Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[O:8][CH2:7][C@@:6]2([CH3:12])[C:9]([CH3:11])([CH3:10])[C@:3]1([NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5]2.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[CH3:12][C@:6]12[C:9]([CH3:10])([CH3:11])[C@:3]([NH:13][C:14](=[O:16])[CH3:15])([CH2:4][CH2:5]1)[CH2:2][O:8][CH2:7]2
Reactant: CC(=O)N[C@@]12CC[C@@](C)(COC1O)C2(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N[C@@]12CC[C@@](C)(COC1)C2(C)C
Reaction time: 5 h

Procedure:
To a stirred solution of step 2 intermediate (0.2 g, 0.88 mmol) in dry dichloromethane (5 mL) under nitrogen atmosphere, was added Et3SiH (0.84 mL; 5.28 mmol) at 0° C. To this boron trifluoride etherate (0.33 mL, 2.6 mmol) was added dropwise over a period of 10 minutes. Stirring was continued for 5 hours at room temperature. After completion, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with dichloromethane. Organic layer was separated and dried over anhydrous Na2SO4. Dichloromethane layer was concentrated under reduced pressure to obtain 165 mg of title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 0.78 (s, 3H), 0.89 (s, 3H), 1.1 (s, 3H), 1.60-1.64 (m, 1H), 1.72-1.78 (m, 2H), 1.85 (s, 3H), 2.60-2.67 (m, 1H), 3.06 (d, J=10.96 Hz, 1H), 3.67 (d, J=10.92 Hz, 1H), 3.78 (d, J=10.48 Hz, 1H), 3.92 (d, J=10.48 Hz, 1H) 5.16 (bs, 1H). m/z (M+1): 212.2.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:28]>ClCCl>[C:1]([CH2:3][C:4]([N:18]([CH2:17][C:16]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:5])#[N:2]
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CC#N)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1

Procedure:
To a solution of cyanoacetic acid (43.0 mg, 0.511 mmol) in 1 mL of dichloromethane at room temperature was added PCl5 (106 mg, 0.511 mmol). The mixture was heated to reflux for 10 minutes. A solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (101 mg, 0.255 mmol) in 1 mL dichloromethane was added, and the reaction was refluxed for an additional 1.5 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a yellow foam (117 mg, 99% yield) which was used in the next step without further purification. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 463.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:23][S:24]([O:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:21])[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:22])[F:1])=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 386 (550 mg, 1.73 mmol) in DCM (20 mL) at 0° C. was added TEA (290 μL, 2.08 mmol) and MeSO2Cl (148 μL, 1.91 mmol) and stirring was continued for 1 h at 0° C. The mixture was diluted with EtOAc, washed sequentially with water, dilute HCl solution, aq. satd. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 685 mg (100%) of (R)-3-(tert-butoxycarbonylamino)-3-(4-(difluoromethoxy)phenyl)propyl methanesulfonate (388) containing some of the corresponding chloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])C1C=CC=CC=1.C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.1 %

Procedure:
Methyl 6-[(3-benzyloxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (1.92 g, 4.57 mM) was dissolved in THF (100 ml) and then ethanol (100 ml) and 10% palladium on carbon (250 mg) were added. The reaction was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 20 hours and was then filtered through diatomaceous earth. The filtrates were concentrated under reduced pressure to give methyl 6-[(3-hydroxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless solid (1.42 g); H1 NMR δ (d6-DMSO) 1.24 (6H d) 3.85 (3H s) 4.62 (1H sept) 6.49 (1H s) 6.97 (1H s) 7.04 (1H s) 8.30 (2H s) 8.89 (1H s) 9.67 (1H s) 11.01 (1H s br); [M+H]-331; [M−H] 329.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[NH:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.CO.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][NH:8][CH2:9]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2c(c1)CNC2
Temperature: 0 °C
Yield: 38.3 %

