Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-:24])(=[O:23])[CH3:22].[K+].C(C1C=CC=CC=1)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:21]([O:24][CH2:11][C@@H:10]([OH:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CCc1ccccc1
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
A mixture composed of 2.0 mmol (0.599 g) of (2S, 3S)-3-(t-butoxycarbonylamino)-1-chloro-2-hydroxy-4-phenylbutane, 0.1 mmol (0.032g) of tetrabutylammoniumbromide, 5.0mmol (0.49 g) of potassium acetate and 10 ml of acetonitrile was stirred under reflux for 50 hours. Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Quantitative analysis was curried out by high performance liquid chromatography using ethylbenzene as an internal standard. Thus was obtained 0.289 g (45%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6]([O:14][CH2:15][CH3:16])[CH:5]=1.C(Cl)(=O)C([Cl:21])=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:21])=[C:6]([O:14][CH2:15][CH3:16])[CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Yield: 91.5 %

Procedure:
To a solution of 3-ethoxy-4-hydroxy-5-nitro-benzoic acid methyl ester (2.0 g, 8.29 mmol, 1.0 equiv) in anhydrous DMF (100 mL) at −25° C. under Ar was added slowly oxalyl chloride (1.40 mL, 2.11 g, 16.58 mmol, 2.0 equiv) over a period of 30 min. After the addition was completed the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was poured on ice, the yellow precipitate washed with cold dichloromethane (3×20 mL), filtered and dried providing 1.97 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.24 (q, J=7.0 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.47, 52.91, 66.17, 115.93, 117.25, 120.95, 129.82, 149.61, 156.03, 164.56. MS (ISP): 276.9 [M+NH4]+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[CH3:10][O:11][CH:12]([C:17](OC)=[O:18])[C:13](OC)=[O:14].Cl>C(O)C>[NH2:4][C:3]1[N:5]=[C:17]([OH:18])[C:12]([O:11][CH3:10])=[C:13]([OH:14])[N:2]=1
Reactant: N=C(N)N
Reactant: COC(=O)C(OC)C(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1c(O)nc(N)nc1O
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A mixture composed of 12 g of guanidine hydrochloride, 9 g of sodium ethoxide and 100 ml of ethanol was heated under reflux for 1 hour, and then the reaction solution was cooled to room temperature, further mixed with 10 g of dimethyl methoxymalonate and heated under reflux for 48 hours. The reaction solution was cooled to room temperature, adjusted to a pH value of about 4 by adding 1 N hydrochloric acid solution and stirred, and then the thus precipitated powder was collected by filtration to obtain 2.0 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[F:1])([CH3:32])[CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)#[N:18]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=493, RT=0.75 min.
Reaction SMILES: CC(C)([O-])C.[K+].C[CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([Cl:19])[C:14]=2[Cl:18])[C:9]1=[O:22].C1C=CC=CC=1.O>C(O)(C)(C)C>[Cl:18][C:14]1[C:13]([Cl:19])=[C:12]([O:20][CH3:21])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[CH2:8][C:9]2=[O:22]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (5.06 g., 0.045 mole) dissolved in tert-butanol (100 ml.) is added to a refluxing solution of 2-methyl-4,5-dichloro-6-methoxyindan-1,3-dione (7.8 g., 0.03 mole), prepared by the method described in Example 10, Step A, in tert-butanol (150 ml.)-benzene (150 ml.). The mixture is cooled slightly and solid 2,2'-dithienyliodonium chloride (16.5 g., 0.05 mole) is added in one portion. Heating at reflux is continued for 2 hrs. The reaction mixture is cooled to 25°C., 100 ml. of water is added, and the mixture concentrated to dryness in vacuo to give 2-methyl-2-(2-thienyl(-4,5-dichloro-6-methoxyindan-1,3-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCc1cccc(O)c1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccc(CCNC(=O)OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 12.79 g. (47.1 mMol) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenol, 120 ml. butan-2-one and 19.5 g. pulverised potassium carbonate is maintained at reflux temperature for 1 hour, then cooled, 200 mg. pulverised potassium iodide and 9.12 g. (51.9 mMol) ethyl bromoacetate added thereto and the reaction mixture stirred for 18 hours at 90° C. Subsequently, it is filtered off with suction and the filter cake is washed with hot butan-2-one. The combined butanone phases are evaporated, the oily residue is taken up in diethyl ether and the ethereal phase is extracted twice with ice-cold 2N aqueous sodium hydroxide solution, and thereafter with ice water. After drying with anhydrous sodium sulphate, it is evaporated in a vacuum. There are obtained 15.62 g. (93% of theory) of the desired product in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1[N+](=O)[O-]
Yield: 63.4 %

