Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([C@@H:26]([CH3:28])O)[NH:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH3:24])[CH:8]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:17]([O:16][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:25][CH:26]([CH3:28])[CH:4]([C:3]([O:2][CH3:1])=[O:29])[N:5]=2)=[CH:8][C:9]=1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(NC(=O)OCc2ccccc2)c(C)c1)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1N=C(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)OC1C
Yield: 86.3 %

Procedure:
The same operation as in Example (97b) was performed using N-(4-{[(benzyloxy)carbonyl]amino}-3-methylbenzoyl)threonine methyl ester obtained in Example (108b) (5.37 g, 13.4 mmol), the Burgess reagent (4.0 g, 16.8 mmol) and THF (50 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) gave 4.42 g of the title compound as a colorless solid (86%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[C:6]([CH2:30][OH:31])[CH:5]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCCC1>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:31][CH2:30][C:6]1[CH:5]=[C:4]([Cl:3])[CH:29]=[CH:28][C:7]=1[O:8][CH2:9][C:10]([N:12]1[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14][C@H:13]1[CH3:27])=[O:11])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a 0° C. solution of sodium hydride (0.025 g, 60% dispersion, 1.0 mmol) in tetrahydrofuran (2 mL) was added a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.17 g, 0.40 mmol) and tert-butyl bromoacetate (0.23 g, 3.0 mmol) in tetrahydrofuran (2 mL). The reaction mixture was warmed to ambient temperature overnight, quenched with water and diluted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified via chromatography on silica gel to give the title compound (0.14 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12](O)=[O:13])=[CH:8][CH:7]=[C:6]([CH3:15])[CH:5]=2.ClC(OC)=O.C([N:30](CC)CC)C>>[CH3:1][C:2]1[N:3]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:30])=[O:13])=[CH:8][CH:7]=[C:6]([CH3:15])[CH:5]=2
Reactant: Cc1ccc2c(CC(=O)O)c(C)n(Cc3ccccc3)c2c1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Product: Cc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of 0.48 g (1.64 mmol) of 2,6-dimethyl-1-(phenylmethyl)-1H-indole-3-acetic acid in 25 ml of tetrahydrofuran(THF) was cooled with an ice-water bath, 0.45 ml of triethylamine was added followed by 0.13 ml (1.7 mmol) of methyl chloroformate. After 0.5 hour, gaseous NH3 was bubbled into the reaction mixture for 0.5 hour, the cooling bath removed and the mixture stirred for 2 hours. It was then poured into water and extracted with EtOAc, the EtOAc solution washed with a Na2CO3 solution, dried(Na2SO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/water, to give 0.19 g (39% yield) of 2,6-dimethyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 160-163° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:49]1[C:53]2=[N:54][CH:55]=[CH:56][C:57](Br)=[C:52]2[CH:51]=[CH:50]1)=O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:57]4[CH:56]=[CH:55][N:54]=[C:53]5[NH:49][CH:50]=[CH:51][C:52]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4ccnc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.331 g, 0.48 mmol), 4-bromopyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butylester (0.170 g, 0.573 mmol), Pd(Ph3)4 (55.1 mg, 0.048 mmol) and CuI (109 mg, 0.573 mmol) in toluene (8 mL) was purged with argon, then subjected to microwave irradiation at 140° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was then dissolved in DCM/TFA (8 mL/8 mL) and the resulting solution stirred for 2 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by column chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 70:30 to 40:60) to give 695 as a white powder (0.049 g, 20%). LCMS (Method F): RT 5.07 min, [M+H]+ 521.3. 1H NMR (CDCl3, 400 MHz) δ 8.93 (s, 1 H); 8.43 (d, J=5.2 Hz, 1 H); 8.08 (d, J=5.2 Hz, 1 H); 7.43 (d, J=2.2 Hz, 2 H); 7.38 (s, 1 H); 7.09 (d, J=5.2 Hz, 1 H); 5.24 (d, J=5.2 Hz, 1 H); 4.10 (t, J=4.7 Hz, 4 H); 3.92 (t, J=4.7 Hz, 4 H); 3.86 (s, 2 H); 2.65-2.58 (m, 4 H); 1.60-1.55 (m, 4 H); 1.24 (s, 6 H)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-:12])=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:3]=1.[Br:25]N1C(=O)CCC1=O>CO.C(Cl)(Cl)Cl>[Br:25][C:3]1[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N+:5]([O-:12])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(O)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [O-][n+]1c(CCCCCCCCCCCO)c(Br)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
In this example, 1 m mole of 4-hydroxy-2-(11-hydroxyundecyl) quinoline-N-oxide is dissolved in a liquid mixture of methanol-chloroform (5:1), and 1 m mole of N-bromosuccinimide is added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the solvent is removed therefrom by distillation, and the residue is recrystallized from ethanol, whereby the captioned compound is obtained (yield: 70.5%).
