Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([N:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:18][C@@H:19]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.C(O)(=O)C>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([N:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:18][C@@H:19]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1N
Reaction time: 1 h

Procedure:
The above mentioned tert-butyl (S)-1-(5-(3-(methylamino)-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (1.13 g, 2 mmol) was dissolved in 200 mL MeOH in a 500 mL round bottle flask. To this flask, was added 10% Pd/C 100 mg pre-wet with water and 2 mL acetic acid. The mixture was stirred under an atmosphere of hydrogen under balloon pressure for 1 hour. After filtration through a pad of celite, the solution was evaporated to dryness. The residue was re-dissolved in 200 mL of EtOAc. The solution was washed with saturated sodium bicarbonate three times and dried over sodium sulfate. The product was obtained after removing the solvent. It was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[O:26])[CH2:23][CH2:22]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[C:5]4[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:23][CH2:22]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)CC2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CS(=O)(=O)CC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine 6,6 dioxide (160 mg, 0.5 mmol) in DME/H2O (4:1, 10 mL) were added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (167 mg, 0.55 mmol) and Na2CO3 (159 mg, 1.5 mmol) followed by PdCl2(dppf) (20 mg, 0.025 mmol). The resulting mixture was heated to 70° C. and stirred overnight under nitrogen. The solvent was removed under vacuum to give a residue which was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 filtered and the solvent removed to give a crude product which was purified by preparative TLC (DCM/MeOH=20/1) to give the desired product as a yellow solid (36 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].CC1(C)[O:18][C:17](=O)[CH:16]=[C:15]([CH3:20])[O:14]1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:17](=[O:18])[CH2:16][C:15](=[O:14])[CH3:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1N
Reactant: CC1=CC(=O)OC(C)(C)O1
Product: COC(=O)c1nccnc1NC(=O)CC(C)=O

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (12 g) and 2,2,6-trimethyl-[1,3]dioxin-4-one (15.6 ml) were heated to reflux for 6 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 4:1, then ethyl acetate) to give 3-(3-oxo-butyrylamino)-pyrazine-2-carboxylic acid methyl ester as a beige solid (15 g). 1H-NMR (400 MHz, CDCl3): 2.33 (s, 3H), 3.91 (s, 2H), 4.05 (s, 3H), 8.40 (d, 1H), 8.51 (d, 1H), 10.06 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:28])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.10 mL, 1.5 mmol) and 1-methyl piperazine (0.15 mL, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulted solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1). The resulting material was further purified by preparative HPLC (NH4OAc/CH3CN) to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(4-methylpiperazin-1-yl)carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (94) (0.085 g, 34%) as a white solid. 1H NMR (CDCl3): δ 7.29 (d, 1H), 6.77 (d, 1H), 3.62-3.20 (m, 5H), 2.70-2.00 (m, 10H), 1.78-1.24 (m, 10H), 1.20-1.00 (m, 2H), 0.99-0.92 (m, 4H), 0.88 (s, 3H), 0.82 (s, 3H). MS m/z 489 (C27H40N2O4S+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=O.Cl.[NH2:17][OH:18].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:17][OH:18]
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C=O)c1=O
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](C)n1ccc(Cl)c(C=NO)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (31.8 g) in 2-propanol (300 mL) were added hydroxylamine hydrochloride (14.6 g) and conc. hydrochloric acid (0.43 mL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was crystallized from (2-propanol/diisopropyl ether), and the resulting solid was collected by filtration, and washed with 2-propanol/diisopropyl ether to give the title compound (23.2 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:26]([F:29])([F:28])[F:27])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:5])C.C1COCC1.CCO.O.O[Li].O.Cl>O>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:11]=1)[O:8][CH:7]([C:26]([F:28])([F:29])[F:27])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To 0.440 g (1.036 mmole) of ethyl-6-Chloro-8-[(3-fluorophenyl)ethynyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 5.2 mL of a solvent mixture of THF/EtOH/H2O (7:2:1) followed by 65 mg (1.55 mmole) of LiOH—H2O. The mixture was stirred at 60° C. for two hours. The mixture was concd, diluted with water and acidified with 0.5N HCl. The crude material was purified using reverse phase chromatography to afford 0.387 g (94%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 5.79 (q, 1H, J=6.4 Hz), 7.04-7.09 (m, 1H), 7.21-7.23 (m, 2H), 7.31-7.33 (m, 2H), 7.50 (d, 1H, J=2.4 Hz), 7.84 (s, 1H); MS (ES+) 397 (M+1, 100); HRMS (ES−) m/z calcd for (C19H9O3ClF4) 395.0093, found 395.0092.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[I:32][C:33]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:34]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[I:32][C:33]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:34]=1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)=[O:7]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2I)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of rac-3-Methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example D, 95 mg, 0.27 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred at room temperature for 30 min. After such time the reaction mixture was concentrated in vacuo, and the residue was dissolved in dimethylformamide (3 ml). To the solution were added 2-Iodo-5-methanesulfonyl-benzoic acid (Example C, 81 mg, 0.25 mmol), N-ethyldiisopropylamine (0.29 ml, 1.7 mmol), and TBTU (99 mg, 0.3 mmol). The reaction mixture was then allowed to stir at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2, 20 g, Heptane/EtOAc 0-100%) to give the title compound as a light brown solid (135 mg); MS (m/e): 553.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1.[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35].CC1C(CSC2NC3C=CC=CC=3N=2)=NC=CC=1SCCN1CCOCC1>>[CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[N:24]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2ccccc2[nH]1
Agent: Cc1c(SCCN2CCOCC2)ccnc1CSc1nc2ccccc2[nH]1
Product: CCOC(=O)n1c(SCc2nccc(SCCN3CCc4ccccc4C3)c2C)nc2ccccc21