Procedure:
Using the procedure described in Example 93, Part A, 4-chloroaniline (11.8 mmol) and 2-nitrobenzoyl chloride (12.9 mmol) yielded 2.07 g (64%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:10][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1O
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cccc(Br)c2o1
Yield: 99.4 %

Procedure:
A mixture of 3-bromo-2-hydroxybenzaldehyde (5 g, 24.87 mmol), 2-chloro-N,N-dimethylacetamide (3.33 ml, 32.34 mmol) and potassium carbonate (6.88 g, 49.75 mmol) in DMF (60 ml) was heated at reflux for 1 h. The solids were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with sat. NaCl(aq). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with sodium sulfate, filtered and concentrated to give the title compound (6.63 g, 99%) as a crude product which was used as such in subsequent reaction.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=O)=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].Cl.[NH2:23][OH:24].O1CCCC1.CO>O>[C:1]([C:3]1[C:7]([CH:8]=[N:23][OH:24])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=NO
Reaction time: 8 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.4 g), hydroxylamine hydrochloride (0.4 g), tetrahydrofuran (5 ml), methanol (50 ml) and water (2.5 ml) were stirred overnight. The mixture was partitioned between ether (50 ml) and water. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml), then dried over Na2SO4 and evaporated to provide the title compound as a white solid, m.p. 170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:15][C:11]1[C:2]([NH2:1])=[C:3]([C:12]([OH:14])=[O:13])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1ccc2ccccc2c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: Cc1cc2ccccc2c(C(=O)O)c1N
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
2-Amino-1-naphthoic acid (3.21 g, 17.2 mmol) in 4:1 benzene/CH3OH (125 mL) was treated with trimethylsilyldiazomethane (9.0 mL, 18.0 mmol, 2.0M solution in hexanes), stirred for 2.5 hours, quenched with acetic acid (0.5 mL), and concentrated. The concentrate was purified by flash column chromatography (4:1 hexanes/ethyl acetate) to provide the desired compound (3.25 g). MS (ESI(+)) m/e 202 (M+H)+; (ESI(−)) m/e 200 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>[Cl-].[Na+].O.CN(C=O)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:15][C:11]2[CH:12]=[C:13]([CH3:14])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:16])[CH:10]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1cc(O)cc(=O)n1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OS(=O)(=O)c2ccc(Br)cc2)cc(=O)n1Cc1ccccc1

