Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(N(CC)CC)C>C(O)C>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCOCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-[2-(bromo)ethyloxy]ethyl]phthalimide (5.96 g, 20 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.00 g of the desired product (54.5%, light tan solid).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)[CH2:14][CH3:15]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CCCNCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)c1nc(C)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 82.7 %

Procedure:
A mixture of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.411 g, 2.20 mmol), di-n-propylamine (0.668 g, 6.60 mmol), triethylamine (0.267 g, 2.64 mmol), and THF (5 ml) was stirred at room temperature for 55 min and then at reflux for 1.3 h, at which time is was cooled and partitioned between ethyl acetate and a mixture of brine and aq. sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated and then chromatographed on silica gel using ethyl acetate-hexane (90/10) to give methyl 2-(dipropylamino)-6-methylpyrimidine-4-carboxylate (0.457 g) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[OH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:15][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
4.5 g (0.018 mol) of 4-Octyloxy-benzoic acid, 7.0 g (0.038 mol) of 4,4′-Dihydroxy biphenyl and 0.46 g (3.7 mmol) of DMAP are dissolved in 65 mL of dry THF and 4.4 g (0.021 mol) of DCC is added. After stirring for 18 h at room temperature, the suspension is filtered. The residue is dissolved in a hot solution of hexane:CHCl3:THF=2:2:1 and after cooling to room temperature, the precipitate is filtered off. The recrystallisation is repeated until the TLC indicates pure white product (3.7 g, 49% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:21][O:13][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[CH3:1])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
30 g (114 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid (CAS [43071-45-0]) were suspended in 250 ml of dry CH2Cl2; 20 ml (230 mmol) of oxalyl chloride dissolved in 120 ml of CH2Cl2 were added dropwise and the reaction mixture was stirred at room temperature for 30 min. Two drops of DMF were added and the reaction was stirred for additional 30 min. The solvent was evaporated in vacuo to dryness, the residue was taken up with 100 ml of CH2Cl2 and 100 ml of MeOH, dissolved in 400 ml of CH2Cl2, were added dropwise. After stirring for 18 h the solvent was evaporated in vacuo to dryness, the residue was taken up with CH2Cl2 and washed with 1% NaHCO3; the organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to yield 31.6 g of the title compound as a solid, which was used in the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])[CH3:4].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([Sn](CCCC)(CCCC)CCCC)=[N:34][N:35]2[CH3:38])=[CH:31][CH:30]=1>CN(C=O)C.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.[Cu]I>[OH:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:33]3[C:32]4[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=4)[N:35]([CH3:38])[N:34]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide (120 mg, 0.26 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (319 mg, 0.42 mmol) were dissolved in DMF (2.5 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and copper(I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 122 mg (86%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as an off-white solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(I)CC>C1COCC1>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=1[CH:19]([CH2:1][CH2:2][CH3:3])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 1 h
Yield: 87 %

Procedure:
Potassium t-butoxide (7.7 ml, 1M in THF, 7.7 mmol) was added to a solution of methyl 2-[2,5-bis(trifluoromethyl)phenyl]acetate (2 g, 7 mmol) in THF at 0° C. The resulting yellow solution was stirred for 40 min. n-Propyl iodide (1.7 g, 10.5 mmol) was added and the mixture stirred for 1 h. The mixture was poured onto HCl (2M) and extracted into EtOAc. The combined organic phases were washed with Na2S2O3 solution, brine, then dried (MgSO4) and concentrated in vacuo to give the product as a yellow oil (2 g, 87%). 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J 7.3), 1.23-1.29 (1H, m), 1.35-1.43 (1H, m), 1.67-1.81 (1H, m), 2.05-2.17 (1H, m), 3.69 (3H, s), 4.10 (1H, t, J 7.5), 7.62 (1H, s, J 8.2), 7.78 (1H, d, J 8.2), 7.90 (1H, s).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:6][OH:7])[CH3:5].[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[N:22]=[CH:21][C:20]=3[N:33]=2)[CH:13]=[CH:14][C:15]=1O>>[F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:6][O:7][C:15]1[CH:14]=[CH:13][C:12]([C:17]2[O:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[N:22]=[CH:21][C:20]=3[N:33]=2)=[CH:11][C:10]=1[F:9])[CH3:5]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Reactant: CC1(CO)CC1(F)F
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(C)CC4(F)F)c(F)c3)nc2cn1