Procedure:
280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at 0° C. then heated at reflux overnight. The reaction was cooled to 0° C. then treated cautiously with methanol (100 ml) followed by 2M HCl (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (×3). The aqueous was basified with 2M NaOH then extracted with DCM (×3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1.[H][H]>C(OC)(=O)C.[Pt]=S>[NH2:13][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(SC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: S=[Pt]
Solvent: COC(C)=O
Product: COC(=O)c1ccc(SC)cc1N

Procedure:
A mixture of methyl 4-(methylthio)-2-nitrobenzoate (11.3 g, 49.7 mmol) and 5% platinum sulfide on carbon catalyst (0.7 g) in methyl acetate (40 mL) was hydrogenated at 750 psi and 75° C. until hydrogen uptake ceased. The mixture was filtered through Celite®, and the filtrate solvent was rotary evaporated, leaving methyl 2-amino-4-(methylthio)benzoate as a slightly tan crystalline solid (8.7 g) melting at 57°-59° C.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[C:7]([C:9]1[C:14]2[N:15]=[C:16]([C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=O)[O:17][C:13]=2[C:12]([F:26])=[C:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]=1[CH3:33])#[N:8].[OH-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[C:7]([C:9]1[C:14]2[N:15]=[C:16]([C:18]([CH3:24])([CH3:25])[C:19]([NH2:2])=[O:21])[O:17][C:13]=2[C:12]([F:26])=[C:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]=1[CH3:33])#[N:8]
Reactant: CCOC(=O)C(C)(C)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C(N)=O)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
Ammonium chloride (73 mg, 1.36 mmol) was suspended in benzene (3.3 ml), and under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) was dropwise added with keeping at 5° C. or lower, followed by stirring at room temperature for 2 hours. A benzene (1.6 ml) solution of ethyl 2-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-2-methylpropanoate (I-95) (166 mg, 0.45 mmol) was added, followed by stirring at 50° C. for 17 hours. Since the reaction did not finish, separately, the same amount of ammonium chloride (73 mg, 1.36 mmol) was suspended in benzene (3.3 ml), trimethylaluminium (1.03 M n-hexane solution was dropwise added with keeping at 5° C. or lower, followed by stirring at room temperature for 2 hours to prepare a solution, which was added to the original reaction solution, followed by stirring at 50° C. for 19 hours. Though the reaction did not finish, this was cooled to room temperature, fractionated with ethyl acetate and aqueous 1 N sodium hydroxide solution, and the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative TLC, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) to obtain the entitled compound (58 mg, 38%) as a yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[OH:42])[C:5]([NH:7][N:8]1[CH2:12][CH2:11][N:10]([C:13]([NH:15][S:16]([NH:19][C:20]([N:22]2[CH2:25][C@H:24]([NH:26]C(=O)OCC3C=CC=CC=3)[C:23]2=[O:37])=[O:21])(=[O:18])=[O:17])=[O:14])[C:9]1=[O:38])=[O:6].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].C1(SC)C=CC=CC=1>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:26][C@H:24]1[CH2:25][N:22]([C:20]([NH:19][S:16]([NH:15][C:13]([N:10]2[CH2:11][CH2:12][N:8]([NH:7][C:5](=[O:6])[C:4]3[CH:39]=[CH:40][C:41]([OH:42])=[C:2]([OH:1])[CH:3]=3)[C:9]2=[O:38])=[O:14])(=[O:18])=[O:17])=[O:21])[C:23]1=[O:37]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[1-[[[[[[3-[(3,4-Dihydroxybenzoyl)amino]-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.4 g) was added to a mixture of 6 ml of trifluoroacetic acid and 1.5 ml of thioanisole. The mixture was stirred overnight at room temperature. The trifluoroacetic acid was removed in vacuo and the residue triturated with ether to yield 1.4 g of crude (S)-N-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]-3-[(3,4-dihydroxybenzoyl)amino]-2-oxo-1-imidazolidinecarboxamide, trifluoroacetate salt.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 109.7 %