Procedure:
The same reaction as in Example 17 was carried out except that 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole was reacted with ethyl chlorocarbonate, in place of 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole, to give ethyl 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole-1-carboxylate 1/2 ·ethanol as crystals, melting point 134°-136° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].Cl[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>>[F:1][C:2]1[C:7]([O:8][CH2:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: COc1ccc2nc(CCl)sc2c1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Product: COc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 19 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2-(chloromethyl)-6-methoxy-1,3-benzothiazole according to Method B, scheme 2. Yield 19%, mp 190-192° C., HPLC-MS (method 1): m/z 351 [M+H]+, Rt=3.50 min.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][I:13].[Li+].[OH-].Cl>C1COCC1.O.CCOCC>[I:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:14])=[O:2]
Reactant: COC(=O)CCCCCCCC=CI
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCCC=CI
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of this 10-iodo-9-decenoate methyl ester (51.0 mg, 0.164 mmol, 1.0 eq.) in THF:H2O 3:1 (3.3 mL) was added LiOH (69.0 mg, 1.64 mmol, 10.0 eq.). The reaction was stirred at 50° C. for 4 h before diluting with Et2O (5 mL) and pouring into 1 M aqueous HCl (5 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash chromatography (hexanes:EtOAc 5:1→EtOAc) provided 95 as a pale yellow solid (44.0 mg, 0.149 mmol, 91%). 1H NMR indicated an E:Z ratio of 10:1.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[O:13]=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[C:15]([C:14](=[O:13])[CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(C)=O

Procedure:
3 g (18.61 mmol) of 4-formyl-3-methoxybenzonitrile, 2.6 ml (20.47 mmol) of ethyl 3-oxobutanoate, 1.33 ml (23.26 mmol) of acetic acid and 0.18 ml (1.85 mmol) of piperidine are stirred in 70 ml of dry dichloromethane under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 5.01 g (98% of theory) of the title compound are obtained as E/Z isomer mixture in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH3:21])=[CH:10][CH:11]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl.CCOC(C)=O>[ClH:1].[CH2:18]([C:16]1[C:15](=[O:20])[NH:14][C:13]([CH3:21])=[C:12]([C:9]2[S:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:11][CH:10]=2)[CH:17]=1)[CH3:19]
Reactant: CCc1cc(-c2ccc(CNC(=O)CCl)s2)c(C)[nH]c1=O
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(CNC(=O)CN3CCCC3)s2)c(C)[nH]c1=O
Yield: 33 %

Procedure:
To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:21])[CH3:20].C(OC(=O)C)C.O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8 mmol of 6-Amino-nicotinonitrile were dissolved in THF. 2 eq of DIPEA were added. The reaction mixture was cooled to 0° C. and 1.0 eq of acetylchloride in THF added dropwise and the reaction stirred for 2 h. The product was isolated by extraction from ethylacetate/water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([OH:12])[C:3]=12.[F:13][C:14]([F:25])([F:24])[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>N1C=CC=CC=1>[OH:8][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[C:11]([O:12][C:21]([N:18]3[CH2:17][CH2:16][CH:15]([C:14]([F:24])([F:13])[F:25])[CH2:20][CH2:19]3)=[O:22])[C:3]2=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)nc2[nH]nc(O)c12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(O)nc2[nH]nc(OC(=O)N3CCC(C(F)(F)F)CC3)c12
Reaction time: 2 h