Reaction SMILES: N1[C:5]([C:6]2[CH:19]=C[C:17]3[C:8](=[C:9]4[C:14](=CC=3)C=CC(C3NN=NN=3)=N4)[N:7]=2)=[N:4][N:3]=N1.[C:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:31]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:39]=[CH:38][C:34]([C:35]2[O:36][C:5]([C:6]3[CH:19]=[CH:14][C:9]4[C:8](=[C:17]5[C:9](=[CH:8][CH:17]=4)[CH:14]=[CH:19][C:6]([C:5]4[O:36][C:35]([C:34]6[CH:38]=[CH:39][C:31]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)=[CH:32][CH:33]=6)=[N:3][N:4]=4)=[N:7]5)[N:7]=3)=[N:4][N:3]=2)=[CH:33][CH:32]=1
Reactant: c1cc2ccc3ccc(-c4nnn[nH]4)nc3c2nc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: c1ccc(-c2ccc(-c3nnc(-c4ccc5ccc6ccc(-c7nnc(-c8ccc(-c9ccccc9)cc8)o7)nc6c5n4)o3)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, a mixture of 13 g (0.045 mol) 2,9-bis-(1H-tetrazol-5-yl)-[1,10]phenanthroline and 390 ml pyridine was added to a 250 ml three-necked flask. The mixture was then heated to 50° C., and 46 g (0.21 mol) 4-phenylbenzoyl chloride was then added drop by drop. After the adding, the mixture solution was heated to reflux (110° C.) and stirred overnight. After completion of reaction, as shown in scheme 2, the reaction mixture was cooled to room temperature, filtered. Finally, solids were separated, washed by 100 ml methanol, filtered and purified by column chromatography to obtain white products 2,9-bis-(5-biphenyl-4-yl-[1,3,4]oxadiazol-2-yl)-[1,10]phenanthroline 11 g (0.018 mol, yield 40%). MS(m/z, FAB+), 620, 291, 248, 233, 208, 156, 130, 105.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23]([O:25]CC)=[O:24])=[CH:18]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cccc(NCCCNC(=O)OC(C)(C)C)c2n1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)O)cc2cccc(NCCCNC(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.4 %

Procedure:
A mixture of 0.12 g (0.31 mmol) of ethyl 7-[(3-tert-butoxycarbonylaminopropyl)amino]-1-methyl-2-indolecarboxylate, 2 ml of 5N potassium hydroxide aqueous solution and 5 ml of ethanol was stirred at room temperature for 2.5 hours. After 2N hydrochloric acid was gradually added to the reaction solution to render the pH 6, the reaction mixture was concentrated under reduced pressure. The residue was extracted three times with chloroform. The combined extracts were dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give 0.079 g (72.4%) of 7-[(3-tert-butoxycarbonylaminopropyl)amino]-1-methyl-2-indolecarboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)CO
Solvent: c1ccncc1
Product: OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Glycerol (5.0 g, 54.28 mmol) was dried by coevaporations with dry pyridine and dissolved in the same solvent (100 mL). Trityl chloride (45 g, 0.16 mol) was added portionwise, and the mixture was stirred overnight at RT. All volatiles were removed in vacuo. The residue was dissolved in dichloromethane, washed twice with sat NaHCO3 and dried over Na2SO4. Precipitation from diethyl ether gave the title compound (30 g). 1H NMR (CDCl3): 7.40-7.22 (30H) 3.94 (1H, m); 3.29 (4H, m); 2.29 (1H, d, J 5.9). ESI-TOF MS: required for C41H36NaO3+599.26 (M+Na+), found 599.21.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH:39]3[CH2:44][CH2:43][CH:42]([CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:41][CH2:40]3)[C:30]=2[C:34]([F:37])([F:36])[F:35])[CH:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:18]C(C)(C)C)([O:13]C(C)(C)C)=[O:12])(C)(C)C.Cl.O.C(O)(=O)C>>[NH2:7][C@@:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH:39]3[CH2:44][CH2:43][CH:42]([CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:41][CH2:40]3)[C:30]=2[C:34]([F:35])([F:36])[F:37])[CH:25]=1)([CH3:23])[CH2:9][O:10][P:11](=[O:12])([OH:13])[OH:18]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(OC3CCC(C4CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
