Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH3:21])=[O:13])[CH:3]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Temperature: 2 °C

Procedure:
43 g of 4-(5-chloro-1,6-dihydro-6-oxopyridin-3-yl)-4-oxobutyric acid (crude product, prepared as described in Example 6) was suspended in 730 ml of methanol, and 16 ml of concentrated sulfuric acid was added. The mixture was heated in such a way that approximately 100 ml of methanol distilled off in the course of 4 hours. The reaction mixture which remained was then concentrated to half its volume under reduced pressure and the resulting solution was cooled to 2° C. The product was removed by filtration, washed using 20 ml of cold methanol and dried. The product yield was 38.1 g (83%) of white crystals. The product melting point was 211.5° to 213.5° C. Other data concerning the product was:
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[O:20][C:21]([C:24]4[N:25](C(OC(C)(C)C)=O)[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:22][N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:24]1[C:21]1[O:20][C:19]([NH:18][C:14]2[CH:13]=[C:12]([NH:11][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[N:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-(phenylmethylsulfonamido) phenyl)amino) oxazol-5-yl)-1H-indole-1-carboxylate 28 (0.24 g, 0.441 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroaceticacid (10 mL) at room temperature. Reaction was stirred for 1.5 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using MPLC silica column (Biotage) (Acetone/hexane as an eluent) to obtain N-(3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenyl)-1-phenyl methane sulfonamide 29 (0.14 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)c(Cl)c2Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-(p-nitrophenoxy)phenol (11.5 g., 0.038 mole), ethyl bromoacetate (9.51 g., 0.057 mole) and pulverized potassium carbonate (7.9 g., 0.057 mole) in 100 ml. of 2-butanone was heated at reflux for 2 hours. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was taken into CH2Cl2 and the resulting solution was washed with aqueous NaCl and dried over MgSO4. Evaporation of the solvent was followed by trituration with hexane to furnish the solid product. Recrystallization from cyclohexane gave 12.5 g. of solid, m.p. 90°-91°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]=[CH:13][O:14]C)=[CH:7]2.Cl.CCOCC.O>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]=[O:14])=[CH:7]2
Reactant: COC=Cc1ccc2c(Br)cccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=CCc1ccc2c(Br)cccc2c1
Yield: 105.6 %