Procedure:
1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (from example 35) (10 mmol, 2.15 g), N,N′-dimethylformamide (30 mL), potassium carbonate (20 mmol, 2.76 g), and 4-bromobenzenesulfonyl chloride (10 mmol, 2.55 g) were stirred at room temperature for 16 hours. Hydrochloric acid (1N) was added until the mixture was acidic to pH paper. Brine (50 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate, and filtered. After concentrating, the material was purified by flash column chromatography eluting with ethyl acetate:hexanes (1:2). The appropriate fractions were concentrated to a clear oil, which solidified upon standing several days to a white solid. (3.3 g, 76%): 1H NMR (DMSO-d6/400 MHz) 7.9 (m, 4H), 7.32-7.00 (m, 5H), 7.3 (m, 1H), 6.12 (d, J=2.4 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.20 (s, 2H), 2.2 (s, 3H). ES HRMS m/z 436.002 (M+H, C19H16NO4SBr requires 436.004).
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.[N:43]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:47]2C=CC=CC=2N=N1.CN.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:47][NH:43][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[N:3]1[C:2](=[O:1])[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1
Reactant: O=C(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CNC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 1 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoic acid (Example 611, 41 mg, 0.089 mmol) was suspended in dichloromethane (3 mL), treated with (1H-1,2,3-benzotriazol-1-yloxy) (tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP, 69 mg, 0.13 mmol, 1.5 equiv) and methylamine (1.0 mL, 2 M tetrahydrofuran solution, 2.0 mmol, 22 equiv). After stirring for 1 hour, the mixture was poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with chloroform (3×25 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.11 (1H, s), 8.45 (1H, d, J=2.5 Hz), 8.16 (1H, dd, J=7.9, 1.5 Hz), 8.11 (1H, q, J=5.0 Hz), 7.83 (2H, d, J=8.6 Hz), 7.76 (1H, d, J=8.5 Hz), 7.72 (1H, d, J=1.5 Hz), 7.70 (1H, d, J=7.9 Hz), 7.61 (1H, ddd, J=8.3, 7.3, 1.8 Hz), 7.56-7.52 (2H, m), 7.49 (1H, dd, J=7.7, 1.5 Hz), 7.46 (2H, d, J=8.9 Hz), 7.36 (1H, td, J=7.5, 1.1 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.76 (2H, s), 2.66 (3H, d, J=4.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 475.1896 [(M+H)+; calculated for C28H23N6O2: 475.1877].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21]>>[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-alanine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=140.5-142° C.). The reaction was monitored by tlc (Rf=0.17 in 50% EtOAc/hexanes).
Reaction SMILES: B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=[O:34].[Na+].[Na+].[CH2:51]([O:58][CH2:59]/[CH:60]=[CH:61]/[CH2:62][C@@H:63]([CH2:67][CH3:68])[C:64]([OH:66])=[O:65])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.COCOC.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[CH2:51]([O:58][CH2:59][C@H:60]([C@H:61]1[O:65][C:64](=[O:66])[C@H:63]([CH2:67][CH3:68])[CH2:62]1)[OH:34])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Reactant: CC[C@H](C/C=C/COCc1ccccc1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: O
Solvent: COCOC
Product: CC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
335 ml of a solution of a sodium tetraborate buffer solution (0.05 M) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution, 0.503 g of tetrabutylammonium bisulfate (1.48 mmol) and 8.63 g of 1,2:4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiuro-2,6-pyranose (33.4 mmol) were added to 8.30 g of (2R,4E)-6-benzyloxy-2-ethylhex-4-enoic acid obtained in Example (106b) (33.5 mmol) in a mixed solvent of acetonitrile (167 ml) and dimethoxymethane (333 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was cooled in an ice bath. Then, a solution of 28.4 g of Oxone (trade mark) (46.1 mmol) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution (168 ml) and a solution of 26.7 g of potassium carbonate (193 mmol) in water (168 ml) were separately added dropwise over four hours. The mixture was stirred at the same temperature for one hour and then diluted with 100 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1-1/1) to obtain 6.80 g of the title compound (total yield over two steps: 70%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[O:10][CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([C:23]([CH3:25])([CH3:24])[C:22]#[N:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)C#N
Reactant: COc1c(F)ccc(C)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C#N)ccc(C)c1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 54.4 %

Procedure:
14.48 g (91.56 mmol) of 2,6-difluoro-3-methylanisole is dissolved in 800 ml of toluene. After 272.2 ml (137.35 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added, 25.31 g (366.26 mmol) of isobutyronitrile is added in drops. The batch is stirred for 10 days at room temperature and then added to a 1 M HCl solution. After being extracted three times with methyl-tert-butyl ether, the combined organic extracts are washed with saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent ethyl acetate/hexane), 10.32 g (49.5%) of the desired compound is obtained.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:29]3[C:34]([F:35])=[CH:33][N:32]=[CH:31][N:30]=3)([CH3:28])[N:13]([C@@H](C3C=CC(OC)=CC=3)C)[C:14]2=[O:17])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47](C(OC(C)(C)C)=O)[CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(OCC)(=O)C.CC(C)([O-])C.[K+]>[F:35][C:34]1[C:29]([C:12]2([CH3:28])[C:11]3[C:15](=[CH:16][C:8]([C:44]4[CH:45]=[N:46][NH:47][CH:48]=4)=[CH:9][CH:10]=3)[C:14](=[O:17])[NH:13]2)=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2(C)c2ncncc2F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(c2ncncc2F)NC(=O)c2cc(-c3cn[nH]c3)ccc21
Temperature: 150 °C
Yield: 75.7 %

