Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:37])[CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:28]([N:25]1[C:20]2=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=4)[C:7]([F:8])=[CH:6][CH:5]=3)=[O:37])[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]2[CH:27]=[N:26]1)[CH3:29]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Yield: 66.1 %

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (0.9429 g, 1.638 mmol), (3-formylphenyl)boronic acid (0.300 g, 2.0 mmol), tetrakis (triphenylphosphine) palladium (0) (0.092 g, 0.08 mmol), sodium carbonate (0.530 g, 5.0 mmol), in 1,4-dioxane (12 mL) and water (4 mL) was microwaved for 30 min at 140° C.; however, the reaction failed and appeared to be incomplete by color. The mixture was again microwaved at 150° C. for about two min. The LC-MS showed that the reaction was complete. The reaction mixture was diluted with water, extracted with EtOAc twice. The organic extracts were filtered through a glass-fibre filter and washed with saturated NaCl, then dried over Na2SO4. The organic layer was evaporated to dryness and taken up in a small amount of DCM, introduced onto a Chromatotron Plate (silica gel −2,000μ) and eluted with DCM-MeOH (2-7%). The product fractions were dried to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]propanediamide (650 mg, 62.7%) as a glassy solid. LC-MS m/z 601.4 (M+H)+, 0.83 min (ret time).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[C:5]=1[S:15]C(N(C)C)=O.O.Cl>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[C:5]=1[SH:15]
Reactant: COC(=O)c1ccc(Cl)c(SC(=O)N(C)C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc(Cl)c1S

Procedure:
6.61 g (85% by weight pure, 100.1 mmol) of potassium hydroxide were added to 4.80 g (16.7 mmol) of methyl 4-chloro-3-(dimethylaminocarbonylthio)-2-methylbenzoate in 150 ml of methanol, and the mixture was stirred under reflux for two days. The reaction mixture was freed from the solvent, water was added to the residue, the mixture was acidified with 1M HCl and the solid was removed by filtration. This gave 3.2 g of clean product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:29][CH:26]([CH3:28])[CH3:27])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: CC(C)N
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Solvent: CCO
Product: CC(C)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and isopropylamine (5 ml) in 20 ml of ethanol was placed into a high-pressure reaction apparatus and heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 40:1) to give the desired product as a light yellow solid. MS: 454; 1H NMR (DMSO-d6, 300 MHz): δ 10.28 (brs, 1/2H, NH, D2O exchangeable), 9.62 (brs, 1H, NH, D2O exchangeable), 9.31 (brs, 1/2H, NH, D2O exchangeable), 8.57 (s, 1H, OH, D2O exchangeable), 7.88 (brs, 1H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 3.85 (m, 1H, CH), 1.20 (d, 6H, J=6.3 Hz, 2×CH3).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[C:7]1([C:13]2[CH:14]=[C:15]3[N:20]([CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[O:3]=[C:2]([C:21]1[N:20]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]2)=[CH:14][C:13]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
Oxalyl chloride (2.23 mL, 25.9 mmol) was added to an ice-cold solution of 2-phenylindolizine (4.0 g, 20.7 mmol) in a mixture of toluene (40 mL) and THF (8 mL). The reaction mixture was stirred at r.t. for 5 h then concentrated in vacuo. The residue obtained was recrystallised from DCM-hexane to yield oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (4.6 g, 80%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.CO.C[O-].[Li+].[O:12]1[CH2:16][CH2:15]N=[CH:13]1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>>[CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[CH3:13][O:12][CH2:16][CH2:15][CH2:1][C:2]([NH2:6])=[O:3].[CH3:17][O:18][CH2:19][CH2:20][NH2:21]
Reactant: C1=NCCO1
Agent: CC1=NCCO1
Agent: COCCN
Agent: C[O-]
Solvent: CO
Product: COCCCC(N)=O
Reaction time: 23.5 h
Yield: 82.3 %

