Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N+:12]=1[O-:19].[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.[I-].[K+].[N-]=C=O.C(=O)([O-])[O-]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22]2)=[CH:13][N+:12]=1[O-:19]
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1CCCN(Cc2ccc(Cl)[n+]([O-])c2)C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 99 %

Procedure:
PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was washed with tetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine 1-oxide (100 mg, 0.56 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) was added followed by tetrahydrofuran (1 mL). A solution of 3-methylpiperidine in tetrahydrofuran (1.5 mL) and a catalytic amount of potassium iodide were added, and the mixture was gently stirred (80 r/min) at room temperature for 5 days. PS-Isocyanate (1.10 mmol/g, 1.27 g, 1.40 mmol) was washed with tetrahydrofuran and added to the mixture followed by additional tetrahydrofuran (2 mL). The suspension was gently stirred (80 r/min) at room temperature overnight. N-Ethyl-N,N-diisopropylamine (50 μL, 0.28 mmol) and MP-Carbonate (2.55 mmol/g, 0.66 g, 1.68 mmol) were added, and the containts were mixed and gently stirred for 24 h. The mixture was filtered (20 μm polyethylene filter), and the resins were washed with methylene chloride. Volatiles were removed in vacuo to give 138 mg (99% yield) of the title compound: MS (ES) m/z 241 (M++1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][CH3:15])[CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl.[OH-].[K+].CC1CCCO1>O1CCCC1.C1(C)C=CC=CC=1>[C:13]([C:9]1[CH:8]=[C:7]([B:16]([OH:21])[OH:17])[CH:12]=[CH:11][CH:10]=1)#[C:14][CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC#Cc1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CC#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 3.7 mL, 9.4 mmol) was added dropwise to a solution of 1-bromo-3-(prop-1-ynyl)benzene (Intermediate 31, 1.66 g, 8.51 mmol) and triisopropyl borate (2.2 mL, 9.4 mmol) in tetrahydrofuran (5 mL) and toluene (15 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred for 30 min. and then allowed to reach r.t. and stirred for 1 h. The mixture was cooled to −78° C., and 3 M aq. hydrochloric acid was added and the mixture was stirred at r.t. for 15 min. The mixture was basified by addition of solid KOH. 2-methyl-tetrahydrofuran was added under stirring and the obtained solid was collected by filtration affording the title compound 1.0 g (75% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01 (s, 3 H), 6.92-7.03 (m, 1 H), 7.09-7.20 (m, 1 H), 7.55-7.79 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-Methyl-2-nitrobenzoic acid 67 (30.0 g, 166 mmol, 1.0 equiv.) was suspended in CH2Cl2 (150 ml) and the suspension was cooled to 0° C. using an ice bath. Oxalyl chloride (2.0 M in CH2Cl2, 166 ml, 332 mmol, 2.0 equiv.) was added to the stirred reaction mixture through a pressure equalizing dropping funnel over 30 min. DMF (10 drops) was added dropwise. The reaction mixture was allowed to warm up to room temperature. After 30 min., the reaction was concentrated to dryness on a rotary evaporator. The solid material was re-dissolved in CH2Cl2 (200 ml) and was concentrated to dryness on a rotary evaporator to give 3-methyl-2-nitro-benzoylchloride 68 (32.9 g, 99%) as an off white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].C[O-].[Na+].[O:42]1CCC[CH2:43]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([O:42][CH3:43])[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: C1CCOC1
Agent: CS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, sodium methoxide/tetrahydrofuran was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5 to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 404.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[OH:10][CH2:11][C:12](O)=[O:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(#N)C>[OH:13][CH2:12][C:11]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: O=C(O)CO
Reactant: O=C1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyacetic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile, and hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were then added to the solution in an ice-water bath. The ice-water bath was then removed, and the reaction mixture was stirred overnight at 25° C. The solvent was evaporated, and 20 mL of ethyl acetate was then added to the residue. The mixture was filtered and the filtrate was washed with 20 mL of water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=4)[N:30]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:11].[I-].[Na+]>C1COCC1.CC(N(C)C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:35])[F:36])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(CCl)Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(CC(=O)Nc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 60 °C
Yield: 69.7 %

Procedure:
1-Methylpiperazine (140 μl, 1.27 mmol) was added to 2-chloro-N-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (139 mg, 0.317 mmol) and sodium iodide (10 mg, 0.063 mmol) in a mixture of THF (2 mL) and DMA (0.5 mL). The resulting solution was heated at 60° C. for 2 hours, then cooled and evaporated to give the crude product which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 2-(4-methylpiperazin-1-yl)-N-[4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (111 mg, 70%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([CH3:28])=[CH:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([CH3:28])=[CH:5]2
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (4.89 g, 10.99 mmol) in anhydrous dichloromethane (100 mL) at 0° C. was added Dess-Martin periodinane (5.59 g, 13.18 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3×), brine and dried (MgSO4), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give an off-white solid (4.60 g). 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J=7.0 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.67 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][OH:11])[S:8][C:4]=2[CH:3]=1.[S:14](Cl)([CH3:17])(=[O:16])=[O:15]>C(N(CC)CC)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][O:11][S:14]([CH3:17])(=[O:16])=[O:15])[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1nc2ccc(Br)cc2s1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1nc2ccc(Br)cc2s1

