Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19](=[O:27])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19](=[O:27])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:41]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly yellow solid (31 mg, 45%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]([CH3:48])[C@@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][C@@H:43]([N:42]([CH3:48])[CH3:41])[CH2:44]3)=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CC[C@@H](N(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and (R)-3-dimethylamino-pyrrolidine are used as reactants.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]1[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]2[CH3:24])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 2.12 g, 0.02 mol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.0 g, 0.02 mol) in dichloromethane (200 mL) was added HOBt (1.77 g, 0.02 mol) and N-methyl morpholine (3.8 mL, 0.03 mol) and then the mixture was stirred for 1 h at room temperature. EDC HCl (3.98 g, 0.0208 mol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was added to 2N hydrochloric acid (200 mL). The organic layer was washed with sodium bicarbonate (200 mL), water (250 mL), and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to get methyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.3 g (72%) as white solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)[CH:11]=1
Reactant: Cn1ccnc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cn1ccnc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromo-1-methyl-1H-imidazole (Aldrich), the title compound was obtained as an off-white solid after purification by preparative HPLC.
Reaction SMILES: O.[OH-].[Na+].[S:4](Cl)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(O)(=[O:17])C>O1CCCC1>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]([S:4]([OH:17])(=[O:6])=[O:5])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84731.5 %

Procedure:
To water (288 mL), sodium hydroxide (180 g, 4.5 mol, 5.0 eq) was added. At 0° C., methanol-d3 (32.4 g, 900 mmol, 1.0 eq) was added, and the solution of tosyl chloride (206 g, 1.1 mmol, 1.2 eq) in tetrahydrofuran (288 mL) was dropwise added slowly. The mixture was warmed to room temperature and stirred overnight. The mixture was neutralized to neutral by dropwise adding acetic acid (206 g) at 25° C., filtered and partitioned. The aqueous phase was extracted with ethyl acetate (100 mL). The filter cake was dissolved in water (300 mL) and extracted with ethyl acetate (200 mL). The organic phases were combined and washed with saturated sodium carbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent in the filtrate was removed under reduced pressure to afford the title compound (160.5 g, purity 99%, yield 94%) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1)=[O:5].[Br:19]Br>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:10]1[CH:11]=[C:6]([C:4](=[O:5])[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])[CH:7]=[C:8]([CH2:13][CH3:14])[C:9]=1[OH:12]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)ccc1O
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1O
Reaction time: 48 h
Yield: 93 %

Procedure:
At ambient temperature, to a stirred solution containing 4-(2-chlorobenzoyl)-2-ethylphenol (13.62 g, 52.24 mmol) and pyridine (0.25 mL, 3.23 mmol) in CH2Cl2 (870 mL) was added dropwise bromine (3.3 mL, 62.29 mmol). After 48 h, the reaction was washed with 10% aq. Na2SO4 (1×180 mL), H2O (2×350 mL), brine (1×300 mL), dried (Na2SO4) and concentrated to give 16.50 g (93%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.S(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][S:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[O:38])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)CSc2ccccc2O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)CS(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 2-({2-[4-(2-tert-butyl-4-fluorophenoxy)piperidin-1-yl]-2-oxoethyl}sulfanyl)phenol (292 mg, 0.70 mmol) obtained in Example 239 and m-chloroperbenzoic acid (275 mg, 1.12 mmol) in ethyl acetate (14 mL) was stirred at 0° C. for 3 hr. Saturated aqueous sodium bisulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-20:80) to give 2-({2-[4-(2-tert-butyl-4-fluorophenoxy)piperidin-1-yl]-2-oxoethyl}sulfinyl)phenol (163 mg, 54%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:20]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
2-(Piperazin-1-yl)ethanol (1.000 g, 7.68 mmol) was dissolved in DCM (35.1 ml) and pyridine (0.932 ml, 11.52 mmol) followed by DMAP (0.094 g, 0.77 mmol) were added. tert-butylchlorodiphenylsilane (2.368 ml, 9.22 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to give the title product (2.73 g, yield: 96%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30].O>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:27][CH2:28][CH2:29][Cl:30])[N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Cs2CO3 (2.66 g, 8.2 mmol) was added to a solution of 1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.0 g, 5.4 mmol) in DMF (10 mL) and stirred for 15 min. 1-Bromo-3-chloropropane (1.28 g, 8.2 mmol) was added and stirred under N2 at room temperature for 36 h. Water (50 mL) was added to the reaction and stirred for 5 min. The product precipitated out. The aqueous portion was decanted and water was added to the residue and decanted again. The semisolid was taken up in CH2Cl2 and passed through a short plug of SiO2 (5% MeOH/EtOAc) to obtain 1.06 g (83%) of a pale yellow semisolid. MS (electrospray): exact mass calculated for C17H19Cl2N3O, 351.09; m/z found, 352.0 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.20 (t, J =6.2 Hz, 2H), 3.94 (t, J=5.8 Hz, 1H), 3.76 (t, J=5.8 Hz, 1H), 3.52 (q, J=6.1 Hz, 2H), 2.84 (t, J=5.5 Hz, 1H), 2.77 (t, J=5.6 Hz, 1H), 2.37 (sextet, J=6.1 Hz, 2 H), 2.21 (s, 1.5 H), 2.16 (s, 1.5 H).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:4]2[CH:3]=[C:2]([Br:1])[C:9]([CH3:10])=[CH:8][C:5]=2[C:6]#[N:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1cc(C#N)c(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(OC2CN(C(=O)OC(C)(C)C)C2)cc1Br
Yield: 75.3 %