Procedure:
A 127.6 g portion (1.5 moles) of 2-methyl-2-oxazoline is mixed with 192.0 g (6.0 moles) absolute methanol and 11.4 g (0.3 mole) lithium methoxide in a one-liter stainless steel Parr reactor equipped with a turbine stirrer. The reactor is sealed and heated, with stirring, to between 160° C and 165° C and 220 psig. The reaction is continued under those conditions for a period of 23.5 hours. Samples are periodically taken from the reactor through a dip-pipe which is below the liquid level. Analysis of these samples by gas chromatography with an internal standard indicates that, at 60-75 percent oxazoline conversions, corresponding amide yields are very high (95-100 percent) based upon the amount of oxazoline converted. At higher oxazoline conversions, a significant by-product appears, which is identified as 2-methoxyethylamine. The concentration of this amine levels out, and at 96.4 percent methyl oxazoline conversion, an 82.3 percent yield of 2-methoxyethylacetamide and an 11 percent yield of 2-methoxyethylamine results. Thus, yields of amide and amine, based on a 96.4 percent oxazoline conversion, are 93.3 percent.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:36]([I:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C.O>[Cl:39][C:38]1[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=[C:36]([I:40])[CH:37]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Nc1c(Cl)cc(I)cc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc(I)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methanesulfonyl chloride (0.31 mL, 4.07 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (1.0 g, 3.87 mmol) and triethylamine (0.54 mL, 3.87 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was then stirred for 15 minutes at 0° C. Then, 2-amino-3-chloro-5-iodobenzoic acid (i.e. the product from Step A) (1.15 g, 3.87 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (1.08 mL, 7.74 mmol) in acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5° C. The reaction mixture was stirred 40 minutes at 0° C., and then methanesulfonyl chloride (0.31 mL, 4.07 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated under reduced pressure. The residual solid was purified by chromatography on silica gel to afford 575 mg of the title compound as a crude yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:27]=[O:28])C.P(Cl)(Cl)(Cl)=O>O>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:18]2[CH:23]=[CH:22][C:21]([CH:27]=[O:28])=[CH:20][CH:19]=2)[C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: CN(C)C=O
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)c(C)c2)cc1C
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 95 °C
Yield: 79 %

Procedure:
Into a three-necked flask, 124.6 g of [N,N-bis(3,4-dimethylphenyl)amino]benzene and 35.5 ml of DMF were placed, and 84.4 ml of phosphorus oxychloride was added dropwise thereto with stirring while cooling with ice water. After the addition was completed, the mixture solution was heated to 95° C. to carry out reaction for 5 hours. The reaction solution obtained was poured into 4 liters of warm water, followed by stirring for 1 hour. Thereafter, the precipitate was collected by filtration, and washed with a mixture of ethanol/water (1:1) to obtain 4-[N,N-bis(3,4-dimethylphenyl)amino]benzaldehyde in an amount of 107.6 g (yield: 79.0%).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:11][C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][C:13]1=[O:19]>>[CH3:11][C:12]1([CH3:20])[C:13]2[O:19][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:14]=2[C:15](=[O:18])[CH2:16][CH2:17]1
Reactant: O=C(CO)c1ccccc1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC(=O)c2c(-c3ccccc3)coc21