Procedure:
Compounds of formula (22) can be prepared from 6-bromobenzothiazolone as shown in Scheme 3. 6-Bromobenzothiazolone is heated in the presence of NaOH base to provide a mixture of 2-amino-5-bromothiophenol (15) and its disulfide (16). The mixture is treated with chlorocarbonyl-acetic acid ethyl ester to provide 6-bromo-benzothiazol-2-yl-acetic acid ethyl ester (17) and 7-bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (18), which can undergo rearrangement by treatment with zinc and ethyl acetate to provide compound (17). Compound (17) is reduced with NaBH4 to provide 2-(6-bromo-benzothiazol-2-yl)-ethanol (19). Compound (19) is treated with mesyl chloride in the presence of triethyl amine to afford the corresponding methanesulfonic acid 2-(6-bromo-benzothiazol-2-yl)-ethyl ester (20), which is treated with an amine of formula HNRaRb, wherein Ra and Rb each is as defined for R4 and R5, to provide compounds of formula (21). Compounds of formula (21) can be treated with a boronic acid, wherein Rc is aryl or heteroaryl, to provide compounds of formula (22).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:27])[CH2:13][NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:17]=1[CH3:25].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:22][C:18]1[C:17]([CH3:25])=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][CH:12]([OH:27])[CH2:11][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:26]
Reactant: Cc1c(C(=O)NCC(O)CN2CCc3ccccc3C2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1c(N)cccc1C(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methyl-3-nitrobenzamide (1.6 g, 4.3 mmol) in EtOH (15 mL) and H2O (15 mL) was added Fe powder (1.45 g, 25.8 mmol) and NH4Cl (1.38 g, 25.8 mmol). The mixture was stirred at 60° C. for 4 h. The reaction solution was filtered, and the filtrate was concentrated to remove EtOH. The residue was diluted with water and extracted with DCM. The organic layer was concentrated to give the desired product (1.4 g, Yield 95.9%). The crude product was used in next step without further purification. LCMS (m/z): 340.1 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4][C@@H:3]1[CH2:22][NH:23]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:23][CH2:22][C@@H:3]1[C@H:2]([OH:1])[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4]1
Reactant: COc1cnc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Yield: 90.1 %

Procedure:
To a solution of phenylmethyl [((3S,4S)-4-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.90 g, 1.99 mmol) in MeOH (30 mL) was added catalytic 10% Palladium on carbon (0.20 g) and the resulting solution subjected to H2 at 50 PSI on a Parr shaker. The solution was filtered through a pad of Celite® and concentrated under reduced pressure to give the product (0.571 g, 90%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:6]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1c(Cl)ncnc1-c1ccccc1)OCC
Temperature: 100 °C
Yield: 63.6 %

Procedure:
The 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (1.1 g), phenyl boronic acid (500 mg) and potassium carbonate (556 mg) were dissolved in toluene (15 mL) and water (1.5 mL). The reaction mixture was degassed with nitrogen for 30 minute and then Pd(PPh3)4 (230 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes before heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using EtOAc/hexane (0.5:9.5) as eluent to afford 4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.07-1.10 (t, 6H), 3.21-3.23 (d, 2H), 3.32-3.36 (q, 2H), 3.37-4.00 (q, 2H), 4.79-4.81 (t, 1H), 7.47-7.49 (m, 3H), 7.63-7.66 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20](I)=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:31]#[N:32])=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1
Reactant: N#C[Cu]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 175 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g, 4.0 mmol, 1 eq), CuCN (3.6 g, 40 mmol, 10 eq), and DMF (25 ml) was stirred at 175° C. for 1 hrs. The reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over Na2SO4, and purified by flash chromatography to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g).
Reaction SMILES: S[C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:24])=O.O.C(=O)(O)[O-].[Na+]>ClCCCl.CN1CCCC1=O>[Cl:24][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1
Reactant: Cn1c(S)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: Cn1c(Cl)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
2-Mercapto-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.76 g, 9.33 mmol) in 1,2-dichloroethane (20 ml) and N-methylpyrrolidone (2 ml) was added to a solution of phosphorus oxychloride (3.83 g, 25.0 mmol) and N-methylpyrrolidone (5.22 g, 52.7 mmol) at 50° C. and the mixture was stirred for 20 minutes. The solution was poured into warm water, and sodium bicarbonate (10.2 g, 121 mmol) was added to the solution and the mixture was stirred until no gas was generated. The resulting solution was partitioned between water and dichloromethane, and the organic layer was washed with water and brine and passed through Celite. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography (eluent; hexane/ethyl acetate=2/1 to 1/1) to afford 2-chloro-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.08 g, 75%).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1.[NH:28]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:29]([C:45]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49]([OH:51])=[O:50])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37]CC2C=CC=CC=2)=[CH:33][CH:32]=1.[C:62]([C:64]1[CH:71]=[CH:70][C:67]([CH2:68][NH-:69])=[CH:66][CH:65]=1)#[N:63]>CO.[Pd]>[NH:28]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:29]([C:45]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49]([OH:51])=[O:50])=[O:46])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1.[C:62]([C:64]1[CH:71]=[CH:70][C:67]([CH2:68][NH-:69])=[CH:66][CH:65]=1)#[N:63]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: N#Cc1ccc(C[NH-])cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 6 h