Procedure:
The methyl 5-bromo-2-naphthylvinyl ether (2.8 g) dissolved in tetrahydrofuran (55 ml) was stirred with concentrated hydrochloric acid (10 ml) for 1 hour at room temperature. Ether and water were added and the organic solution separated and washed with water, saturated sodium bicarbonate and saturated sodium chloride solutions. Evaporation gave a liquid (2.8 g), nD20 =1.6444.
Reaction SMILES: C[C:2]([O-:5])([CH3:4])C.[K+].[CH2:7]([SH:13])[C:8]1OC=CC=1.Br[CH:15]([CH2:19][CH3:20])[C:16](=[O:18])[CH3:17].O>O1CCCC1>[O:5]1[CH:2]=[CH:4][C:7]([S:13][CH2:17][C:16](=[O:18])[CH2:15][CH2:19][CH3:20])=[CH:8]1
Reactant: SCc1ccco1
Reactant: CC(C)(C)[O-]
Reactant: CCC(Br)C(C)=O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)CSc1ccoc1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
11.2 g of potassium tert-butylate, dissolved in 100 ml of dry tetrahydrofuran, are initially introduced into the reaction vessel at room temperature. 11.4 g of furfurylmercaptan are added dropwise at 20° C. When the addition is complete, the mixture is subsequently stirred for a further 30 minutes. 16.5 g of 3-bromopentan-2-one are then added dropwise in the course of 30 minutes and the mixture is subsequently stirred for one hour. For working up, the mixture is poured onto 100 ml of water and extracted twice with diethyl ether, and the combined organic phases are washed with water, dried over sodium sulphate and concentrated. 19 g of crude product (purity 84.1%) are obtained. For further purification, the product is subjected to bulb tube distillation. 10 g of 3-furfurylthio-pentan-2-one, which has a purity of 97.5%, are obtained. The IR, NMR and mass spectra of the compound agree with the structure described for it.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>N1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:6]([NH:24][NH2:25])[N:7]=1
Reactant: Clc1ccc(-c2nc(Cl)nc(Cl)c2-c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nc(Cl)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
2,4-Dichloro-5,6-bis(4-chlorophenyl)pyrimidine (1.8 g, 4.86 mmol) was dissolved in pyridine (5 mL) and hydrazine monohydrate (0.26 mL, 5.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic extracts were washed with water, followed by saturated aqueous NaCl, dried (MgSO4), and concentrated at reduced pressure to obtain 1.7 g of the title compound, as a mixture with its regioisomer, as a yellow solid. HPLC/MS: title compound retention time=3.261 min, [M+H]30 =365; regioisomer retention time 3.385 min.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:8][CH2:9]Cl)[CH2:5][CH2:6]Cl.[CH3:11][O:12][CH2:13][CH2:14][OH:15]>>[CH2:3]([N:4]([CH2:8][CH2:9][O:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:5][CH2:6][O:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:2][O:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: COCCO
Reactant: ClCCN(CCCl)CCCl
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
To the aforesaid reaction mixture (i), 51.6 g tris(2-chloroethyl)amine chlorhydrate (0.215 moles) were added. The mixture was then heated with reflux of 2-methoxyethanol (125° C.) for 12 hours, followed by the distillation of the solvent under reduced pressure. The excess sodium 2-methoxyethanolate was then neutralized by addition of 11.6 cm3 aqueous HCl (10 N). The sodium chloride was filtered off and the solution distilled.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[C:4](=O)[CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1>ClCCCl>[Br:14][C:15]1[CH:20]=[CH:19][N:18]2[C:17](=[N:21][C:4]3[CH2:3][C:2]([CH3:1])([CH3:13])[CH2:7][CH2:6][C:5]=3[C:8]2=[O:10])[CH:16]=1
Reactant: COC(=O)C1CCC(C)(C)CC1=O
Reactant: Nc1cc(Br)ccn1
Solvent: ClCCCl
Product: CC1(C)CCc2c(nc3cc(Br)ccn3c2=O)C1
Temperature: 25 °C

Procedure:
A solution of methyl 4,4-dimethyl-2-oxocyclohexanecarboxylate (0.5 g, 2.7 mmol, 1 eq), 4-bromopyridin-2-amine (0.51 g, 2.97 mmol, 1.1 eq) and PPA in 1,2-dichloroethane was stirred at 80° C. for 4 hours. After it was cooled to rt, the reaction mixture was quenched with saturated Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:29]2[CH2:30][CH2:31][N:26]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:27][CH2:28]2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)N2CCN(Cc3ccccc3)CC2)c1
Reaction time: 4 h

Procedure:
3-Methoxyphenylacetic acid (100 g, 600 mmole) was dissolved in methylene chloride (600 mL) and treated with oxalyl chloride (60 mL) and DMF (1 mL) at room temperature. The mixture was stirred for four hours until gas evolution ceased. The solvent was evaporated and the residue dried under vacuum to remove excess oxalyl chloride. The oil obtained was dissolved in methylene chloride (400 mL). Half of this solution (200 mL, approx. 300 mmole) was cooled in ice and treated with a solution of 1-benzylpiperazine (60 mL, 350 mmole) and triethylamine (30 mL) in methylene chloride (100 mL) dropwise. The mixture was stirred at room temperature for 16 hours. Sodium bicarbonate solution was added and the mixture stirred for 15 minutes. The layers were separated. The organic phase was washed with water, brine, dried over K2CO3 and evaporated to an oil. Wt. 90 g. A small portion was characterized as the hydrochloride, m.p. 229°-231° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24]>>[CH2:23]([C:24]1[O:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:20][N:21]=1)[CH3:22]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Product: CCc1nnc(-c2ccc3occ(-c4ccc(SC)cc4)c3c2)o1
Yield: 9 %