Procedure:
Using (2,2-difluoro-1-methylcyclopropyl)methanol and N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide, and in the same manner as in Step B of Example 4, the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])C(=O)OC(C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(CC)N(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Trifluoroacetic acid (42 mL, 544 mmole) was added to a chilled (0° C.) solution of tert-butyl N-benzyloxy-N-(1-ethylpropyl)carbamate (21.6 g, 73.6 mmole) in methylene chloride (300 mL). The reaction was stirred at ambient temperature for about 18 hours then concentrated under vacuum. Saturated aqueous sodium bicarbonate (100 mL) was added to the residue followed by a quantity of solid sodium carbonate sufficient to adjust the pH of the reaction mixture to pH 9. The reaction mixture was extracted with diethyl ether (4×50 mL). The extracts were combined, dried over sodium sulfate then concentrated to provide 10.9 g of N-benzyloxy-N-(1-ethylpropyl)amine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19](OC)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.OS(O)(=O)=O>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[CH2:19][OH:20])=[CH:24][CH:25]=1)[CH:6]=[N:5]2
Reactant: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Yield: 54 %

Procedure:
In 50 ml. anhydrous ethyl ether, 0.5 g. (1.5 m mol) of methyl 2-[4-(6-fluoro-2-quinoxalyloxy)phenoxy]propionate was dissolved and 10 ml. of a solution containing 0.11 g.(3.0 mmol) of LiAlH4 in anhydrous ethyl ether was added dropwise and the mixture was refluxed for 12 hours. After the reaction, 10 ml. of water and 7 ml. of 2N—H2SO4 were added to the reaction mixture and the organic layer was separated and washed with water and dehydrated over anhydrous sodium sulfate and the solvent was distilled off to obtain viscous liquid. This viscous liquid was crystallized and the crystal was washed with n-hexane to obtain 0.25 g. of the object compound (yield of 54%).
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]([F:54])([F:53])[CH2:42][O:43][C:44]1[C:49](B(O)O)=[CH:48][CH:47]=[CH:46][N:45]=1>>[CH3:16][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:49]1[C:44]([O:43][CH2:42][C:41]([F:54])([F:53])[F:40])=[N:45][CH:46]=[CH:47][CH:48]=1
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: CNc1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-methylpyridin-3-amine (example 98, intermediate b) and 2-(2,2,2-trifluoroethoxy)pyridin-3-ylboronic acid after a reaction time of 5 hours at 90° C. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless oil (76%). MS (ESI): m/z=284.10 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].C(C1(C(OCC)=O)CC1)CC=C>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: C=CCCC1(C(=O)OCC)CC1
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CC1

Procedure:
N-{[(1-But-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (Steps 2 and 3) by using ethyl 1-but-3-en-1-ylcyclopropanecarboxylate-instead of ethyl 2,2-dimethylhex-5-enoate in Step 2. LRMS (ESI) m/z 284.3 [(M+H)+; calcd for C15H26NO4: 284.2].
Reaction SMILES: [NH:1]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:43]([N:45]1[CH2:73][CH2:72][CH2:71][C@H:46]1[C:47]([NH:49][C@H:50]([C:61]([O:63]CC1C=CC=CC=1)=[O:62])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:60])[NH:56][N+]([O-])=O)=[O:48])=[O:44])[CH2:32][C:33](=[O:42])[O:34]CC1C=CC=CC=1)=[O:29])[C@@H:18]([CH3:27])[O:19]CC1C=CC=CC=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[H][H]>C(O)(=O)C.O.CO.[Pd]>[NH:1]([C:74]([O:76][C:77]([CH3:78])([CH3:80])[CH3:79])=[O:75])[C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:43]([N:45]1[CH2:73][CH2:72][CH2:71][C@H:46]1[C:47]([NH:49][C@H:50]([C:61]([OH:63])=[O:62])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:60])=[O:48])=[O:44])[CH2:32][C:33](=[O:34])[OH:42])=[O:29])[C@@H:18]([CH3:27])[OH:19])=[O:15])[CH2:3][C:4](=[O:5])[OH:13]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 30 h
Yield: 40 %