Procedure:
The subtitle compound was prepared according to the procedure of example 2 using hydroxyacetophenone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:26]=[O:27]>C(OCC)C>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:26]=[O:27]
Reactant: OCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cccc(CCO)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture 2-(3-bromophenyl)ethanol (1.00 g, 0.67 mL, 4.9 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.5 mL) in anhydrous diethyl ether (10 mL) was cooled to −78° C. in a dry-ice acetone bath. n-Butyl lithium (2.4 M solution in hexanes, 4.0 mL, 9.8 mmol) was added dropwise and the resulting mixture was allowed to warm to −20° C. (over 1 h) and then cooled again to −78° C. Anhydrous N,N-dimethylformamide (5 mL) was added and the resulting mixture was allowed to reach room temperature and stirred for an additional 1 h. The reaction mixture was quenched with a saturated solution of ammonium chloride and the aqueous portion was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate-hexanes 2:3 as eluent to provide the desired compound as colorless oil. Yield: 88%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:22][CH2:23][N:24]([CH3:26])C.Cl.ON1C(=O)CCC1=O.CCN(C(C)C)C(C)C.N1CCC1>C(Cl)Cl>[N:24]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:23][CH2:22][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CNC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (50.0 g, 230.1 mmol), EDC hydrochloride (52.9 g, 276.2 mmol) and 1-hydroxypyrrolidine-2,5-dione (39.7 g, 345.2 mmol) was mixed in DCM (180 mL). The mixture was cooled to 0° C. and DIPEA (160 mL, 920.6 mmol) was added. After 1 h at 0° C. was azetidine (18.62 mL, 276.2 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (200 mL). The organic phase was washed with NaHCO3 (saturated, 2×150 mL), HCl (1M aq. solution, 2×200 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (42 g, 71%). The obtained crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)[CH:3]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:22][C:23]1[C:24]([O:15][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:2]([Cl:1])=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccc(F)cc4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
6-Chloro-4′-fluoro-4-(pyridazin-4-yl)biphenyl-3-ol (Preparation 102, 150 mg, 0.50 mmol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 345 mg, 0.75 mmol), and potassium carbonate (207 mg, 1.50 mmol) were suspended in dimethyl sulfoxide (2 mL). The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (2×50 mL) and dichloromethane (3×50 mL). The organic layers were combined, dried over MgSO4, filtered and evaporated. The residue was purified by semi preparative reverse phase HPLC (solvent A: 0.05% formic acid in acetonitrile; solvent B: 0.05% formic acid in water; flow rate: 15 mL/min; gradient 0 min 5% A, 2.5 min 5% A, 22.5 min 95% A, 32.5 min 95% A then return to initial conditions) to afford the title compound (100 mg, 27%) as a glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.COCCOC.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O>[Cl:18][C:19]1[CH:24]=[C:23]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[N:22]=[CH:21][N:20]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: Clc1cc(Cl)ncn1
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(F)c1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
A reaction vessel was charged with [1,1′-bis(diphenylphosphino)ferrocene dichloropalladium]methylene chloride complex, 1.007 g of 2,6-difluorophenylboronic acid, and 2.707 g of tripotassium phosphate n-hydrate, to which 16 ml of 1,2-dimethoxyethane, 4 ml of water, and 0.95 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 5 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.241 g of 4-chloro-6-(2,6-difluorophenyl)pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:60]C(OC(C)(C)C)=O)[C:16]([O:18][C@H:19]1[C@@H:23]([OH:24])[C@H:22]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:21][C@H:20]1[CH2:35][O:36][P:37]([O:40][C@H:41]1[CH2:45][C@H:44]([N:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48][C:47]2=[O:53])[O:43][C@@H:42]1[CH2:54][O:55][P:56]([OH:59])([OH:58])=[O:57])([OH:39])=[O:38])=[O:17])=[N+:9]=[N-:10]>ClCCl>[NH2:60][C@H:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[C:16]([O:18][C@H:19]1[C@@H:23]([OH:24])[C@H:22]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:21][C@H:20]1[CH2:35][O:36][P:37]([O:40][C@H:41]1[CH2:45][C@H:44]([N:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48][C:47]2=[O:53])[O:43][C@@H:42]1[CH2:54][O:55][P:56]([OH:59])([OH:58])=[O:57])([OH:39])=[O:38])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk50) (30.2 mg, 0.034 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-azidohexanoate (Lys(N3)-pdCpA) (Compound tk51) (19.4 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21]([C:24]4[N:25]=NN(C)N=4)=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4]>C1COCC1.N.[Zn]>[F:32][C:2]([F:1])([F:33])[C:3]([NH:5][C@@H:6]1[CH2:31][CH2:30][N:9]2[C:10]3[CH:23]=[CH:22][C:21]([C:24]4[CH:2]=[CH:3][N:5]=[CH:6][N:25]=4)=[CH:20][C:11]=3[C@H:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:8]2[CH2:7]1)=[O:4]
Reactant: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc(-c3nnn(C)n3)cc21
Agent: N
Agent: [Zn]
Solvent: C1CCOC1
Product: C[C@@H]1c2ccccc2[C@H]2C[C@H](NC(=O)C(F)(F)F)CCN2c2ccc(-c3ccncn3)cc21
Reaction time: 5 h
Yield: 170.1 %

Procedure:
To a stirred solution of 10 (R8═C4H2N2Cl, R2═COCF3; 614 mg, 1.26 mmol) in THF (50 mL) and ammonia (22 mL), zinc (2.17 g 33.2 mmol) was added. The reaction mixture was stirred for 5 hours under reflux. The reaction was quenched with a saturated NaHCO3 solution in H2O and filtered over decalite. The product was extracted into ethyl acetate, washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica affording rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide (10: R8═C4H3N2, R2═COCF3; 485 mg, 85%). Data: (m/z)=453 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:16]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(COC)OC>[C:35]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N+:23]([O-:49])=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:16]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Solvent: COCCOC
Product: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
100 mg (0.19 mmol) of N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]aniline were reacted with 36 mg (0.21 mmol) of m-chloroperbenzoic acid in 4 ml of dimethoxyethane. The solution was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and aqueous NaHCO3, the organic layer dried over Na2SO4 and the solvent removed under reduced pressure. The residue was triturated with diethylether and collected by filtration giving 80 mg (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=1)=[O:26])=[O:27])([CH3:38])[CH3:37]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a suspension of 150 mg (0.30 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,8-diaza-phenanthren-4-one in 6 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 78 μL (0.91 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 100 mg (65%) of a white solid; LC/MS:503/505 (M+H)+, m.p.: 182-183° C.