Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:38])([S:34](F)(=[O:36])=[O:35])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27].C(OC)(C)(C)C>O>[F:29][C:26]([F:27])([F:28])[C:25]([F:30])([F:31])[C:24]([F:32])([F:33])[C:23]([F:38])([F:22])[S:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1)(=[O:35])=[O:36]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 16 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A 12 liter flask fitted with a mechanical stirrer, a constant addition funnel, a thermometer, and a reflux condenser was charged with of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (300 g, 1.05 mol), perfluorobutanesulfonyl fluoride (378 g, 1.25 mol), and tert-butylmethylether (3 L) under positive nitrogen pressure and was cooled with an ice bath to 16° C. 1,8-Diazobicyclo[5.4.0]undec-7-ene (180 g, 1.18 mol) was added to the resulting mixture over 25 minutes, while maintaining the temperature of the mixture below 20° C. After the addition was complete, the mixture was stirred at room temperature for 2 hours, and then 3 liters of water was added. The resulting aqueous phase was separated from the resulting organic phase, and the organic phase was washed with a mixture of 2.25 liters of water and 0.75 liters of concentrated HCl. The solvent was removed from the organic phase under reduced pressure to yield 697 g of crude product, which was recrystallized from ethanol to yield 4-(5-octyl pyrimidine-2-yl)phenyl nonafluorobutane sulfonate (499 g, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(Cl)nc1NCc1ccncc1
Reactant: NCCN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(NCCN2CCOCC2)nc1NCc1ccncc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and 2-morpholin-4-ylethylamine (300 μL) was stirred at 80° C. for 20 h. The reaction mixture was purified on silica gel chromatography to yield N-(3,4-dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+): 501 (M+H)+; (ES−): 499 (M−H)−. Calc'd for C24H26Cl2N6O2 500.15.
Reaction SMILES: [O:1]=[N+:2]=[O:3].F[B-](F)(F)F.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:26])[CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:26])[CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[C:17]([N+:2]([O-:3])=[O:1])[CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nitronium-tetrafluoroborate (2.14 g, 16.10 mmol) was dissolved in 40 mL aceonitrile, cooled to 0° C. and stirred for 15 min. A solution of N-(4-tert-Butyl-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 1, 2.0 g, 8.05 mmol) in 40 mL acetonitrile was added drop-wise over 10 min. The solution was stirred for 30 min at 0° C., warmed to RT, and stirred an additional 16 h. The reaction was extracted into EtOAc, washed twice with water, once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield a crude mixture that was purified by silica gel chromatography using a 10% MeOH/CH2Cl2 gradient to give the title compound as a brown oil. The correct regioisomer was determined to be the only product by H-NMR analysis. MS (M+H)+=294; Calc'd 293.40 for C16H27N3O2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[CH3:12])(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH3:12][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])[O:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1S(C)(=O)=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(Oc2ccc(Cl)c(Cl)c2)ccc1S(C)(=O)=O
Yield: 63.4 %

Procedure:
A slurry of 6.14 g of 4-chloro-2-methylphenyl methyl sulfone, 8.35 g of 3,4-dichlorophenol and 7.08 g of K2CO3 in 150 ml of sulfolane was heated at 170° C. for 7 hrs. The product (6.3 g, 63.4% yield) was isolated from the reaction mixture essentially as described in Example 18. Recrystallization from ethanol afforded purified 4-(3-methyl-4-(methylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 154°-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H][H]>C(O)C.O=[Pt]=O>[NH2:1][CH2:2][C:3]1([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Yield: 64.7 %

Procedure:
Tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (355 mg, 1.22 mmol) and 1.15 g PtO2 (5.1 mmol) in 125 ml ethanol were shaked in PARR apparatus under 60 psi of hydrogen for 20 hours. Celite was loaded on top of an ion exchange cartridge (MCX, Phenomenex, 6 g adsorbent). The crude reaction slurry was filtered through this set-up, the pyrophoric catalyst washed with ethanol and water and removed. The cartridge was washed with methanol and then the product eluted with a 2 M solution of NH3 in MeOH. The eluent was concentrated to give 234 mg of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]3([N:25]4[CH:29]=[N:28][C:27]([Cl:30])=[N:26]4)[CH2:24][CH2:23]3)[CH2:21][O:20]2)=[CH:15][CH:14]=1>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2([N:25]3[CH:29]=[N:28][C:27]([Cl:30])=[N:26]3)[CH2:24][CH2:23]2)([OH:20])[CH2:21][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 44.3 %