Procedure:
12.5 g of Boc-(D)-Tyr(Bzl)OH were converted as in Example 3 into 18.9 g of Boc-(D)-Tyr(Bzl)-Pro-p-cyanobenzylamide, dissolved in 780 ml of MeOH and hydrogenated with Pd/C at room temperature. After 6 h, the catalyst was filtered off and the solvent was stripped off. Boc-(D)-Tyr-Pro-p-cyanobenzylamide was obtained in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].[C:19]([C:27]1[CH:51]=[CH:50][C:30]([O:31][CH2:32][CH2:33][CH2:34]OC2C=CC(C[C@H](OCC)C(O)=O)=CC=2)=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:50]=[CH:51][C:27]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)c(Cl)c1)OCC
Reactant: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(Cl)c1)OCC

Procedure:
The title compound was prepared from (S)-2-ethoxy-3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester and [4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (Example 256) using the Standard Procedure I. The product was purified by column chromatography on silica gel using a 4/1 Hexane/Ethyl acetate mixture as eluent to give the title product. MS(ES) for C29H31ClO6 [M+H]+: 511.1
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([F:18])[C:5]([N:19](S(CCCOC2C=CC(OC)=CC=2)(=O)=O)[S:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:22])=[O:21])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:18])[C:5]([NH:19][S:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(OCCCS(=O)(=O)N(c2ccc(Cl)c(C(=O)OCc3ccccc3)c2F)S(=O)(=O)CCCOc2ccc(OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCCCS(=O)(=O)Nc2ccc(Cl)c(C(=O)O)c2F)cc1
Temperature: 25 °C

Procedure:
A 100 mL, round-bottomed flask was charged with benzyl 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)-N-(3-(4-methoxyphenoxy)propylsulfonyl)propylsulfonamido)benzoate (1.08 g, 1.47 mmol), potassium hydroxide (4.40 mL, 4.40 mmol) and MeOH (10 mL). The reaction mixture was stirred at room temperature until TLC showed that the starting material had been consumed (about 12 hours). HCl (5 mL, 1N) was added. Then the reaction mixture was partitioned between EtOAc (500 mL) and water (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield crude 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzoic acid. The crude product was purified by silica gel chromatography (EtOAc/hexane from 1/4 to 1/0, v/v) to afford 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzoic acid (0.58 g, 95.1%). 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.39-7.53 (m, 2H), 6.81 (m, 4H), 4.01 (t, 2H), 3.64 (s, 3H), 3.34 (t, 2H), 2.11 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:16]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:16]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)CCc1ccccc1
Reactant: CCCCN1CCNC(=O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(CCc2ccccc2)C(=O)OC)C(=O)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-butylpiperazine-2,3-dione (Intermediate D, 500 mg, 2.9 mmol) in 4 mL DMF, cooled to 0° C., was added sodium hydride (60% dispersion in mineral oil, 128 mg, 3.2 mmol). The reaction was stirred at rt for 30 min, recooled to 0° C. and a solution of methyl 2-bromo-4-phenylbutanoate (Intermediate C, 820 mg, 3.2 mmol) in 1 mL DMF was added dropwise. The mixture was stirred at rt for 1 h, quenched with brine and extracted with EtOAc. Drying, solvent evaporation and flash chromatography (silica gel, 35-90% EtOAc/hexanes) gave methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-4-phenylbutanoate. 1H NMR (CDCl3) δ 7.29 (m, 2H), 7.18 (m, 3H), 5.27 (X of ABX, 1H, J=10.8 Hz, J=4.6 Hz), 3.72 (s, 3H), 3.63 (m, 1H), 3.54 (m, 1H), 3.47 (m, 2H), 3.38 (m, 1H), 3.28 (m, 1H), 2.67 (m, 2H), 2.36 (m, 1H), 2.03 (m, 2H), 1.57 (m, 2H), 1.35 (m, 2H), 0.95 (t, 3H, J=7.3 Hz).