Procedure:
Prepared according to Example 28 using 4-bromo-2-fluoro-5-methyl-benzonitrile (1.0 g, 4.7 mmol), 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 6.5 mmol), DMF (20 mL) and NaH (60% in mineral oil, 156 mg, 6.5 mmol) to provide the title compound (1.3 g, 74%). MS (ESI): mass calcd. for C16H19BrN2O3, 366.1; m/z found, 389.1 [M+Na]+. 1H NMR (CDCl3): 7.45 (s, 1H), 6.83 (s, 1H), 4.97-4.88 (m, 1H), 4.35 (ddd, J=9.8, 6.4, 0.9 Hz, 1H), 4.09 (dd, J=10.0, 3.9 Hz, 1H), 2.36 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OC(=O)C)(=O)[CH3:10]>>[CH3:9][C:10]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3,4-diaminopyridine (20.0 g, 183 mmol) and acetic anhydride (360 ml) was heated at 100° C. for 16 hours. The excess reagent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate:methanol, 3:1. The product was a brown solid, (15.5 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=2)[C:3]=1[Br:33].[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[C:3]=1[Br:33]
Reactant: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(Br)c(Oc2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude compound, methyl 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate from step E was dissolved in THF (5 mL) and LiOH (1N, 1 mL) was added. The mixture was stirred at room temperature overnight. The solvent was removed under vacuo, and the resulting residue was taken over with water and the pH value was adjusted to 5˜6. The solid was collected with filtration and purified with HPLC gave the product, 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetic acid. HPLC-MS tR=1.53 min (UV254 nm); Mass calculated for formula C23H16BrN5O3, 489.0, observed LCMS m/z 490.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
In a 3-neck 1 L round-bottom flask fitted with a condenser, nitrogen inlet, and 2 stoppers was added 2,6-dibromopyridine (15.3 g, 64.58 mmol), phenylboronic acid (7.87 g, 64.58 mmol), and potassium carbonate (17:85 g, 129.16 mmol) in 228 mL of dimethoxyethane and 150 mL of water. Nitrogen was bubbled directly into the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) was added (1.85 g, 1.60 mmol) and the reaction mixture was heated to reflux. The reaction was complete after 3 h of heating. It was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 2% ethyl acetate/hexanes followed by vacuum distillation using a Kugelrohr collecting product at 150° C. 5.2 g of product was obtained (34%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:22])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([Cl:22])[C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c(=O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 g, 4.64 mmol) and NCS (0.68 g, 5.10 mmol) in DMF (30 mL) was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1 N HCl solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 1.10 g (95%) of 4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([CH3:54])([CH3:53])[CH2:5][CH2:6][O:7][CH2:8][N:9]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[C:11]=1[Br:44].[CH2:55](Br)[CH:56]=[CH2:57]>CN(C=O)C.O>[CH2:57]([N:30]([C:12]1[C:11]([Br:44])=[C:10]([N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:3])([CH3:53])[CH3:54])[CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:50])[CH3:52])[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=4)=[C:14]2[N:13]=1)[CH:31]1[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]1)[CH:56]=[CH2:55]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NaH (60%, 40.2 mg, 1.00 mmol) was added in one portion to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate (205 mg, 0.25 mmol) in DMF (6 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0° C. and allyl bromide (60.8 mg, 0.50 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-(allyl(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carboxylate: LCMS tR=1.99 Min (5 min run, UV254nm), Mass calculated for M+855.3, observed LC/MS m/z 856.3 (M+H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:25]2[C:26]3=[C:27]4[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[C:18]4[CH:17]=[CH:16][C:15]3=[CH:14][CH:13]=1)=[O:5])C.[S:28](=[O:32])(=[O:31])([OH:30])O>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([S:28]([OH:32])(=[O:31])=[O:30])[C:15]2[CH:16]=[CH:17][C:18]3[C:27]4[C:26]=2[C:25]=1[CH:24]=[CH:23][C:22]=4[C:21]([S:28]([OH:30])(=[O:32])=[O:31])=[CH:20][C:19]=3[S:28]([OH:30])(=[O:32])=[O:31])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCCCNc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=S(=O)(O)O
Product: O=C(O)CCCCCNc1cc(S(=O)(=O)O)c2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)c4ccc1c2c43
Temperature: -30 °C
Reaction time: 5 h