Procedure:
15.6 g (0.276 mol) of 1,2,4-triazole and 1.7 g (0.015 mol) of potassium tert. butoxide are initially introduced into 40 ml of abs. dimethylformamide and 21 g (0.071 mol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in 30 ml of absolute dimethylformamide are added dropwise at 80° C. The mixture is allowed to react at 100° C. for 6 hours and the solvent is then evaporated in vacuo. The residue is taken up in ethyl acetate/toluene, the solution is washed with water and dried over sodium sulphate, and the solvent is stripped off in vacuo. Chromatography on silica gel (eluent dichloromethane/ethanol =98/2) yields 11.5 g of the title compound of m.p. 156° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][C:34](B(O)O)=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[O:15])[C:5]4[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=4[N:7]=3)=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: OB(O)c1ccc2[nH]nnc2c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]nnc4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 1H-1,2,3-benzotriazol-5-ylboronic acid (39.7 mg, 0.243 mmol), DMSO(2 mL), sodium carbonate (0.281 mL, 0.562 mmol) and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 22 mg (26%). LCMS E-S (M+H)=457.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, 6 J=6.4 Hz, H), 2.14 (s, 3 H), 2.24 (s, 3 H), 4.43 (d, J=4.3 Hz, 2 H), 5.31-5.46 (m, 1 H), 5.91 (s, 1 H), 8.07 (br. s., 1 H), 8.34 (s, 1 H), 8.41 (m, 2 H), 8.85 (br. s., 1 H), 9.02 (br. s., 1 H), 11.59 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccn(CC3CCCO3)c12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (200 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=2[O-])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.NCCO>C(#N)C>[NH2:22][C:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: NCCO
Solvent: CC#N
Product: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (29.8 g, 104 mmol) was dissolved in a mixture of acetonitrile (662 mL) and pyridine (33.8 mL, 418 mmol) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (pTsCl, 25.9 g, 136 mmol) was added and the reaction mixture was heated at 75° C. for 5 hours. 2-Aminoethanol (166 mL, 2.75 mol) was added after allowing the reaction mixture to cool to room temperature. After one hour, the acetonitrile was evaporated and the crude product was partitioned between ethyl acetate and a saturated aqueous solution of sodium chloride. The layers were separated and the organic layer was evaporated to dryness and then purified on 1.5 kg of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (15.2 g, 51%) as a white solid. ESI-MS m/z calc. 284.1, found 285.2 (M+1)+. Retention time 1.16 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.99-7.98 (m, 1H), 7.90-7.87 (m, 1H) 7.72-7.7.69 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 6.42 (d, J=8.3 Hz, 1H), 5.83 (s, 2H), 2.11 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(OC(=O)C)(=O)C>>[C:30]([O:34][C:35](=[O:36])[NH:37][CH2:38][C:39]([N:25]1[CH2:26][CH2:27][CH:23]([N:6]2[C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]2)[CH2:24]1)=[O:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
(2-{3-[5-Chloro-2-(3-methanesulfonyl-pyrazolo[3,4-c]pyridin-1-ylmethyl)-benzoimidazol-1-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester was prepared in analogy to Example 2-16 by using 1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-(tert-butoxycarbonylamino)acetic acid (14 mg) instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride, MS obsd. (ESI+) [(M+H)+] 588.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccoc2cc(OCCCCl)ccc12

Procedure:
A mixture of 7-hydroxy-4H-1-benzopyran-4-one, VII (40.5 g; 0.25 mole; prepared according to G. N. Dorafeenko and V. V. Tkachenko, Chem. Heterocyclic Compounds, 1972 (8) 935), 1-bromo-3-chloropropane (78.5 g; 0.50 mole) and anhydrous potassium carbonate (49 g; 0.50 mole) in 1000 ml of acetone was heated at reflux for 16 hours. The mixture was filtered through celite and concentrated in vacuo. The thick red oil which remained was triturated with ether, upon which 57.8 g (97%) of the title compound was obtained, mp 72°-73° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:9]=[C:10]2[NH:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:5][CH:4]=1.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([Cl:2])[CH:12]=3)[CH:7]=[C:8]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:9]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(N[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a mixture of (S)-3-(7-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (120 mg) in DCM (8 mL) was added 2,6-dimethylpyridine (105 mg, 0.978 mmol). The resulting mixture was cooled to −78° C. and acryloyl chloride (48 mg, 0.530 mmol, 10 mg/mL in dry DCM) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (22 mg, 18% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H), 11.72 (s, 1H), 8.51 (S, 1H), 7.88 (m, 1H), 7.60-7.70 (m, 2H), 7.56 (d, 1H, J=4.0 Hz), 6.55-6.57 (m, 1H), 6.13-6.19 (m, 1H), 5.63-5.70 (m, 1H), 5.17-5.18 (m, 1H), 3.65-4.17 (m, 4H), 2.01-2.37 (m, 2H); ESI-MS m/z [M+H]+ 385.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][Si](C)(C)C)[CH:15]=3)[C:10]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]indazole-3-carboxamide (250 mg, 0.66 mmol) in methanol (5 mL) and DCM (10 mL) was added K2CO3(182.57 mg, 1.32 mmol). The reaction mixture was stirred for 1 hr and then filtered by suction filtration. The precipitate was washed with DCM and methanol and the filtrate was concentrated in vacuo to give the title intermediate: 1H NMR (250 MHz, DMSO) delta 3.08 (3H, s), 3.29 (3H, br. s.), 4.42 (1H, s), 7.06 (1H, d, J=5.63 Hz), 7.14 (2H, br. s.), 7.41-7.48 (1H, m), 7.97 (1H, d, J=8.22 Hz), 8.31 (1H, d, J=5.48 Hz), 9.04 (1H, s); LC-MS: m/z=+307.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([F:8])[CH:7]=1.O.[NH2:11][NH2:12]>C(O)CC>[NH:11]([C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)[NH2:12]
Reactant: NN
Reactant: Fc1cc(Cl)cnc1F
Solvent: O
Solvent: CCCO
Product: NNc1ncc(Cl)cc1F