Procedure:
BOC-Asp(OBzl)-Thr(Bzl)-Asp(OBzl)-Pro-Arg(NO2)-OBzl, was dissolved in a mixture of acetic acid (500 ml), water (500 ml), and methanol (3-5 liters). Palladium 10% on activated carbon (100-200 g) was added to the solution and hydrogen gas passed through the mixture for 20-40 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was triturated with ether (3-4 liters), and the resulting solid filtered to produce BOC-Asp-Thr-Asp-Pro-Arg. The yield was about 40-60%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][C@@H:20]([C@H:22]4[CH2:27][O:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][O:23]4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].[C:35](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][C@@H:20]([C@H:22]4[CH2:27][O:26][C@H:25]([C:28]([O:30][CH3:35])=[O:29])[CH2:24][O:23]4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](C(=O)O)CO4)C3)nc(C)n2)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CO[C@@H]([C@@H]2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred solution of (2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylic acid (0.3 g, 0.632 mmol, Example #P.1) in DMF (2 mL) was added potassium carbonate (0.131 g, 0.948 mmol) followed by iodomethane (0.108 g, 0.759 mmol). The reaction mixture was stirred at RT for about 3 h. The reaction mixture was quenched with water (15 mL), the product separated as solids and collected by filtration, washed with water (10 mL) and dried under vacuum to obtain (2S,5R)-methyl 5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylate 0.270 g, (87%), ES-MS: m/z 489 (m+H)+, LC/MS (Table 1, method d) Rt=2.25 min.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1>C(#N)C.CCOC(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][OH:4])[CH2:32][CH2:31]3)=[O:28])=[C:20]2[CH:19]=1
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: OCCBr
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 4 h
Yield: 7.3 %

Procedure:
2-Bromoethanol (18 mg, 0.14 mmol) was added to stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (50 mg, 0.12 mmol) (Example-32) in acetonitrile (0.5 mL) and stirring was continued at 70° C. for 4 h. The reaction mixture was diluted with EtOAc, washed the organic layer with water and dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford the crude product, which was purified by Preparative HPLC [Column: 21.2×150×5 um, waters×bridge C-18, Mobile phase-A: 0.1% TFA in water, B: ACN, Gradient (Time/% B): 0/20, 2/30, 1870 and Flow rate: 20 mL/min] to afford 4.1 mg of the title compound.
Reaction SMILES: CO[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].C[O-].[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>>[NH2:6][C:5]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: COC=C(C#N)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1scc(-c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
3-Methoxy-2-phenylacrylonitrile (17.9 g, 112.5 mmol) was dissolved in NaOMe (5 M in MeOH, 31.5 ml, 157.5 mmol), and then methyl thioglycolate (16 ml, 180.0 mmol) was added thereto. The mixture was heated with stirring at 65° C. for 24 hr. After the completion of the reaction was confirmed by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was washed with distilled water and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure, and the concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 5.1 g (21.9 mmol, 26% yield in three steps) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=3)[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]2[N:8]=1
Reactant: O=c1[nH]cnc2c1CNCC2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A, 90 mg, 0.253 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (134 mg, 0.633 mmol), and N,N-diisopropylethylamine (98 mg, 0.757 mmol) in DMF (1.012 mL) was stirred at 100° C. for 90 min, then cooled to rt and maintained overnight. The mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a yellow solid (76.6 mg, 64%). 1H NMR (DMSO-d6) δ: 12.63 (br. s., 1H), 11.45 (s, 1H), 9.29 (s, 1H), 8.53-8.69 (m, 1H), 8.13 (s, 1H), 8.09 (dd, J=8.3, 0.8 Hz, 1H), 7.40 (s, 1H), 6.21 (s, 1H), 4.51 (s, 2H), 4.13 (t, J=5.7 Hz, 2H), 2.73 (s, 2H), 2.41 (s, 3H); ESI-MS: m/z 471.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[N:8]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:4]=[CH:5][C:6]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCOc1ccc(CN)nc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)nc1O

Procedure:
A mixture of 6-aminomethyl-3-propoxy-pyridin-2-ol (91 mg, 0.50 mmole), 7 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (165 mg, 0.50 mmole) is added and the reaction mixture stirred for 4 hours. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a beige solid, 152 mg, (63%);m.p. 275-81° C. dec; MS (ES +): m/z 478.1 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:10][N:11]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccccc1
Reactant: CNC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)C1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (642 μl, 3.67 mmol) was added to a mixture of N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D13 (177 mg), benzoic acid (93 mg, 0.765 mmol), HATU (349 mg, 0.918 mmol), aza-HOBt (62.5 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2551 μl). The mixture was stirred at room temperature during 2 h. Then the solvents were evaporated. The crude was finally purified via MDAP using a high pH method. Because of the NMR the solid was purified again using the High pH MDAP method. Fractions of each MDAP were combined and evaporated together to give a white solid of E30 in 51 mg. LCMS [M+H]+336.19@0.62 min (2 min run)