Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=[O:10].[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH:9]([C:5]1[N:4]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:8]=[CH:7][N:6]=1)=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=Cc1ncc[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1C=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To an acetonitrile (500 mL) solution of 1H-imidazole-2-carboaldehyde (64 g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added at room temperature. The reaction solution was stirred at 50° C. for 16 hours. After the reaction solution was cooled to room temperature, the precipitated crystal was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain the crude title compound. The washing was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the crude title compound. The obtained compound was combined with the crystal obtained previously and then washed with ether to obtain the title compound (88.32 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[C:15]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:14]=2[N:13]=1.CCOC(/N=N/C(OCC)=O)=O.[C:39]1(O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN1CCOCC1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12]1[N:16]([CH2:17][CH2:18][O:19][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:14]=2[N:13]=1
Reactant: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1CCO
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CN1CCOCC1
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To 2-((1-(2-hydroxyethyl)-5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid methyl ester (45 mg, 0.23 mmol) in N-methylmorpholine (3 ml), Pph3 (62 mg, 0.24 mmol) and DEAD (10.6 ml, 40% in toluene, 0.24 mmol) were added and the mixture was stirred at room temperature. After 10 minutes, phenol (11.3 mg, 0.12 mmol) was added thereto, which was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was purified by thin layer chromatography (hexane:ethyl acetate=1:1) to obtain 2-((5,6-dimethyl-1-(2-phenoxyethyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (44 mg, yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:25])[CH:17]=2)[N:12]=1)=[O:4].[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:25])[CH:17]=2)[N:12]=1)=[O:4]
Reactant: COC(=O)c1ccccc1-c1cc(C(=O)OC)c2cc(C)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccccc1-c1cc(C(=O)O)c2cc(C)ccc2n1
Reaction time: 24 h
Yield: 67.6 %

Procedure:
In 2 ml of methanol were dissolved 377 mg (1.23 mmol) of methyl 2-(2-methoxycarbonylphenyl)-6-methyl-4-quinolinecarboxylate obtained in Example 3 and 49 mg (1.2 mmol) of sodium hydroxide. 3 ml of water were added thereto and the resulting mixture was stirred for 24 hours. After concentrated under reduced pressure, water was added to the residue, the aqueous layer was acidified and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by distillation under reduced pressure. The resulting residue was purified by flash silica gel chromatography using a mixed solvent of chloroform and methanol (70/1) to obtain 267 mg of 2-(2-methoxycarbonyl-phenyl)-6-methyl-4-quinolinecarboxylic acid. NMR (270 MHz, CD3OD):
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[I-:39].[K+]>CC(C)=O>[I:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: ICc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 94.5 %

Procedure:
A mixture of 4.0 g of 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 2.2 g of potassium iodide in 50 ml of acetone is heated at reflux for 50 minutes. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with cold water and the resulting solid collected by filtration, washed with water and air dried to give 4.1 g of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1
Reactant: CN1CCC(=O)C(c2ccccc2F)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC[C@H](O)[C@H](c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7.98 g of 3-(2-fluorophenyl)-1-methyl-4-piperidone in 40 ml of dry tetrahydrofuran is cooled to 5° C. under nitrogen and treated dropwise with 49 ml of a 1.0 molar tetrahydrofuran solution of lithium tri-secondary butylborohydride, keeping the pot temperature below 10° C. The mixture is then stirred 18 hours at room temperature under nitrogen. The mixture is cooled while 175 ml of 10% aqueous NaOH solution are added, keeping the pot temperature below 10° C. 117 ml of 30% H2O2 solution are added to the cooled mixture at a rate sufficient to keep the pot temperature at 30°-40° C. The mixture is stirred for 18 hours at ambient temperature followed by refluxing for one hour under nitrogen. The mixture is cooled and the phases are separated. The aqueous phase is extracted with dichloromethane and the combined organic phases are concentrated in vacuo. The residue is treated with 250 ml of cyclohexane and the mixture is concentrated. The residue is partitioned between dichloromethane and saturated NaCl solution. The dichloromethane phase is dried over anhydrous Na2SO4, filtered and concentrated to vacuo to a solid. This material is triturated with ether, filtered and dried to afford a solid. This material is recrystallized from benzene to afford cis-3-(2-fluorophenyl)-1-methyl-4-piperidinol, m.p. 158.5°-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10](O)[N:9]=[C:8]([CH3:16])[N:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([Cl:19])[N:9]=[C:8]([CH3:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1c(O)nc(C)nc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1c(Cl)nc(C)nc1C(=O)OCC
Temperature: 85 °C