Procedure:
1-(5-ethoxycarbonylpentyl)aminopyrene (1 g) was added in small portion to a stirred solution of 30% fuming sulfuric acid (8 mL) cooled to −30° C. After the addition, the solution was slowly warmed to room temperature and stirring continued at room temperature for 5 hours. The reaction mixture was poured over ice and the resulting precipitate was collected by suction filtration. The crude product was purified by HPLC on a C18 reverse phase column using triethylammonium acetate as the eluting buffer. The collected fractions containing the desired product were pooled and concentrated. The concentrate was acidified using HCl to precipitate out the product, which was then dried on a lyophilizer.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:3]=12.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1>O1CCCC1>[CH3:28][N:24]1[C:4]2=[N:5][CH:6]=[C:7]([C:8](=[O:9])[NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=3)=[O:12])[C:2]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:3]2[C:26]([CH3:27])=[N:25]1
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)c(Cl)c12
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2c(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)cnc3c2c(C)nn3C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl )-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide (40 mg) was dissolved in tetrahydrofuran (5.0 mL), ethyl piperidine-4-carboxylate (160 mg) was added, and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, the residue was suspended in water (10 mL), the resulting solid was filtered, washed with water, and dried under high vacuum to give ethyl 1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylate as a white powder.
Reaction SMILES: [OH-].[Li+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1>O.C1COCC1>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCC(=O)N2CCc3ccccc3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1ccc(CCC(=O)N2CCc3ccccc3C2)cc1
Yield: 89.1 %

Procedure:
Lithium hydroxide (14.4 mg, 0.6 mmol) dissolved in water (1 ml) was added into 70377 methyl 2-({4-[3-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]phenoxy}methyl)benzoate (129 mg, 0.3 mmol) in THF (2 ml). The mixture was put in a microwave oven (Smith Synthesizer) and irradiated at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜5, and extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99) as eluant gave 111 mg the desired product yield 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33](O)[CH2:32]1)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(/N=N/C(OCC)=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:33]4[CH2:34][CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN1CCCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN1CCCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)C1
Yield: 17 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-ethyl-3-hydroxypiperidine (775 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 nmol) were converted to product by the procedure of Example 11 to give 256 mg of the title compound. Yield: 17%. MS(FD) 501(M+). EA calculated for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 72.10; H, 6.47; N, 3.07.