Procedure:
In the same manner as in Example 239 and using 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide instead of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide and using triethyl orthopropionate instead of triethyl orthoacetate, the title compound (yield 9%) was obtained as colorless crystals.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3(C#N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:13]2[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=2[NH:11]1.[NH4+].[Cl-].O>C1COCC1>[C:1]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:14]4[C:13]5[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=5[NH:11][C:10]4=[O:9])[CH2:16][CH2:17]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCC1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
To a solution of phenylmagnesium bromide (3M solution in diethyl ether, 0.75 ml, 2.25 mmol) in THF (1 ml) was added a suspension of 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cyclohexanecarbonitrile (230 mg, 0.71 mmol) in THF (2 ml) at 0° C. Then the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added sat.NH4Cl aq. solution (1 ml) followed by addition of water (5 ml). The white precipitate appeared was collected by filtration, washed faith water and CH2Cl2, and dried to give 75 mg (28.1%) of title compound. The filtrate of CH2Cl2 wash was concentrated to give 171 mg of title compound and the starting material mixture, which was purified by column chromatography (silica gel:30 g, CH2Cl2/MeOH:50/1 to 15/1) to give 60 mg(22.5%) of title compound as white powder.
Reaction SMILES: CCCCCC.S(Cl)([Cl:10])(=O)=O.C(O)(=O)C.[F:16][C:17]([F:43])([F:42])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[NH:28][C:29]1[N:34]([CH2:35][CH3:36])[C:33](=[O:37])[CH:32]=[C:31]([C:38]([F:41])([F:40])[F:39])[N:30]=1>CCOCC>[F:43][C:17]([F:42])([F:16])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:19]=1[NH:28][C:29]1[N:34]([CH2:35][CH3:36])[C:33](=[O:37])[C:32]([Cl:10])=[C:31]([C:38]([F:39])([F:40])[F:41])[N:30]=1
Reactant: CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 0 °C
Yield: 53.2 %

Procedure:
While stirring under ice-cooling, 10% hexane solution of sulfuryl chloride (0.019 ml, 0.24 mmol) was added to acetic acid (3 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone (0.10 g, 0.24 mmol), followed by stirring for 1.5 hours while gradually returning to room temperature. After completion of the reaction, ice-water (10 ml) and ether (10 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (10 ml×3). The organic layers were combined, washed with water (20 ml×2) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By recrystallizing the thus obtained crude product from chloroform/hexane, 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 49] was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.ClC(Cl)(O[C:39](=[O:45])OC(Cl)(Cl)Cl)Cl.[NH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1>C(Cl)(Cl)Cl>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:14]4[CH2:20][CH2:19][CH:18]3[CH2:17][O:16][CH2:15]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:39]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=4)=[O:45])=[CH:23][CH:22]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: Nc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a solution of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) in CHCl3 (1 mL) were added Et3N (25 mL, 0.18 mmol) and triphosgene (18 mg, 0.06 mmol). The mixture was stirred at room temperature for 15 min and 4-aminopyridine (17 mg, 0.18 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound as off-white solid (1TFA salt, 8.8 mg, 24% yield). MS (ESI) m/z 489.2.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CO.[O:46]1[CH2:49][C:48](=O)[CH2:47]1>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:22][CH2:23][N:24]([CH:48]7[CH2:49][O:46][CH2:47]7)[CH2:25][CH2:26]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=C1COC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCN(C3COC3)CC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reaction time: 0.75 h

Procedure:
To a solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: 3.78 (TFA salt) (28 mg) in DCM (2 mL) and MeOH (1 mL) was added oxetan-3-one (4.98 mg, 0.069 mmol) and TEA (1 mL) (to neutralize TFA). The mixture was stirred for 45 minutes then followed by addition of Na(CN)BH3 (5.1 mg, 0.081 mmol). Reaction mixture was stirred for 30 minutes. Reaction was done based on LCMS. The solvent was removed and the residue was purified by prep HPLC (MeCN:water gradient, TFA modified) to provide 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one: (3.79) as a TFA salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:3]=[C:4]([N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][CH2:19]3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.3 %