Procedure:
4-Methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diol (1 g, 6.05 mmol), 4-trifluoromethyl-piperidine-1-carbonyl chloride (1.436 g, 6.6 mmol) and triethylamine (1.68 ml, 12.11 mmol) were stirred in 25 ml of pyridine at room temp for 1 h. Addition of 0.5 ml of triethylamine was followed by stirring for 2 h, concentration and addition of ethyl acetate and water. The resulting precipitate was filtered off with suction and dried. Yield: 765 mg (37%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 96 mg (5%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. M+H+: 345.13; 102 mg (3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl ester, M+H+: 524.20; 106 mg (3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-yl ester, M+H+: 524.52; 54 mg (1.3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-6-yl ester, M+H+: 703.36.
Reaction SMILES: [CH3:1][C:2](=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.[Br:19][C:20]1[C:21](Cl)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]>CC#N.CCOCC>[Br:19][C:20]1[C:21]([N:7]2[CH2:8][CH2:9][C:4](=[C:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]2)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]
Reactant: CC(C)=C1CCNCC1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=C1CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
To a solution of 4-(propan-2-ylidene)piperidine (500 mg, 3.99 mmol) and DIEA (2.1 mL, 11.98 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.48 g, 3.99 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to an 80 g ISCO silica gel cartridge and gradient eluted (0-35% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 1.04 g (61.8%). 1H NMR (500 MHz, DMSO-d6) δ 5.09-5.04 (m, 1H), 3.50-3.48 (br. s, 2H), 3.03 (br. s, 2H), 2.60 (s, 3H), 2.30 (s, 3H), 2.23 (br. s, 4), 1.64 (s, 6H), 1.25 (d, J=6.2 Hz, 6H). UPLC (M+H)=425.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[NH:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:16][C:15]=3[CH2:14]2)=[O:12])=[CH:5][C:4]=1[F:32].[CH3:33][C:34](OC(C)=O)=[O:35].C(Cl)Cl>O>[C:34]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([F:32])[CH:5]=1)[NH:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:25])[CH3:26])=[N:16][C:15]=2[CH2:14]1)=[O:12])(=[O:35])[CH3:33]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCCN1)CC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1

Procedure:
A solution of 83 and Ac2O (6.45 μL, 0.0683 mmol), TEA (25.9 μL, 0.186 mmol) and DCM (5 mL) was stirred for 1 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 0.020 g (65.9%) of I-87: MS m/z (APCI-pos) M+1=489.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:17])[C:10]([NH:14][CH2:15][CH3:16])=[C:11](I)[CH:12]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:19][C:20]1[C:21](B(O)O)=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.N12CCCN=C1CCCCC2.CN1CCCC1=O>CCOC(C)=O.[Cl-].[NH4+].O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:17])[C:10]([NH:14][CH2:15][CH3:16])=[C:11]([C:21]3[C:20]([CH3:19])=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[N:26]4)[CH:12]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: CCNc1c(N)cc(-c2c(C)noc2C)cc1I
Reactant: Cc1ccc2ncccc2c1B(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCNc1c(N)cc(-c2c(C)noc2C)cc1-c1c(C)ccc2ncccc12
Temperature: 110 °C
Reaction time: 0.03 h

Procedure:
4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-iodobenzene-1,2-diamine (105 mg, 0.29 mmol), 6-methylquinolin-5-ylboronic acid (274.86 mg, 1.47 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.26 mL, 1.76 mmol), 1-Methyl-2-pyrrolidinone (5 mL), and water (2 mL) were placed in microwave vial, pre-stirred for 2 minutes, then heated to 110° C. for 15 minutes. Reaction mixture was diluted with EtOAc and aqueous ammonium chloride and extracted with EtOAc (3 times). Organics were washed with ammonium chloride, water and brine and dried over sodium sulfate. Solvent was evaporated to dryness. Crude material was purified by silica gel chromatography (DCM/MeOH as eluent) to afford 4-(3,5-dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine.