Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4])(=[O:13])[CH3:12]
Reactant: NC(C(=O)O)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C(=O)O)C1CC1
Reaction time: 0.75 h
Yield: 8.9 %

Procedure:
DL-α-aminocyclopropyl acetic acid (29.4 g.) was added with stirring to a solution of sodium hydroxide (20.9 g.) in distilled water (140 ml.). The solution became homogeneous, was cooled to ca. 5° and acetic anhydride (53 g.) was added dropwise over a period of 1.5. hr. whilst maintaining the temperature below 20°. The pH of the solution was adjusted to 3.0 after stirring for a further 0.75 hr., and was then extracted with chloroform: n-propanol, 3:1 (7×100 ml.) and the combined extracts evaporated down to give a white solid which was dried in vacuo over fresh phosphorus pentoxide. Freeze-drying of the aqueous layer and similar work-up to the above gave further product (total yield 26.0 g., 65%). A sample of the solid was recrystallised from chloroform:n-propanol:ether to give crystals of DL-α-acetamidocyclopropyl acetic acid [m.p 150°-154°, found C, 53.2; H. 7.0; N,8.7; C7H11NO3 requires C, 53.5; H, 7.0; N, 8.9 %. νmax (KBr) 3340 (NH), 1720 (CO2H) 1600 and 1550 (amide I and II) cm-1, τ](CD3)2SO]-0.46 (H, broad, CO2H), 1.87 (H,d, 6.9 Hz., NH), 6.32 (H,t, 8.0 Hz., side-chain CH), 8.18 (3H,s,methyl), 8.95 (H, broad, ring methine), 9.65 (4H, broad, complex, ring methylenes)].
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=3[CH:32]=2)[C:11]=1[CH3:12])[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.C1COCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:9]=[C:4]([CH:3]=[CH:2][C:11]=4[CH3:12])[C:5]([OH:7])=[O:6])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:22][CH:23]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)cc(F)c3C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (0.3 g, 0.68 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then cooled in an ice-water bath. It was acidified slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.2 g (60%). 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 2.82-2.84 (d, 3H, J=4.6 Hz), 7.39-7.43 (m, 3H,), 7.61 (s, 1H), 7.66-7.70 (d, 1H, J=8.6 Hz), 7.66-7.70 (m, 1H), 7.78-7.80 (d, 1H, J=8.5 Hz), 8.01-8.03 (m, 2H), 8.49-8.51 (d, 1H, J=4.76 Hz), 13.2 (s, 1H). LCMS: (ES−) m/z=420.0 (M−H) Chromolith SpeedROD C18 (4.6×3.0 mm-5.0 μm) Mphase A: 10% CH3OH-90% H2O-0.1% TFA Mphase B: 90% CH3OH-10% H2O-0.1% TFA.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:19][CH3:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:21])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:21])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([O:19][CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: CON(Cc1ccc(C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)cc1)OC
Yield: 69 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methylbenzyl)-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-D to give the title ester as white crystals (69% yield); mp 83–84° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.59 (3H, s, CH3), 3.94 (3H, s, OCH3), 4.15 (3H, s, OCH3), 5.05 (2H, s, NCH2), 6.72 (1H, s, CH), 7.41 (2H, d, J=8.1 Hz, aromatics), 7.47 (2H, d, J=8.1 Hz, aromatics), 13.75 (1H, broad s, OH). Anal. calcd for C14H17NO5: C, 60.20; H, 6.13; N, 5.01. Found: C, 60.24; H, 6.09; N, 4.85.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[O:14])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[C:18]([C:34]([F:37])([F:36])[F:35])[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26](/[CH:30]=[C:11]4/[C:12](=[O:13])[N:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[C:9](=[O:14])[S:10]/4)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[C:18]([C:34]([F:35])([F:37])[F:36])[CH:17]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CN1CCN(N2C(=O)CSC2=O)CC1
Product: CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(4-methylpiperazin-1-yl)-1,3-thiazolidine-2,4-dione was prepared from 3-(4-methyl-piperazin-1-yl)-thiazolidine-2,4-dione and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure E.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CC(C)([O-])C.[K+].Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=1>C(O)(C)(C)C>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:28][N:27]=1)[CH3:31]
Reactant: CCOc1ccc(CCl)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.58 g, 3.0 mmol, Aldrich, Cat. 525057) in tert-butyl alcohol (5.0 mL) was added a solution of potassium tert-butoxide in tert-butyl alcohol (5.0 mL, 5.0 mmol, 1.00 M, Aldrich Cat. 331341). The reaction mixture was stirred at r.t. for 10 minutes followed by an addition of 5-(chloromethyl)-2-ethoxypyridine (0.54062 g, 3.15 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction mixture was cooled to r.t., quenched with aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with water and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 20% ethyl acetate in methylene chloride as eluent to afford the desired compound. LCMS (M+H)+: m/z=330.4.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18].C([N-]C(C)C)(C)C.[Li+].Br[CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].Cl>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[C:15]([CH:16]([CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]1=[O:45])[C:17]([OH:19])=[O:18])([F:21])[F:20]
Reactant: O=C(O)CC(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCN1C(=O)c2ccccc2C1=O)C(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 1) in tetrahydrofuran cooled to -78° C. is added dropwise two equivalents of lithium diisopropylamide. The solution is stirred for 30 minutes at -78° C. followed by the dropwise addition of a solution of N-(3-bromopropyl)phthalimide (1 equivalent) in tetrahydrofuran. The reaction mixture gradually warms to 0° C., at which time aqueous hydrochloric acid (HCl) (1 M) is added. The product is partitioned between ethyl acetate and water, the layers separated, and the organic portion is washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product is purified using silica gel chromatography (elution with chloroform/methanol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=2)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:20][N:19]=[C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:17]=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:43]([N:24]1[CH2:25][CH2:26][CH:21]([C:18]2[N:17]=[C:16]([NH:15][C:14]3[N:13]=[CH:12][C:11]([O:27][C:28]4[CH:29]=[CH:30][C:31]([CH:32]=[O:33])=[CH:34][CH:35]=4)=[CH:10][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[S:20][N:19]=2)[CH2:22][CH2:23]1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(Oc2cnc(Nc3nc(C4CCNCC4)ns3)c(Sc3ccccc3Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
4-(5-(2-chlorophenylthio)-6-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)benzaldehyde (154 mg, 0.294 mmol) was dissolved in methylene chloride (3 mL) and triethylamine (81.9 μL, 0.588 mmol) and acetic anhydride (33.3 μL, 0.353 mmol) were added. After stirring for 20 minutes, the reaction was poured into saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was concentrated to afford 4-(6-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-chlorophenylthio)pyridin-3-yloxy)benzaldehyde (161 mg, 0.284 mmol, 96.8% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:39]=[CH2:40])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([CH2:31][N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:39][CH3:40])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[C:23]([CH2:31][N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1
Yield: 32.5 %