Procedure:
210 mg of (S)-6-chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2-amine, 56 mg of 2-aminopyrazine, mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 66 mg of sodium t-butoxide and 25 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 120 mg of (S)—N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder.
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[C:16](SCCC)[N:15]=[C:14]([Cl:22])[CH:13]=1.[CH2:24]1[CH2:28]OC[CH2:25]1>O.CO>[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[C:16]([S:1]([CH2:25][CH2:24][CH3:28])(=[O:6])=[O:2])[N:15]=[C:14]([Cl:22])[CH:13]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCCSc1cc(C(=O)OC)cc(Cl)n1
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
Add a suspension of potassium peroxymonosulfate (35.6 g, 57.7 mmol) in water (80 mL) to a cooled solution of 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (4.71 g, 19.2 mmol) in methanol (40 mL) and THF (40 mL). Stir the mixture at room temperature for 3 days. Dilute the mixture with water and extract with dichloromethane (3×100 mL). Wash the combined extracts with water, dry (magnesium sulfate), concentrate and purify (silica gel chromatograpy, eluting with 20:80 ethyl acetate:hexanes) to give the title product (2.75 g, 52%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2-(4-Phenylbutyl)isoindole-1,3-dione 12 (1.9 g, 6.8 mmol) was added to chlorosulfonic acid (10 mL, 138 mmol) at 0° C. and the mixture was stirred for 1 h at the temperature. After storing in refrigerator at −5° C. overnight, the reaction mixture was poured onto crushed ice (100 g) and precipitates were collected by a suction filtration and dried under high vacuum to afford the desired product 13 (2.48 g, 99% yield). 1H NMR (300 MHz, CDCl3) 61.70 (m, 4H), 2.78 (m, 2H), 3.70 (m, 2H), 7.40 (d, 2H) 7.70 (d, 2H), 7.85 (d, 2H), 7.95 (d, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:13]([O:15]C=O)C>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]=[O:15]
Reactant: NCCCCCCCCCCN
Reactant: CCOC=O
Solvent: CCO
Product: NCCCCCCCCCCNC=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,10-diaminodecane (6.88 g, 40 mmol) were dissolved in 100 ml of ethanol and 3.22 ml of ethylformate was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours and evaporated to dryness. The residue was chromatographed on a silica gel column using 25% methanol/methylenechloride as the eluent to obtain 4 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][O:30][N:29]([CH3:28])[C:10](=[O:11])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: CNOC
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Temperature: 22 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 306 mg (1.25 mmol) of (2S)-(3,4-dichlorophenyl)-4-pentenoic acid (prepared according to the procedure of Hale, J. J.; Finke, P. E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993,3, 319-322) and 202 mg (1.50 mmol) of 1-hydroxybenzotriazole hydrate in 10 mL of methylene chloride was cooled to 0° C. and treated with 287 mg (1.50 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide. The cooling bath was removed and after 45 min. a solution of 365 mg (3.75 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 522 μl (3.75 mmol) of triethylamine in 10 mL of methylene chloride was added via cannula. The mixture was then stirred at 22° C. for 4 hours and then quenched with 10 mL of water and diluted with 8 mL of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2×10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 75 g of silica gel using 1:9 v/v ethyl acetate/hexane as the eluant afforded 319 mg (89%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ 2.40 (pentet, 1H), 2.75 (pentet, 1H), 3.13 (s, 3H), 3.52 (s, 3H), 3.99-4.01 (m, 1H), 4.96-5.05 (m, 2H), 5.63-5.70 (m, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H). Mass Spectrum (FAB): m/z 290 (M+H, 37Cl+35Cl isotope, 50%), 288 (M+H, 37Cl+37Cl isotope, 100%).