Procedure:
N,N-Dimethylpropane-1,3-diamine (4.90 ml, 39 mmol) and potassium carbonate (6.37 g, 46 mmol) were added to 1-fluoro-4-nitrobenzene (5.0 g, 35 mmol) and the mixture was heated at 70° C. for 3 hours. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with water (3×100 ml) and saturated sodium chloride (100 ml) and dried. The solvent was removed by evaporation to give the product as a yellow oil (8.57 g). MS (MH+): 248.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:22])=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (7.53 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate were dissolved in 18 ml of tert-butanol, and 5 ml of water were then added. After cooling to 0° C., 2.35 g (15.1 mmol) sodium dihydrogenphosphate dihydrate, 2.73 g (30.1 mmol) of sodium chlorite and 3.17 g (45.2 mmol) of 2-methyl-2-butene were added in succession. After 1 hour at 20° C., water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure (logP: 1.38)
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.[O:35]=[C:36]1[O:40][CH:39]([C:41](Cl)=[O:42])[CH2:38][CH2:37]1>C1COCC1>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:41]([CH:39]3[CH2:38][CH2:37][C:36](=[O:35])[O:40]3)=[O:42])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(N)c2)cc(-c2ccccc2O)nc1N
Reactant: O=C1CCC(C(=O)Cl)O1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(-c2cccc(NC(=O)C3CCC(=O)O3)c2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-(3-aminophenyl)-6-(2-hydroxyphenyl)nicotinate (starting compound 6, 0.626 g, 1.659 mmol) in THF (7 mL) including pyridine (0.148 mL, 1.824 mmol) was added a solution of 5-oxotetrahydro-2-furancarbonyl chloride (0.271 g, 1.824 mmol) in THF (3 mL). After 1 hr., the mixture was allowed to warm to room temperature and the stirring was continued for 2 hrs. The mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:ethyl acetate, 1:4-1:19) to give tert-butyl 2-amino-6-(2-hydroxyphenyl)-4-(3-{[(5-oxotetrahydro-2-furanyl)carbonyl]amino}-phenyl)-nicotinate as a pale yellow foam (0.677 g, yield 83%).
Reaction SMILES: [H-].[Li+].[CH2:3]=[O:4].CO.Cl[CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[CH2:13]([C:8]1([O:4][CH2:3]1)[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=O
Reactant: CCCCCCCCCCCCCCC(Cl)C(=O)OC
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCC1(C(=O)OC)CO1
Reaction time: 1 h