Procedure:
In 3 mL of methanol, 20 mg (0.1 mmol) of 1-[4-(6-amino-8-vinylpurin-9-yl)phenyl]-3-[3-(4-methylpiperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]urea was dissolved, and 10 mg of 10% palladium carbon was added thereto, and the mixture solution was refluxed with stirring in a hydrogen atmosphere for one hour. The palladium carbon was removed by filtration and the reaction solution was concentrated under reduced pressure, and the obtained crude product was triturated with diethyl ether to obtain 18 mg (90%) of a target product as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O)(=O)C>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:33])=[N:18][N:17]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(ccn2Cc2ccccc2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3c(ccn3Cc3ccccc3)n12
Yield: 65 %

Procedure:
di-tert-Butyl 1-(1-benzyl-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (31 mg, 0.071 mmol, from Step 2) in acetic acid (4.0 mL) was heated in the microwave to 180° C. for 5 minutes. The solvent was removed in vacuo and the mixture was reconstituted in MeOH and purified using preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) and the eluent was frozen and lyophilized to afford a white powder (12 mg, 65%).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][CH3:19])=[O:5].[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH3:19][O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4](=[O:5])[CH3:21]
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCc1nc(-c2ccccc2)sc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methoxy-methyl amide (6.706 g, 22.9 mmole, 1.0 eq) in dry THF (25 ml) at 0° C. was added dropwise a solution of 1.4M methylmagnesium bromide in (3:1)toluene-THF (32.7 ml, 45.8 mmole, 2.0 eq). The resulting tan suspension was stirred under nitrogen at room temperature for 30 minutes, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography using a gradient elution of (9:1) to (4:1) hexanes-ethyl acetate provided the title compound (6.033 g, 81%) as a yellow crystalline solid. 1H NMR (CDCl3): δ 2.7 (s, 3H), 3.5 (s, 3H), 4.9 (s, 2H) 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CCCCC2)c(C)c1
Yield: 95.2 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Step A (5.00 g, 18.1 mmol) and cyclohex-1-en-1-yl trifluoromethanesulfonate (4.58 g, 19.9 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane, afforded the title compound (3.97 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([Br:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[Br:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][N:13]=[CH:12]3)[S:3][CH:4]=1
Reactant: COC(=O)c1c(Br)csc1N
Reactant: O=C(O)Cc1cccc2cnccc12
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12

Procedure:
This compound was prepared from methyl 2-amino-4-bromothiophene-3-carboxylate and 2-(isoquinolin-5-yl)acetic acid using protocol A. Method[1], MS(ESI) 404.9 [M+H], Retention time=1.678 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[CH3:14][NH2:15]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH3:14])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CN
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Product: CNC(=O)c1ccc(N)c(OC)c1

Procedure:
4-Amino-3-methoxy-N-methylbenzamide was prepared by the procedure described in Example 7 using 4-amino-3-methoxybenzoic acid and methylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](OC(C3C=CC=CC=3)C)=[N:8][C:7]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[N:6][C:5]=2[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:9]1[C:10]2[C:2]([Cl:1])=[CH:3][NH:4][C:5]=2[N:6]=[C:7]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(Oc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12)c1ccccc1
Product: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Temperature: 70 °C
Yield: 22 %