[(R)-1-[6-(4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester (11 mg, 0.000015 mol) was added 12 M of hydrogen chloride in water (1 mL, 0.01 mol; Supplier=Aldrich) and acetic acid (1 mL, 0.02 mol) and the solution was stirred for 1.5 h at RT. All solvent was then removed inder reduced pressure and the residue was dried on high-vac over night to give the desired product 8 mg was a white HCl salt (98%). ESI-MS: 499 (M−16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.19-8.07 (m, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.63-7.42 (m, 2H), 7.22 (dd, J=5.0, 9.0 Hz, 1H), 5.10 (br. s., 1H), 4.32-4.11 (m, 1H), 3.72 (m, 2H), 2.18-1.98 (m, 2H), 1.92-0.71 (m, 21H)
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)=[CH:25][CH:24]=1.[NH2:45][CH2:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[N:50]([CH3:52])[CH3:51]>>[CH3:51][N:50]([CH3:52])[C:49]1[CH:48]=[C:47]([CH:55]=[CH:54][CH:53]=1)[CH2:46][NH:45][C:40]([C:36]1[S:35][C:34]([N:31]2[C:32](=[O:33])[N:28]([CH2:27][C:26]3[CH:43]=[CH:44][C:23]([F:22])=[CH:24][CH:25]=3)[N:29]=[CH:30]2)=[N:38][C:37]=1[CH3:39])=[O:42]
Reactant: CN(C)c1cccc(CN)c1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccc(N(C)C)c1
Yield: 50 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-N,N-dimethylaniline, the title compound was obtained as a colourless solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.35 (dd, J=8.5, 5.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 7.09 (dd, J=7.9, 6.9 Hz, 2H), 6.66 (s, 1H), 6.58 (dd, J=7.7, 7.7 Hz, 2H), 4.96 (s, 2H), 4.35 (d, J=5.8 Hz, 2H), 2.83 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 163.7, 161.3, 160.5, 151.6, 151.2, 150.9, 150.1, 140.3, 132.7 (d, 3JC-F=11 Hz), 132.4, 130.4 (d, 2JC-F=33 Hz), 129.2, 123.1, 115.9 (d, 1JC-F=86 Hz), 115.6, 111.7, 111.4, 48.2, 43.6, 40.5, 17.3; MS (ES+) m/z 467.16 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[Cl:8][CH:9](CO)[CH:10]([OH:13])CO.S(=O)(=O)(O)O.[OH-].[Ba+2].[OH-]>CC(C)=O.O>[Cl:8][CH:9]([CH:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1)[CH2:10][OH:13]
Reactant: COC(C)(C)OC
Reactant: OCC(O)C(Cl)CO
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(C(Cl)CO)O1
Reaction time: 2 h

Procedure:
Within 2 hours, 258 ml of 2,2-dimethoxypropane is added dropwise to a stirred and water-cooled solution of 272 g of 3-chloro-1,2,4-butanetriol and 0.5 ml of concentrated sulfuric acid in 1 liter of acetone. The reaction is completed after another 4 hours. The solution is neutralized by the addition of 3.8 g of barium hydroxide, stirred for 30 minutes, filtered off from the solid matter, and concentrated to dryness under vacuum, yielding 2-chloro-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([N:34]5[CH2:35][CH2:36][N:31]([C:28](=[O:30])[CH3:29])[CH2:32][CH2:33]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: CC(=O)N1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-acetylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 52.5 mg of 124. MS (Q1) 492.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
A solution of 2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 4-azetidin-3-yl-morpholine (191 mg, 1.34 mmol) in DCE (12 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 90:10) to afford the title compound as a tan solid (357 mg, 81%). LCMS (Method H): RT=2.26 min, M+H+=394
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ncco2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(1,3-oxazol-2-yl)benzoate (690 mg, 3.4 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (20 mL) is added lithium hydroxide (430 mg, 3 mmol). The reaction mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is acidified to pH 1 with 1 N hydrochloric acid and a precipitate is observed. The solid is collected by filtration to afford the title compound. 