Procedure:
Lithium hydride (0.32 g, 0.040 m), paraformaldehyde (0.16 g, 0.0053 m), and methanol (0.32 g, 0.010 m) were heated together in 25 ml DMF at 30°-40° C. After 1 hour, methyl α-chloropalmitate (3.05 g, 0.010 m) was added; the remaining paraformaldehyde (0.16 g, 0.0053 m) was added in two portions. The reaction was worked up after 51/2 hours of heating. The reaction mixture was extracted with hexane; the hexane was washed with water and dried over Na2SO4. The mixture was filtered and stripped to a crystalline residue. The residue was recrystallized from methanol to give 2.49 g (83.5%) yield of methyl tetradecylglycidate (m.p. 47°-48° C., glc purity>99%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]([C:14]3([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[CH:10]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:54]1[CH:59]=[C:58]([Cl:60])[CH:57]=[C:56]([F:61])[C:55]=1[C:62]1[N:66]=[C:65]([CH3:67])[O:64][N:63]=1>CS(C)=O.O.[Pd](Cl)Cl>[Cl:60][C:58]1[CH:57]=[C:56]([F:61])[C:55]([C:62]2[N:66]=[C:65]([CH3:67])[O:64][N:63]=2)=[C:54]([C:2]2[CH:3]=[N:4][C:5]3[CH:6]([NH:11][C:12]([C:14]4([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]4)=[O:13])[CH2:7][CH2:8][C:9]=3[CH:10]=2)[CH:59]=1
Reactant: O=C(NC1(C(=O)NC2CCc3cc(Br)cnc32)CC1)C(F)(F)F
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)C(F)(F)F)CC2)no1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-3-bromo-6,7-dihydro-5H-[1]pyrindin-7-yl)-amide (intermediate A-5) (0.2 g, 510 μmol), potassium acetate (150 mg, 1.53 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (155 mg, 612 μmol) were dissolved in DMSO (8.0 ml). The reaction vessel was closed and evacuated, then charged with argon; this procedure was repeated five times. After 10 minutes (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.5 μmol, eq: 0.05) was added and the reaction mixture was stirred at 90° C. for 1.5 hours. After cooling to RT, potassium carbonate (141 mg, 1.02 mmol), dissolved in water (1.0 ml) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) (164 mg, 561 μmol) were added, followed by (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.5 μmol, eq: 0.05). This reaction mixture was stirred at 80° C. for 3 hours, then poured into H2O (50 ml) and extracted with CH2Cl2 (3×25 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.364 g), which was purified by flash chromatography (silica gel, 20 g, 0% to 2% MeOH in CH2Cl2) to yield the title compound (0.134 g, 50%) as light grey solid. MS: 524.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:7]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:32])[C@:19]4([CH3:31])[CH2:20][CH2:21][C@H:22]5[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C@:23]5([CH3:30])[C@H:18]4[CH2:17][CH2:16][C@@H:15]3[C@@:10]2([CH3:33])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][OH:6].[N:34]1C=CC=CC=1.C(N(CC)CC)C.[C:47](Cl)(=[O:51])[C:48]([CH3:50])=[CH2:49]>ClCCl.C(OCC)C>[C:47]([NH2:34])(=[O:51])[C:48]([CH3:50])=[CH2:49].[CH3:1][C@@H:2]([C@@H:7]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:32])[C@:19]4([CH3:31])[CH2:20][CH2:21][C@H:22]5[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C@:23]5([CH3:30])[C@H:18]4[CH2:17][CH2:16][C@@H:15]3[C@@:10]2([CH3:33])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccncc1
Agent: C[C@H](CCCO)[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(C)CCCC(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(N)=O
Temperature: 25 °C

Procedure:
Into a one-liter, 3-neck flask equipped with a reflux condenser, a pressure equalizing addition funnel and a magnetic stirrer are charged 200 g (0.07 mole) of Monol I, 22 g (0.28 mole) of pyridine and 200 ml of anhydrous diethyl ether. Under a static nitrogen purge with cooling to ~2° C., 14.4 g of toluene sulfonyl chloride dissolved in 25 ml of diethyl ether is added with stirring over a period of one half of an hour. The reaction mixture is allowed to warm to room temperature and stirred for 12 hours. Thereafter, the diethyl ether is removed under reduced pressure at temperatures less than 40° C. The reaction mixture is filtered to remove pyridine hydrochloride and then charged into a one-liter, 3-neck flask equipped with a reflux condenser, gas sparge addition tube and a magnetic stirrer. To this flask is added with stirring 200 ml of dichloromethane and anhydrous ammonia is sparged through the reaction mixture for 11/2 hours followed by sparging with nitrogen for 2 hours. The reaction mixture is filtered and then subjected to reduced pressure to remove dichloromethane. Into the aforementioned flask are added the reaction product, 200 ml of dichloromethane and 7.0 g (0.07 mole) of triethylamine. To the resulting solution is added with stirring and refluxing, 7.9 g (0.075 mole) of methacryloyl chloride diluted in 25 ml of dichloromethane over a period of 30 minutes and stirred overnight. The resulting product is cooled and subjected to reduced pressure to remove dichloromethane. To this product is added 200 ml of diethyl ether, then filtered and subjected to reduced pressure to remove diethyl ether thereby providing the aforementioned desired adduct.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1.Cl>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCl, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2 SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122°-123° C. CIMS m/z 721 (M+H)+.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][C:21]=2[CH3:23])[O:16][CH2:15]1>>[CH3:23][C:21]1[CH:20]=[N:19][CH:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12
Reactant: CON=C1COc2cncc(C)c21
Agent: NC1COc2nnccc21
Product: Cc1cncc2c1C(N)CO2

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-methylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;