Procedure:
5-chloro-N-(1-methyl-1H-pyrazol-4-yl)-4-(1-phenylethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (1.65 g, 4.47 mmol) was suspended in POCl3 (9 mL) and the reaction was heated to 70° C. for 40 min, then further heated to 100° C. for 0.5 hr. The reaction mixture was cooled, concentrated in vacuo and diluted with water (50 mL). NH4OH was added to adjusted the pH 8 and the mixture was extracted with EtOAc (three×75 mL), and concentrated under reduced pressure. A precipitate was formed upon concentrating that was filtered off, and the filtrate was concentrated and the resulting residue was purified by flash chromatography eluting with a gradient of 30% 100% EtOAc in heptanes to afford the title compound (282 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br. s., 1H) 9.58 (br. s., 1H) 7.87 (s, 1H) 7.52 (s, 1H) 7.37 (s, 1H) 3.81 (s, 3H). m/z (APCI+) for C10H8Cl2N6 283.15 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:35])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (173 mg, 0.39 mmol) in CH2Cl2 (5 ml) was added mCPBA (142 mg, ˜0.59 mmol). The reaction was stirred at room temperature for 1 hour, and was directly loaded on Celite, purified by flash column chromatography on silica gel (30-70% EtOAc in hexane) to yield the title compound (40 mg, 22%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[CH3:1][C:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)c1ccsc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)Cl)c1ccsc1
Reaction time: 0.5 h

Procedure:
The 2-methyl-2-(3-thienyl)propionic acid (34.0 g); obtained in Example 8, was dissolved in chloroform (60 ml) and to this solution was added thionyl chloride (31.0 g), followed by a 30 minute-refluxing under heating. After the reaction, the solvent and remaining thionyl chloride was removed under reduced pressure. The remaining crude product was distilled under reduced pressure to obtain 2-methyl-2-(3-thienyl) propionic acid chloride with bp 86°-88° C./2.Otorr.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC=C(N2CCCC2)CC1

Procedure:
A 50 mL round-bottomed flask containing 4-tert-butylcyclohexanone (6.01 gm) in anhydrous toluene (20 mL) was fitted with a Dean-Stark trap containing 3 A molecular sieves, reflux condenser and a heating mantle. Pyrrolidine (6.00 mL) was added, and the solution heated to reflux for 18 hr. The solvent was evaporated and the crude product was used directly for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17]CC2C=CC=CC=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Yield: 92.5 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (15.0 g, 32.1459 mmol) was dissolved in methanol (200 ml), added to a methanolic suspension (200 ml) of 10% palladium-carbon (1.0 g) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (11.2 g, 29.7340 mmol, 92%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]5[N:29](CC6C=CC(OC)=CC=6)[N:30]=[C:31]([C:32]6[CH:37]=[CH:36][C:35]([C:38]([N:40]7[CH2:45][CH2:44][O:43][CH2:42][CH2:41]7)=[O:39])=[CH:34][CH:33]=6)[C:24]=45)=[C:18]([F:55])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]5[NH:29][N:30]=[C:31]([C:32]6[CH:37]=[CH:36][C:35]([C:38]([N:40]7[CH2:45][CH2:44][O:43][CH2:42][CH2:41]7)=[O:39])=[CH:34][CH:33]=6)[C:24]=45)=[C:18]([F:55])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(-c5cnc(CC6CCCCC6)n(C)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CC2CCCCC2)ncc(-c2ccc(Oc3ccnc4[nH]nc(-c5ccc(C(=O)N6CCOCC6)cc5)c34)c(F)c2)c1=O

Procedure:
A solution of 2-(cyclohexylmethyl)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one (0.027 g, 0.0363 mmol) in TFA (1 mL) was stirred at 60° C. for 3 minutes and then at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and saturated NaHCO3. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined EtOAc layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The product was obtained (17.3 mg; 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H), 8.27 (s, 1H), 8.08 (d, 2H), 7.89 (m, 1H), 7.71 (m, 1H), 7.59-7.49 (m, 4H), 6.43 (d, 1H), 3.60 (m, 8H), 3.53 (s, 3H), 2.73 (d, 2H), 1.96 (m, 1H), 1.82-1.59 (m, 5H), 1.34-0.99 (m, 5H). LRMS (APCI pos) m/e 623 (M+1).
Reaction SMILES: C([N:3]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])(C)C)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:6]([O:5][C:4](=[O:10])[NH:3][CH:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=2)[CH2:15][CH2:16]1)[CH3:9]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)NC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 70.4 %

Procedure:
A mixture of tert-butyl ethyl(piperidin-4-yl)carbamate (10.95 mmol, 2.5 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.95 mmol, 3.69 g) and sodium hydrogencarbonate (16.42 mmol, 1.380 g) in acetonitrile (40 ml) was refluxed for 2 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The suspension was filtered and the filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (3.3 g). MS (ESI) m/z 485.1 [M+H]+