Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=3)[NH:28][CH:27]=[C:26]4[CH:35]3[CH2:36][CH2:37][N:38]([S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H2O (0.25 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65° C. to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[CH3:13][NH2:14]>CO.C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:14][CH3:13])=[O:11])[CH:4]=1
Reactant: CN
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0°0 C. was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5° C. The resulting mixture was stored at 3° C. for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C1COCC1.[CH3:12][N:13]1[C:17]([N:18]2[CH2:24][C:23](=O)[CH2:22][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][CH2:19]2)=[C:16]([N+:34]([O-:36])=[O:35])[CH:15]=[N:14]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]=[C:23]1[CH2:24][N:18]([C:17]2[N:13]([CH3:12])[N:14]=[CH:15][C:16]=2[N+:34]([O-:36])=[O:35])[CH2:19][CH2:20][C@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1
Reactant: CC(C)(C)[O-]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](NC(=O)OC(C)(C)C)CC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Methyl triphenylphosphonium bromide (3.09 g, 8.49 mmol) was suspended in toluene (25 mL). Potassium tert-butoxide (1.0 mol/L) in THF (7.07 mL, 7.074 mmol) was added and the mixture turned bright yellow. It was stirred at room temperature for 4 h, then tert-butyl N-[(4S)-1-(2-methyl-4-nitro-pyrazol-3-yl)-6-oxo-azepan-4-yl]carbamate (1000 mg, 2.83 mmol) (second eluting peak in the chiral separation) in 5 mL toluene was added. The mixture was stirred at RT for 30 min, quenched with saturated ammonium chloride, and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate (699 mg, 70%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[CH:21]1([CH2:24][C:25](N(OC)C)=[O:26])[CH2:23][CH2:22]1>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:15])=[C:11]([C:25](=[O:26])[CH2:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=[CH:13][CH:14]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CON(C)C(=O)CC1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CC2CC2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A 1 L round bottom flask was charged with 84.A (17.0 mL, 73.0 mmol) and THF (70 mL) and cooled to −78° C. under N2. To the cold solution was added sec-butyllithium (1.20 M/cyclohexane) (66.3 mL, 79.6 mmol) dropwise. The mixture was stirred for 30 minutes, and to it was added a solution of 84.B (9.31 mL, 66.3 mmol) in THF (70 mL) dropwise. The final mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl (70 mL) and diluted with EtOAc (100 mL). The organic phase was washed with water (100 mL), 1 N HCl (100 mL) and brine (100 mL). The organic phase was then dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (2% EtOAc/hexane) to afford 84.C (14.9 g, 73% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:34])[F:35])[CH:18]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: COC(=O)C1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of compound 8.0 6-bromo-4-chloro-3-nitroquinoline (0.29 g, 1.0 mmol, 1 equiv.) in dioxane (5 mL) at room temperature was added 8.1 methyl 1-(4-amino-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.3 g, 1.0 mmol, 1 equiv.). The resulting mixture was heated overnight to 85° C. under argon. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3, diluted with EtOAc (50 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (Hexanes: EtOAc=4:1) to afford desired product 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.50 g; 90%). LC-MS (M+H): 555.10
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2c(COC)nnc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of 9-butyl-3-(methoxymethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (6 mg, 21.7 mmol), N-bromosuccinimide (4.64 mg, 26.0 mmol) in tetrahydrofuran (10 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep LCMS to yield the desired product. LCMS calculated for C13H18BrN6O2 (M+H): 369.1. found 371.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[N:11]1[CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
Sulfonation of 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione by benzenesulfonyl chloride following the method used in Example 6 gave N-(3-(3-(1,3-dioxoisoindolin-2-yl)propyl)phenyl)benzenesulfonamide as a yellow semi-solid. Yield (0.80 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.87-7.81 (m, 4H), 7.72 (d, J=7.6 Hz, 2H), 7.58-7.49 (m, 3H), 7.11 (t, J=8.0, 1H), 6.92 (s, 1H), 6.88-6.85 (m, 2H), 3.52 (t, J=7.2 Hz, 2H), 2.50-2.49 (m, 2H), 1.81-1.74 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[CH3:9][C:10](C)=[O:11].C(=O)=O.C1OC1>CO>[CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][OH:11]
Reactant: CC1(C)COCCN1
Reactant: CC(C)=O
Agent: O=C=O
Solvent: CO
Solvent: C1CO1
Product: CC1(C)COCCN1CCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
In a pressure vessel containing 3,3-dimethylmorpholine (12.15 g, 106 mmol) in MeOH (17 mL) at −78° C. (external temperature, acetone/CO2(s)) was added ethylene oxide (6.2 mL, 125 mmol, 1.2 equiv., condensed at −78° C.). The solution was sealed and stirred over 20 hours, during which time the temperature warmed to room temperature. The reaction mixture was concentrated in vacuo and the crude product was distilled (75° C., 0.5 torr) to provide 2-(3,3-dimethyl-morpholin-4-yl)-ethanol (14 g, 82%) as a colorless oil contaminated with ˜15% of 3,3-dimethyl-morpholine. LC/MS found 160.10 (M++H, C8H18NO2 requires 160.13).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15](=[O:28])[NH:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:2].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])=[CH:9][C:8]=1[C:15](=[O:28])[NH:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(CO)cc1C(=O)NCc1cccc2ccccc12
Reactant: Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(COc2ccccc2C)cc1C(=O)NCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
