Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:18]([NH:20][C@@H:21]([C:23]([NH2:25])=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@@H:21]([C:23]([NH2:25])=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(N)=O

Procedure:
1 G. of the product of Example 2 was hydrogenated in methanol at TR and 1 atmosphere with 600 mg. of 10% Pd. on carbon catalyst with a few drops of glacial acetic acid for 20 hours at TR. The catalyst was removed by filtration and the methanol evaporated to dryness in vacuo. The product was lyophyllized from water to yield 500 mg. of title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])O
Product: Cn1c(Cl)c([N+](=O)[O-])c(=O)n(C)c1=O

Procedure:
To 25 ml of surfuric acid was gradually added 8.5 g (0.049 mol) of 6-chloro-1,3-dimethyluracil as described in Synthesis Example 1. To the solution was gradually added at 0° to 5° C. 8.5 ml of fuming nitric acid and the mixture was stirred for 5 minutes. The reaction solution was poured onto ice and extracted twice with chloroform. The organic layer was dried with anhydrous magnesium sulfate, concentrated and the crystals thus-obtained were recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 7.5 g of 6-chloro-1,3-dimethyl-5-nitrouracil.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1)([O-:3])=[O:2].[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>CO>[N+:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[OH:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOP([O-])OCC
Reactant: O=Cc1csc([N+](=O)[O-])c1
Solvent: CO
Product: CCOP(=O)(OCC)C(O)c1csc([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
A solution containing 2-nitro-4-thiophenecarboxaldehyde (2.61 g, 16.6 mmol), diethyl phosphite (2.14 mL, 16.6 mmol), and methanol (5 mis) was adsorbed onto excess basic alumina. After 16 hours the product was extracted with methylene chloride, concentrated and purified by column chromatography (silica gel). Elution with methylene chloride-methanol 19:1 gave the product (3.55 g) as an oil. 1H NMR (CDC13): d, 5.05 (dd,1H,PCH), 4.15 (m,4H,CH2), 1.33 (dt,6H,CH3). MS (DCl): 296 (MH+). C9H14NO6PS.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:26]=[O:27])=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][OH:27])=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2CO)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2′-formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide, Example 28, (90 mg, 0.25 mmol) in MeOH (2 mL) was added sodium borohydride (20 mg, 0.51 mmol) and the mixture was stirred for 10 min at 0° C. The reaction mixture was diluted with EtOAc (50 mL) and washed with satd NH4Cl (5 mL). The EtOAc layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (gradient, 40 to 90% EtOAc/hexane) to provide the title compound as a yellow amorphous solid. MS (ESI, pos. ion.) m/z: 355 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](B(O)O)[CH3:16]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Ag-]=O.C1COCC1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH2:15][CH3:16])[CH:7]=1
Reactant: CCB(O)O
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=[Ag-]
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CCc1cncc(Br)c1
Temperature: 25 °C

Procedure:
3,5-dibromo-pyridine (0.4 g, 1.688 mmol), potassium carbonate (0.7 g, 5.064 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.138 g, 0.169 mmol), silver(I) oxide (0.902 g, 4.22 mmol), ethyl boronic acid (0.150 g, 2.03 mmol) and THF (8 ml) are mixed together, purged with argon and heated to reflux overnight. After cooling to room temperature the reaction mixture is filtered through Celite® (filter agent) washing with DCM. The DCM is reduced in vacuo and the residue is purified by flash chromatography by loading onto a 20 g silica column eluting with DCM to afford the title compound, [MH+ 185.91 and 187.91].
Reaction SMILES: C[C:2]1([CH3:26])[O:6][C:5](=[O:7])/[C:4](=[C:8](\[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=O)=O)=[CH:11][CH:10]=2)/[CH2:3]1.Cl[C:28]1C=C(/C(=C2\C(=O)OCC\2)/C2C=CC(S(C)(=O)=O)=CC=2)C=CC=1>>[CH2:26]([CH:2]1[O:6][C:5](=[O:7])[C:4](=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:18])=[CH:13][CH:14]=2)[CH2:3]1)[CH3:28]
Reactant: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(Cl)c2)cc1
Reactant: CC1(C)C/C(=C(/c2ccc(F)cc2)c2ccc(S(C)(=O)=O)cc2)C(=O)O1
Product: CCC1CC(=C(c2ccc(F)cc2)c2ccc(SC)cc2)C(=O)O1

Procedure:
Prepared by the procedure of Example 4 from the derivative of Example 32. The mixture of the two isomers, (E) and (Z), is used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[C:15]([CH3:25])([CH3:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>CN(C)C=O>[CH3:24][C:15]1([CH3:25])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(Br)C(=O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (3.00 g) in N,N-dimethyl-formamide (30 mL) was added potassium fluoride (3.40 g), and the mixture was stirred at room temperature for 15 minutes, and thereto was added 2-bromo-2-methylpropiophenone (4.42 g). The mixture was stirred at room temperature for 0.5 hour, at 60° C. for 20 hours and at 80° C. for 3 days. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=10/1) to give 2,2-dimethyl-7-nitro-3-phenyl-2H-1,4-benzoxazine (3.65 g) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:28]([CH3:29])[CH3:30])([CH3:17])([CH3:19])[CH3:18]
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (685 mg, 3.0 mmol) in DCM (18 mL) at 0° C. were added (S)-2-tertbutoxycarbonylamino-3-methylbutyric acid (720 mg, 3.3 mmol), HOAt (0.450 g, 3.3 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) and the resulting mixture stirred at 0° C. for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]-2-methylpropyl}carbamic acid tert-butyl ester (790 mg). LCMS (Method J): RT 2.10 min [M+H]+ 403.3
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH3:27])=[O:8])=[CH:5][C:4]=1[N+:30]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:30][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:3]=1[N:2]([CH3:33])[CH3:1])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=1[CH3:27])=[O:8]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c(N)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitrobenzamide (3.0 g, 6.2 mmol) (see Example I6) was dissolved in isopropanol (50 ml) and tin chloride (4.2 g, 22.3 mmol) was added. The mixture was cooled to 0° C. and a solution of concentrated hydrogen chloride (6 ml) was added slowly. The reaction mixture was stirred at 80° C. for 2 hours. Then ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and a solution of aqueous sodium hydroxide (4N) to adjust the pH to 7-8. The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was used without further purification (2.7 g, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8](OC)=[O:9])[N:5]([CH3:12])[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([CH3:12])[N:4]=1
Reactant: COC(=O)c1cc(OC)nn1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CO)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of methyl 3-methoxy-1-methyl-1H-pyrazole-5-carboxylate (2.03 g, 11.9 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.57 g, 12 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (2.0 mL) were added to the reaction mixture, and the precipitated solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.67 g, yield 98%) as a colorless oil.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1F)[CH2:7][CH2:8][CH3:9]>C(OCC)C.[Cl-].[Mn+2].[Cl-]>[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1[CH:1]1[CH2:3][CH2:2]1)[CH2:7][CH2:8][CH3:9]
Reactant: BrC1CC1
Reactant: CCCCN=Cc1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Agent: [Mn+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Cyclopropylbromide (3.84 g, 32 mmol) was added to magnesium (771 mg, 32 mmol) in 20 mL diethylether and refluxed for 10 min. Manganese(II) chloride (160 mg, 1.27 mmol) and butyl-[1-(2-fluoro-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate M, 4 g, 13 mmol) was added. The reaction mixture was refluxed for 2 h. The reaction mixture was quenched with 8 mL water and filtered through dicalite. The organic phase was separated and dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (3.54 g, 82%) was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:27]([CH2:30][C@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH:37]C(OCC3C=CC=CC=3)=O)[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1>CCOC(C)=O.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:27]([CH2:30][C@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH2:37])[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)N)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)—((R)-1-(4-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl carbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl)2-(benzyloxy-carbonyl-amino)propanoate (74.7 mg, 0.1 mmol) in a mixture of EtOAc (15 mL) and MeOH (10 mL) was added catalytic amount Pd/C (10%, ˜55% w/w water content, 20 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 20 minutes under H2 balloon. The mixture was filtered and the residue was washed with MeOH (5 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: [CH2:1]([O:4]C(F)=C(F)F)[CH:2]=C.C(N(CC)CC)C.[F:17][C:18]([F:25])([CH2:22][CH:23]=[CH2:24])[C:19](F)=[O:20]>C(O)C>[F:17][C:18]([F:25])([CH2:22][CH:23]=[CH2:24])[C:19]([O:4][CH2:1][CH3:2])=[O:20]
Reactant: C=CCOC(F)=C(F)F
Reactant: C=CCC(F)(F)C(=O)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCC(F)(F)C(=O)OCC
Temperature: 0 °C

Procedure:
The start of the reaction in the reactor is indicated by a rise in temperature within the reaction chamber 5 from originally -74° C. to about -45° C. During the rest of the reaction period the temperature in the reaction chamber varies from about -45° C. to about -55° C. The reaction mixture from outlet conduit 18 containing the 1,2,2-trifluorovinyl allyl ether is conducted to a stirred solution of 434 g (600 mL, 4.3 mol) of triethylamine in 358 g (450 mL, 7.8 mol) of absolute ethanol cooled in an ice bath. Upon warming to the ice bath temperature, the 1,2,2-trifluorovinyl allyl ether spontaneously rearranges to 2,2-difluoro-4-pentenoyl fluoride, which in the presence of ethanol reacts to yield the desired ethyl 2,2-difluoro-4-pentenoate. The reaction mixture is divided into two equal batches which are treated separately. The following describes the workup of one batch.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([NH:25][C:26]1[CH:27]=[C:28]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2Br)=[CH:30][CH:31]=1)(=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.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>[C:22]([NH:25][C:26]1[CH:27]=[C:28]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]([C:32]2[C:33]([C:10]3[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:31]=1)(=[O:24])[CH3:23]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 68.7 %

Procedure:
A mixture of [2-[(phenylmethyl)oxy]-5-(trifluoromethyl)phenyl]boronic acid (118 mg, 0.4 mmol), ethyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate (121 mg, 0.33 mmol), potassium carbonate (414 mg, 3 mmol) and tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.033 mmol) in 1:1 toluene/ethanol (5 ml) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was chromatographed with ethyl acetate/iso-hexane (1:2) to yield 121 mg of the title compound as a colourless gum.
Reaction SMILES: CC(C)(C)CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][O:23][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Reactant: CC(C)(C)CCO
Product: CC(C)(C)CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
This compound is synthesized analogously to (85) from 3,3-dimethyl-butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14](OC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[O-].[Na+].[Na].Cl.[NH2:36][OH:37]>>[OH:37][NH:36][C:14](=[O:15])[CH:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: NO
Reactant: COC(=O)C(CCS(C)(=O)=O)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(CCS(C)(=O)=O)C(=O)NO)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(methylsulfonyl)butyrate (900 mg, 2.0 mmol), sodium methoxide previously generated from sodium metal spheres (100.0 mg, 4.5 mmol), and hydroxylamine hydrochloride (280.0 mg, 4.0 mmol) is refluxed for 2 days. The mixture is cooled to room temperature, concentrated in vacuo, diluted with water, acidified with citric acid, and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and and the solvent is evaporated. The product is purified by silica gel chromatography (ethyl acetate) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(methylsulfonyl)butyramide, [M+1]=157.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:37]C(OC(C)(C)C)=O)[CH2:26][O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=3[I:36])[C:31]#[N:32])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC(C)C)C(C)C.[C:56]1([S:62](Cl)(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(OCC)(=O)C>Cl.O1CCOCC1>[C:56]1([S:62]([NH:37][C@@H:25]([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[CH:23][CH:22]=2)[CH2:26][O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[I:36])[C:31]#[N:32])(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cc(C#N)ccc1I)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: CCN(CC(C)C)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(I)c(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 g (2.7 mmol) of 3-[(2S)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]-2-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. 1 ml (6 mmol) of N,N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added to the solution under cooling with ice, and they were stirred for 2 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1>C(OCC)C>[Br:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Brc1cccc(Br)n1
Solvent: CCOCC
Product: Clc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 150 °C
Yield: 100.8 %

Procedure:
A microwave vial was charged with 4-chloro benzylamine (700 mg; 5 mmol; 5 equivalents) and 2,6-dibromo pyridine (238 mg, 1 mmol). The reaction mixture was stirred in the microwave at 150° C. for three times ten minutes (200 W maximum). The reaction mixture was diluted with diethyl ether (50 ml), washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic was dried over magnesium sulfate and, after filtration, concentrated in vacuo to afford an oil as the title compound (300 mg, 100% yield). LC/MS: 299 [M+H]
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:9]=[C:10]=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]>C(Cl)(Cl)Cl.ClCCCl>[C:4]([NH:9][C:10]([N:2]([CH3:3])[CH3:1])=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: CNC
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)N(C)C
Yield: 99.9 %

Procedure:
To a solution of dimethylamine (0.45 g; 10 mmol) in chloroform (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (20 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloyl-3,3-dimethylurea (1.56 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[F:29][C:30]1([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:32][CH2:31]1>>[F:29][C:30]1([C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:31][CH2:32]1
Reactant: FC1(c2nc3ccccc3[nH]2)CC1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4(F)CC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(1-fluorocyclopropyl)-1H-benzimidazole were reacted to give 307. LCMS m/z: 549.3 (MH+)