2n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)CNC(=O)OC(C)(C)C)c3)ncnc2n1
Reaction time: 16 h
Yield: 68.8 %

Procedure:
A mixture of the product of Example 109 (0.068 g, 0.1 mmol), tert-Butoxycarbonylamino-acetic acid (0.023 g, 0.13 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.025 g, 0.13 mmol), 1-Hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol) and N,N-diisopropylethylamine (0.029 g, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred for 16 hours, poured into water and extracted with ethyl acetate (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide a residue which was purified by chromatography on silica eluting with 96:4 dichloromethane/methanol to provide the title compound (50 mg, 69%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J=6.62 Hz, 6 H), 1.38 (s, 9 H), 3.13-3.27 (m, 1 H), 3.68 (d, J=5.88 Hz, 2 H), 6.63-6.71 (m, 1 H), 7.04 (t, J=6.43 Hz, 1 H), 7.08 (d, J=8.46 Hz, 1 H), 7.24 (d, J=4.78 Hz, 2 H), 7.26-7.37 (m, 2 H), 7.49 (s, 1 H), 7.58 (d, J=8.46 Hz, 1 H), 7.72-7.79 (m, 1 H), 7.92 (dd, J=8.64, 2.02 Hz, 1 H), 8.11 (s, 1 H), 8.19 (d, J=1.47 Hz, 1), 8.59 (s, 1 H), 8.76 (d, J=8.46 Hz, 1 H), 10.00 (s, 1 H), 10.05 (s, 1 H), 10.39 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(F)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(F)c1
Yield: 98.6 %

Procedure:
3-Fluorobenzaldehyde (5 g, 40.28 mmol) in pyridine (50 mL) was reacted with malonic acid (5.4 g, 52.3 mmol) and piperidine (343 mg, 4.0 mmol) at 75° C. for 12 hours to afford 6.6 g (96.9%) of the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:18][O:19][C:20](=[O:31])[C@@H:21]([NH2:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:18][O:19][C:20](=[O:31])[C@@H:21]([NH:30][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: CCC(C)CNc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Yield: 75 %

Procedure:
As per Procedure A, 5-chloro-2-(2-methyl-butylamino)-benzoic acid (12.44 mmol, 3 g) was treated with (2S)-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (12.44 mmol, 3.66 g), HBTU (14.92 mmol, 5.66 g) and diisopropylethylamine (37.32 mmol, 4.82 g) to yield 3-(4-bromo-phenyl)-(2S)-[5-chloro-2-(2-methyl-butylamino)-benzoylamino]-propionic acid methyl ester. (4.4 g, 75% yield). LC-MS m/z: 482.8 (M+1)+.