Procedure:
A mixture of 2-methyl-5-propyl-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester (10 mmol) and POCl3 (25 mL) is heated at 85° C. for 4 hours. The solvent is removed in vacuo and EtOAc (40 mL) and water (30 mL) are added to the residue. NaHCO3 is carefully added until the pH of aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 mL). The combined extracts are washed with brine (50 mL), dried (Na2SO4), and evaporated. Flash column purification of the residue with 3:1 EtOAc, hexane provides 2-methyl-5-propyl-6-chloro-pyrimidine-4-carboxylic acid ethyl ester as a light yellow oil. Step 4. Preparation of 2-Methyl-5-propyl-4-chloromethyl-6-chloro-pyrimidine
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C@@H:50]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)[C:51]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:59]=1)=[O:52].CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:11](=[O:13])[NH:49][C@@H:50]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)[C:51](=[O:52])[N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:59]=1)[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of Boc-N-methyl-L-alanine (771 mgs, 3.79 mmol), HOBt (700 mgs, 5.17 mmol), and HBTU (2.0 g, 5.17 mmol) in DMF (10 mL) is added (S)-2-amino-2-cyclohexyl-1-[(S)-2-(3-phenoxy-phenyl)-pyrrolidin-1-yl]-ethanone and DIPEA (3 mL, 17.25 mmol). The mixture is stirred for 30 minutes and diluted with brine (20 mL) and extracted with EtOAc (3×10 mL). The organics were combined, dried over Na2SO4, filtered, concentrated under reduced pressures and purified by silica gel column chromatography (50% EtOAc/Hexanes) to give the product ((S) 1-{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolodin-1-yl]-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester as a white powder (1.3 g, 84%). LCMS m/z 564 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@:18]3([CH3:29])[O:22][C:21]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]4[CH2:19]3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C=O.[B-][C:35]#N.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH3:29][C@@:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:35])[C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)[O:22][C:21]2=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]2[CH2:19]1
Reactant: [B-]C#N
Reactant: C[C@]1(CN2CCC(Nc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(c1ccc(OC(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
(S)-2-[4-(4-Trifluoromethoxyphenyl)aminopiperidin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 282 (400 mg, 0.90 mmol) was dissolved in methanol (10 ml). To the solution, a 37% formaldehyde solution (0.13 ml, 4.52 mmol), sodium cyanotrihydroborate (170 mg, 2.71 mmol) and acetic acid (0.17 ml, 2.71 mmol) were added followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and recrystallized from methylene chloride-diisopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-methyl-4-trifluoromethoxyaniline (309 mg, yield 78%) as a light yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[NH2:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:12][CH:13]([OH:15])[CH2:14]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(1S)-Benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (515 mg, 1.6 mmol) was dissolved in cold 4N HCl-dioxane, the mixture stirred 2 h at 25° C., concentrated, and the residue with ether giving a colorless solid (415 mg, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)N1CCCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 7 was prepared according to procedures described in Example 3 substituting tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)azepane-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.29 (d, J=7.70 Hz, 1 H), 6.22 (s, 1 H), 6.17 (d, J=7.70 Hz, 1 H), 4.90-5.02 (m, 1 H), 4.48-4.56 (m, 1 H), 3.36-3.63 (m, 4 H), 3.11 (s, 3 H), 1.91-2.17 (m, 5 H), 1.64-1.77 (m, 1 H), 1.27 (d, J=6.05 Hz, 6 H). MS (ESI) 449 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH2:9]([O:16][NH:17][C:18]([C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[S:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([F:44])[CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:9]([O:16][N:17]([CH3:1])[C:18]([C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[S:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([F:44])[CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(OCc1ccccc1)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
Anhydrous potassium carbonate (736 mg, 5.33 mmol) and iodomethane (0.133 ml, 2.13 mmol) were added to a solution of N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (549 mg, 1.07 mmol) [prepared as described in Step 3 above] in dimethylformamide (11 ml) at RT. After 2 h, the reaction mixture was diluted with ethyl acetate (50 ml) and then washed with 0.1 M HCl, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (71%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])=[C:14]([F:31])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH2:21])=[O:19])=[C:14]([F:31])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)c(F)c2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NN)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl)carbamoyl]hydrazinecarboxylate (141.6 mg, 0.314 mmol) in anhydrous dichloromethane (2 ml) was added 4M hydrogen chloride dioxane solution (2 ml). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate (10 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (2 ml) and ethyl acetate (4 ml), filtered, washed twice with ethyl acetate, and dried under reduced pressure to give N-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl)hydrazinecarboxamide hydrochloride (123.6 mg, 0.319 mmol, quantitative) as a white solid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([C:53]2[N:58]=[CH:57][C:56]([C:59]3[CH:60]=[C:61]4[C:67]([C:68]5[CH:69]=[N:70][N:71]([CH2:73][CH2:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH:72]=5)=[CH:66][N:65](S(C5C=CC(C)=CC=5)(=O)=O)[C:62]4=[N:63][CH:64]=3)=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][N:47]1[CH2:48][CH2:49][N:50]([C:53]2[N:58]=[CH:57][C:56]([C:59]3[CH:60]=[C:61]4[C:67]([C:68]5[CH:69]=[N:70][N:71]([CH2:73][CH2:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH:72]=5)=[CH:66][NH:65][C:62]4=[N:63][CH:64]=3)=[CH:55][CH:54]=2)[CH2:51][CH2:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cn2)CC1
Yield: 98.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.088 mmol) was hydrolyzed with lithium hydroxide (18 mg, 0.44 mmol) in THF/methanol/water (2/2/1 mL) to yield 40 mg (98.5% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.55-8.50 (d, 2H), 8.40 (s, 1H), 8.19-8.10 (dd, 1H), 7.89-7.84 (d, 2H), 7.68 (s, 1H), 7.24-7.21 (m, 3H), 7.15-7.11 (m, 3H), 4.50-4.50 (t, 2H), 3.20-3.10 (t, 2H), 2.98 (s, 3H). MS: m/z=464.2 (M+1), HPLC: 93.96% in method A.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Li].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](=[O:39])[CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]3[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)=[CH:8][CH:9]=2)=[O:3])=[CH:36][CH:35]=1
Reactant: CC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C(=O)CC(=O)c3ccc(Cl)cc3)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
tert-Butyl 2-(4-acetylphenyl)morpholine-4-carboxylate (210 mg, 0.69 mmol) was dissolved in THF (3.5 ml). Lithium-bis-(trimethylsilyl)-amide solution (2.05 ml, 2.05 mmol, 1.0 M solution in THF) was added dropwise and the yellow reaction mixture was stirred at −78° C. for 1 hour. 4-Chlorobenzoyl chloride (120 mg, 0.69 mmol) was added and the reaction mixture was stirred for 90 min and was quenched by addition of 1M aqueous hydrochloric acid. Ethyl acetate was added and the organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (10 g silica gel, 10 to 50% ethyl acetate in heptane) to yield an off-white solid (215 mg, 70%). MS (ISP): 388.2 ([{35Cl}M-tBu+H]+), 390.3 ([{37Cl}M-tBu+H]+).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH2:19][CH3:20])[C:12](=O)[C:13]([O:15]CC)=[O:14]>C1(C)C=CC=CC=1>[CH2:19]([C:11]1[S:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: CCOC(=O)C(=O)C(Br)CC
Reactant: NC(=S)c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1sc(-c2ccccc2)nc1C(=O)O