Procedure:
7.5 g of the compound obtained in Step 3 and 9.57 ml of hydrazine monohydrate were added to 50 ml of n-propanol, the resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The resulting residue was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 7.26 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O-:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].S(C1C=CC(C)=CC=1)(O[CH2:24][C@@H:25]1[O:27][CH2:26]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:24][C@H:25]1[CH2:26][O:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc([O-])c(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A 30 L jacketed reactor is charged with potassium 2-(benzyloxy)-4-nitrophenolate (1.31 kg, 4.62 mol), (R)-glycidyl tosylate (1.13 kg, 4.96 mol) and DMF (6.5 L). The resulting suspension is heated until an internal temperature of 65° C. is obtained, and is then stirred for 18 h. The solution is cooled to 20° C., and then water (2 L) is added over 30 min. The solution is seeded with 2 g of the desired product, and the addition of water is resumed (9 L over 1.25 h). The slurry is stirred for 2.5 h, and then collected by vacuum filtration. The reactor and filter cake are washed with water (5 L total) and suction dried to give the title compound (1370 g, 98%) as an off-white powder. LCMS (Standard Method): 2.74 min, 302 (M+H)−. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[CH:21]([O:23][CH:24](C)Cl)C>C(Cl)Cl>[Cl:1][C:2]1[C:9]([O:10][CH2:21][O:23][CH3:24])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)c(O)c1
Reactant: CC(Cl)OC(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C#N)cnc1Cl
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol) in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol) followed by the addition of chloro-methyl methylether (0.66 mL, 8.69 mmol) slowly at 0° C. After overnight at room temperature, the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (0.68 g, 50%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 5.42 (s, 2H), 3.40 (s, 3H); MS (ES) m/z: 199 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([N:9]([C:17](=[O:22])[C:18](OC)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1([CH3:8])[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:18](=[O:19])[C:17](=[O:22])[N:9]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(C)(C)N(Cc1ccccc1)C(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)C(=O)N(Cc2ccccc2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl 3-methyl-3-[[(methyloxy)(oxo)acetyl](phenylmethyl)amino]butanoate (6.9702 g, 22.68 mmol) in toluene (110 mL) was added 25% w/w NaOMe in MeOH (14 mL). The mixture was heated at 80° C. and stirred for 2 h. The solution was then cooled to room temperature and concentrated in vacuo to ca. ½ volume. The residue was partitioned between DCM (200 mL) and 1 N aq. HCl (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting white solid was triturated with hexanes and collected by vacuum filtration to afford methyl 2,2-dimethyl-4,5-dioxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (5.5965 g, 88%) as a white solid. LCMS: (M+H)+: 276.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](=O)=O.C(Cl)(Cl)Cl>CI>[OH:8][C:7]1[C:2](=[O:1])[N:3]([CH3:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccnc1O
Reactant: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-Dihydroxypyridine (5.55 g) is suspended in methyl iodide (20 ml) in a sealed tube and heated for 24 hours at 140° C. The reaction is taken to be complete when a dark brown residue forms as a separate phase from the methyl iodide and the tube is then cooled in solid carbon dioxide and opened. The excess methyl iodide is poured off, distilled water (10 ml) is added to the brown residue, and sulphur dioxide gas is bubbled through the mixture until the aqueous phase becomes clear. The pH of the reaction mixture is adjusted to a value of 6 with 1M aqueous sodium carbonate and the resulting solution then saturated with ammonium sulphate and extracted with chloroform until the chloroform layer no longer gives a blue colouration when added to ferric chloride solution. The chloroform extracts are combined and dried over sodium sulphate. The solvent is then evaporated under vacuum and the resulting residue is crystallised from petroleum ether (b.p. 100°-120° C.) using activated charcoal to give 3-hydroxy-1-methylpyrid-2-one, m.p. 129°-131° C.; νmax (nujol) 1,660, 3,100 cm-1 ; δ(d6DMSO) 3.6(s,3H), 6.1(t,1H), 6.8(m,2H), 7.3(s,1H); M+ 125.