To the solution of the compound prepared in Example 4 (300 mg) and 2-methylphenol (0.12 ml) in tetrahydrofuran (4 ml) were added triphenylphosphine (300 mg) and diethyl azodicarboxylate (0.5 ml, 40% toluene solution) at room temperature and the mixture was stirred overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (330 mg) having the following physical data.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCC1CCCCC1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Agent: Cl
Product: CC1CN(CCCC2CCCCC2)CCC1(F)c1cccc(OCc2ccccc2)c1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride with 1-bromo-3-cyclohexylpropane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 48% overall yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11].O>C(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccncc1F
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cnccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a solution of (3-fluoropyridin-4-yl)methanol (910 mg, 7.2 mmol) in anhydrous chloroform (25 mL) was added dropwise a solution of phosphorus tribromide (675 μL, 7.2 mmol) in anhydrous chloroform (10 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3-fluoropyridine was obtained (260 mg, 19% yield) and used in the next step without further purification; 1H NMR (400 MHz, MeOd4): δ 0.81 (s, 2H), 8.25 (t, J=6.4 Hz, 1H). 8.76 (d, J=5.9 Hz, 1H), 9.05 (d, J=3.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].[CH3:15][S:16][CH2:17]Cl>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:15][S:16][CH3:17])[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CSCn1nc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (2.10 g, 14.3 mmol) in acetone (20 mL) was added K2CO3 (2.37 g, 17.1 mmol) followed by chloromethyl methyl sulfide (1.3 mL, 5.7 mmol). The light yellow suspension was stirred at room temperature for 96 hr. At this time the reaction was thick with white precipitate. The reaction mixture was stripped off volatiles, diluted with methylene chloride and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:51]=[C:52]([OH:56])[CH:53]=[CH:54][CH:55]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[C:52]([OH:56])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (120 mg, 0.188 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61.9 mg, 0.281 mmol) and 2M Na2CO3 (0.188 mL, 0.375 mmol) in DMF (2 mL) was degassed for 15 min by bubbling N2 through the reaction mixture. Then, tetrakis(triphenylphosphine)pallafium(0) (15.17 mg, 0.013 mmol) was added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by biotage (10-40% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol, 73.5% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.02 (t, J=1.6 Hz, 1H), 7.82 (dt, J=7.6, 1.4 Hz, 1H), 7.54-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.02-7.00 (m, 1H), 6.98 (s, 2H), 6.93 (s, 1H), 6.81 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 6.42 (dd, J=8.1, 2.3 Hz, 2H), 6.39-6.35 (m, 1H), 6.10-5.98 (m, 1H), 5.40-5.30 (m, 2H), 5.07 (s, 1H), 4.29-4.18 (m, 2H), 3.67 (s, 3H), 3.18 (t, J=4.4 Hz, 2H), 2.87 (s, 3H), 1.18 (s, 9H). LCMS (M+H)=653.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:19](CC)CC)[CH3:18].ClC(OCC(C)C)=O.C(N)C>O1CCCC1.CN(C)C=O>[CH2:17]([NH:19][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:18]
Reactant: CCN(CC)CC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 60.5 %

Procedure:
33.48 g (0.15 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 225 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 22.95 ml (0.15 mol) of triethylamine and 19.8 ml (0.15 mol) of isobutyl chloroformate were then added and the solution was stirred at -10° C. for 20 minutes. To this mixture was then added a solution of 7.53 g (0.15 mol) of monoethylamine in 215 ml of dimethylformamide. The solution was stirred at -10° C. for 5 minutes and then left to stand for 16 hours at room temperature. The solvents were removed by evaporation and the residue was triturated with 450 ml of ethyl acetate and washed successively with 200 ml of 1-N hydrochloric acid, 200 ml of water and 200 ml of 5% sodium bicarbonate solution. After drying over sodium sulphate and filtration, the solvent was removed by evaporation. The resulting oil crystallised on the addition of petrol to yield 22.70 g (60.5%) of N-benzyloxycarbonyl-L-alanine ethylamide of melting point 127°-128° C.; [α]D20 =+11.2° (c=0.83% in dimethylformamide).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H-].[Na+].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:10][C:8]1[CH:7]=[C:6]([Br:11])[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OCC(=O)OC(C)(C)C)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid methyl ester (10.2 g) and tert-butyl bromoacetate (9.7 ml) in anhydrous DMF was added sodium hydride (60% dispersion in mineral oil, 2.69). After 30 min water (10 ml) aws added. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was removed and the organic phase washed with further water, 1M sodium hydroxide solution and dried with brine and over sodium sulphate. Concentration under reduced pressure gave the title compound as dark yellow gum (12.8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>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].C(Cl)Cl.COCCOC>[C:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=[N+]([O-])c1cnccc1C1=CCCCC1
Yield: 82 %

Procedure:
A solution of 4-chloro-3-nitro pyridine (1 eq.), cyclohexenyl boronic acid (1.7 eq.), and Pd(dppf)Cl2—CH2Cl2 (0.05 eq) in 3:1 DME/2M Na2CO3, at a concentration of 0.1 M was heated at 95° C. for 16 hours. Upon cooling the reaction was partitioned between EtOAc and H2O, was washed with NaCl(sat.), dried over MgSO4, was filtered and the volatiles were removed in vacuo. The material was purified by SiO2 chromatography (20% EtOAc/hexanes eluant) to yield 4-cyclohexenyl-3-nitropyridine (82%). LCMS (m/z): 205.0 (MH+); LC Rt=3.84 min.