Procedure:
Intermediate 2C was prepared as described above for the preparation of intermediate 2B from 4.61 g of thiobenzamide, 5.0 g of ethyl 3-bromo-2-oxo-pentanoate, and 14 mL of toluene. Solids were collected and washed with cold water after cooling of the NaOH solution. Heating these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 3.74 g (72% yield) of intermediate 2C; 1H NMR (CDCl3, 300 MHz) δ7913-7.91 (m, 2H), 7.51-7.50 (m, 3H), 3.39 (q, 2H, J=7.8), 1.42 (t, 3H, J=7.8); low resolution MS (ES+)m/e 233.81 (MH+).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:5]=1[CH2:6][C:7]#[N:8]>[Ni].C(O)C>[NH2:14][C:10]1[C:11]([F:13])=[CH:12][C:4]([Cl:3])=[C:5]([CH:9]=1)[CH2:6][C:7]#[N:8]
Reactant: N#CCc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: N#CCc1cc(N)c(F)cc1Cl

Procedure:
Hydrogen is injected at 25°-30° C., under normal pressure, into a mixture consisting of 8.9 g of 2-chloro-4-fluoro-5-nitrobenzyl cyanide, 1 g of Raney nickel in 90 ml of absolute ethanol, until the stoichiometric amount of hydrogen has been absorbed. After completion of the absorption of hydrogen, the reaction mixture is filtered and the alkaline filtrate is concentrated by evaporation. The residue consists of 7.5 g of 5-amino-2-chloro-4-fluorobenzyl cyanide having a melting point of 85°-86° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:39]([NH2:42])[CH2:40][NH2:41].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH2:41][CH2:40][CH2:39][NH:42][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(Cl)cccc2s1
Reactant: NCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(NCCN)cccc2s1
Temperature: 90 °C

Procedure:
Into a mixture of tert-butyl (3R)-3-[[5-(4-chloro-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (150 mg, 0.25 mmol, 1.00 equiv), ethane-1,2-diamine (48.0 mg, 0.80 mmol, 3.00 equiv), sodium 2-methylpropan-2-olate (52.0 mg, 0.54 mmol, 2.00 equiv) and o-biphenyl(t-Bu)2P (10.7 mg, 0.04 mmol, 0.12 equiv) in toluene (6.0 mL) was added tris(dibenzylideneacetone) dipalladium (30.0 mg, 0.03 mmol, 0.10 equiv) and nitrogen was bubbled in for 5 min. The resulting mixture was heated for 12 h at 90° C. in an oil bath. After removed the solvent, the residue was purified by flash chromatography on silica gel, eluting with a mixture of 10% MeOH in CH2Cl2 to give the title compound as a yellow solid. MS m/z [M+H]+ (ESI): 585.