1H NMR (300 MHz, CD3OD) δ 8.14 (s, 4H), 8.05 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH3:22])[N:12]=1)=[O:10])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[C:15]([S:2]([OH:5])(=[O:4])=[O:3])=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:13]([CH3:22])[N:12]=1)=[O:10])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(C)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nn(C)c(-c2ccccc2)c1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.5 ml of chlorosulfonic acid and 15 xl of dry chloroform was cooled to 0° C., and a solution of 11.5 g (0.05 mol) of 3-ethoxycarbonyl-1-methyl5-phenylpyrazole in 25 ml of dry chloroform was added dropwise thereinto. Then, the mixture was stirred at room temperature for one hour and under reflux for 3 hours. After the reaction, by evaporation of chloroform, there was obtained oily 3-ethoxycarbonyl-1-methyl-5-phenylpyrazole-4-sulfonic acid. As the next step, at room temperature 20.9 g of phosphorus pentachloride was added portionwise, followed by stirring at 90° to 100° C. for one hour. The reaction mixture was added into ice-water and extracted with ether to obtain 14.7 g of 3-ethoxycarbonyl-1-methyl-5-phenylpyrazole-4-sulfonylchloride. Then, the resultant sulfonylchloride was dissolved in 20 ml of acetone and 4.48 g of KHCO was added to the solution. After a solution of 2.7 g of aqueous ammonia (28 %) and 6.5 ml of acetone was added dropwise thereinto at room temperature, the mixture was heated at 50 to 60 ° C. for 30 minutes. After evaporation of acetone, water was added to the residue, whereby 12.9 g of the title compound was precipitated as a solid. Recrystallization from benzene gave 8.4 g of the product. m.p. 141°-144° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[C:9]1([C:15]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]=2[NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:16]=2[NH:17][C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1=O
Reactant: Nc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Yield: 116.7 %

Procedure:
Follow a procedure similar to that of Preparation 2 except use 1,2-cyclohexanedione (1.0099 g, 9.0065 mmol); 2,6-diphenylaniline (2.2258 g, 9.0731 mmol); toluene (22 mL); p-toluenesulfonic acid monohydrate (0.0859 g, 0.4516 mmol); reflux reaction mixture for 2.3 hours; to isolate 3.5678 g of a brown thick oil. Purify the thick oil be chromatography using a Biotage SNAP 50 g KP-Sil column, loading the thick oil with small amount of 4% ethyl acetate/96% hexanes and 100% ethyl acetate and eluting with a gradient of 4-8% ethyl acetate in hexanes to afford after isolation 1.1388 g (37.2%) of the 2-((1,1′:3′,1″-terphenyl)-2′-ylamino)-2-cyclohexen-1-one as a yellow thick oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]4([C:37]([NH:39][C@H:40]([CH2:45][OH:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:24][CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1>CS(C)=O.C(Cl)Cl>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([NH:30][C:31]4([C:37]([NH:39][C@H:40]([CH:45]=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:26][CH:27]=3)[N:21]=2)[CH2:13][CH2:12]1
Reactant: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CSCC[C@@H](C=O)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
Under an argon gas atmosphere, 453 mg (3.5 mmol) of N,N-diisopropylethylamine was added dropwise to a solution of 658 mg (3.5 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrous dimethyl sulfoxide and in 5 ml of anhydrous methylene chloride under ice-cooling, and the mixture was stirred for 15 minutes. Further, under ice-cooling, a solution of 319 mg (0.58 mmol) of N-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol in 3 ml of anhydrous dimethyl sulfoxide was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured to ice-water and extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, after it was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 18 hours. The obtained crystal was collected by filtration to obtain 203 mg (64%) of the title compound.