Procedure:
Combine RuPhos Palladium(II) phenethylamine chloride (60 μmol, 43 mg), dioxane (0.5 mL) and potassium tert-butoxide (1 M tetrahydrofuran, 60 μmol, 60 μL) under nitrogen, sonicate the mixture for 0.5 minute. Add the Ruphos catalyst mixture to a reaction vessel under nitrogen containing 6-bromo-3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (544 mg, 1.192 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.79 mmol, 526 mg), 1,4-dioxane (6 mL), sodium carbonate (3.6 mmol, 2.4 mL 1.5 M aqueous) and heat in a microwave at 150° C. for 30 minutes. Dilute the mixture with ethyl acetate, wash with aqueous 1.5 M sodium carbonate, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter through diatomaceous earth, and evaporate to a light yellow residue. Dissolve the residue in anisole (1 mL) and trifluoroacetic acid (7 mL) and heat to 80° C. for 4 hours, then heat to 70° C. for 18 hours. Evaporate the mixture under reduced pressure, dissolve in methanol, load on a 10 g SCX column, wash with methanol (100 mL), elute with 2 M ammonia in methanol and evaporate. Purify on 40 g silica gel with a gradient of 1-8% methanol/dichloromethane to give the title compound as a white foam (279 mg, 76%). ES/MS m/z: 310 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27](B5OC(C)(C)C(C)(C)O5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=1)[C:48]([NH2:50])=[O:49].O1CCOCC1>C(Cl)(Cl)Cl.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:43]5[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=5)[C:48]([NH2:50])=[O:49])[CH:28]=4)[O:23]3)[CH2:21][CH2:22]2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2O3)nc2c(OC)cccc12
Reactant: NC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(N)=O)c4)ccc2O3)nc2c(OC)cccc12
Reaction time: 21 h

Procedure:
350 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one, 151 mg of 5-bromonicotinamide, 72.5 mg of Pd(PPh3)4 and 1.4 mL of 2M Na2CO3aq were heated with 1,4-dioxane at 100° C. and stirred for 21 hours. The reaction solution was diluted with CHCl3, filtered through Celite, and the filtrate was dried with magnesium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (CHCl3/MeOH=9/1) to obtain the intended compound. 1H-NMR (400 MHz, CDCl3) δ: 8.90-9.00 (2H, m), 8.36 (1H, s), 8.15 (1H, s), 7.70-7.80 (2H, m), 7.40-7.55 (11H, m), 7.19 (1H, s), 7.17 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=7.8 Hz), 6.3-6.5 (1H, br), 5.7-6.1 (1H, br), 4.50-4.60 (1H, m), 4.10-4.15 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.55-3.70 (1H, m), 3.35-3.50 (1H, m), 2.88 (1H, d, J=16.6 Hz), 2.82 (1H, d, J=16.6 Hz), 2.20-2.30 (1H, m), 2.05-2.15 (1H, m), 1.80-2.05 (2H, m). MS [M+H]+=553.
Reaction SMILES: Br[CH:2]1[CH2:6][O:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[CH2:3]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:4]1[O:5][CH2:6][CH:2]([S:17][C:15](=[O:18])[CH3:16])[CH2:3]1
Reactant: CC([O-])=S
Reactant: Fc1ccc(C2CC(Br)CO2)c(F)c1
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)SC1COC(c2ccc(F)cc2F)C1
Yield: 76.7 %

Procedure:
The title compound is prepared by the procedure of Example 5 using 1.9 g of product from Example 165, 0.866 g of potassium thioacetate and 30 ml of acetonitrile to give, after chromatography (silica gel: 5% ethyl acetate/hexane), 1.43 g of the desired product, as a mixture of isomers.