Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(S([S:21][CH2:22][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:24][S:25]S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:25][CH2:24][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:22][S:21]1)=[O:8])[CH3:11]
Reactant: CN(C)C(CSS(=O)(=O)c1ccccc1)CSS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)SCC(N(C)C)CS1
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To 20 ml of chloroform were added 1.6 g (0.01 mole) of diethyl malonate and 4.3 g (0.01 mole) of 1,3-bis(benzenesulfonylthio)-2-(N,N-dimethylamino)propane, and then 2.1 g (0.02 mole) of triethylamine was added thereto at room temperature. After completion of addition, the reaction was allowed to proceed at 40° C. for 4 hours. The reaction mixture was washed with two 20-ml portions of water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was heated in 20 ml of ether-hexane (1:1) for dissolution and the solution was allowed to stand in the cold overnight. The resulting crystalline precipitate was collected by filtration to give 2.7 g (90%) of 2,2-diethoxycarbonyl-5-(N,N-dimethylamino)-1,3-dithiane as light-yellow crystals melting at 38°-39° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]CBr)=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:20]2[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][CH2:19]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Reactant: CCN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(CN2CCN(CC)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:39])[N:32](C1CCNC1)[CH3:33])([CH3:29])([CH3:28])[CH3:27].C([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])C>CN(C=O)C.O>[C:26]([O:30][C:31](=[O:39])[NH:32][CH2:33][CH:46]1[CH2:44][CH2:43][N:42]([C:14]2[CH:13]=[C:12]3[C:17]([C:18](=[O:19])[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10](=[O:25])[N:11]3[CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:20])[CH2:45]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Temperature: 70 °C
Yield: 55 %

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.162 g, 0.44 mmol) in DMF (3.0 mL) was reacted with pyrrolidin-3-yl-methyl-carbamic acid tert-butyl ester (0.40 g, 2.0 mmol) and triethylamine (0.63 mL, 4.5 mmol) then heated to 70° C. for 2 days. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.127 g of the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=[C:11]2[N:10]=[CH:9]1)=O)(C)(C)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([Br:35])[CH:30]=1.[Li+].CC([N-]C(C)C)C>>[CH3:25][N:23]([CH3:24])[CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:13]=[C:12]3[NH:8][C:9]([C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([Br:35])[CH:30]=4)=[O:27])=[N:10][C:11]3=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: CN(C)C1CCN(c2ccc3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CN(C)C1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Yield: 39.8 %

Procedure:
Starting with 5-(4-dimethylamino-piperidin-1-yl)-imidazo[4,5-b]pyridin-3-carboxylic acid tert-butyl ester [Example 135, Step 4 (Step 4)] (711 mg, 2.05 mmol) and methyl-2-bromo-isonicotinate (445 mg, 2.05 mmol), the reaction was performed by following General procedure J (LDA metallation) followed by work up method D. Purification by SiO2 chromatography (CH2Cl2/MeOH) gave [5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-[2-bromo-pyridin-4-yl]-methanone (350 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 1.43 (m, 2H), 1.93 (m, 2H), 2.26 (s, 6H), 2.47 (m, 1H), 2.87 (m, 2H), 4.53 (m, 2H), 6.95 (d, J=9.54 Hz, 1H), 7.83 (d, J=9.03 Hz, 1H), 8.14 (d, 5.03 Hz, 1H), 8.42 (s, 1H), 8.47 (d, J=5.02 Hz, 1H). MS(ESI) m/z 430 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1C(C2CCCCC2)CCN1Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-(3-cyclohexyl-2-oxo-pyrrolidin-1-ylmethyl)-phenyl ester (0.80 g, 1.69 mmol), 4-methoxycarbonylphenylboronic acid (0.457 g, 2.53 mmol), sodium carbonate (0.538 g, 5.07 mmol) in THF (20 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.098 g, 0.084 mmol), raise the reaction temperature to 80° C., and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 20% ethyl acetate in hexanes to afford 0.62 g (80%) of the titled product. MS (m/z): 460 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:19])([CH3:18])[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>ClCCl.C(N(CC)CC)C>[CH3:18][C:7]1([CH3:19])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: CC1(C)Cc2ccc(N)cc2CN1C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C(=O)C(F)(F)F)C(C)(C)C3)cc1C(F)(F)F
Yield: 62.1 %

Procedure:
A solution of 7-amino-3,3-dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline (408 mg; 1.5 mmol) in dichloromethane (20 ml) and triethylamine (0.6 ml) was treated with 4-methoxy-3-trifluoromethylbenzoyl chloride (358 mg; 1.5 mmol). The resultant solution was stirred at 25° C. for 1 h. The reaction mixture was then washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1% methanol in dichloromethane, to give the title compound (442 mg).
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:11]=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1ccc2ccccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
1,4-Benzenedialdehyde (30 g, 0.22 mol), 2-methylquinoline (21 g, 0.15 mol) and acetic anhydride (41.5 ml, 0.40 mol) were dissolved in 160 ml of xylene. The resulting mixture was refluxed for 7 hours. After the mixture was allowed to cool down to room temperature, it was added to 200 ml of petroleum ether which had been warmed to 40-60° C. The resulting precipitate was filtered off. The mother liquor was concentrated and the crude product so obtained was recrystallized twice from etnanol, whereby 13.6 g of the title compound were obtained (yield: 35%).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([CH3:30])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:33]N>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:33][N:2]=[CH:3][C:4]=2[CH3:30])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 36 above, with compound B, 6-(3-dimethylamino-2-methyl-acryloyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:3]([S:4]([CH3:7])(=[O:6])=[O:5])[C:8]1[CH:13]=[C:12]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-Ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (3.2 g, 12.2 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO at 50° C. for 5 hours. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. The product was purified by flash chromatography (ethyl acetate:petrol 1:1). Yield 2.6 g (48%) 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.33 Hz, 3H), 1.39 (s, 9H), 2.0 (br, 2H), 2.99 (s, 3H), 3.2 (br, 2H), 3.54-3.75 (br, 8H), 6.65 (br d, J=9.3 Hz, 1H), 6.67 (d, J=2.93 Hz, 1H), 8.1 (d, J=9.3 Hz, 1H); MS (ESI+) for C19H30N4O6S m/z 442 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:14][CH2:15][C:16](N)=[NH:17].C(O)C.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:16]([CH2:15][O:14][C:13]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:11]([Cl:10])[CH:12]=2)[N:17]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(COc2ccc(Cl)c(Cl)c2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 9.6 g (0.080 mole) of 3-amino-2-pyrazinecarbonitrile and 26.3 g (0.12 mole) of 2-(3,4-dichlorophenoxy)acetamidine in 520 ml of absolute ethanol. Refluxing time: 3 hours. Yld: 18.0 g (70%), m.p. 261°-263° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [NH3:1].CS([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]3[CH:30]=[N:29][NH:28][C:15]3=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:9]=[CH:8][N:7]=1)(=O)=O>C1COCC1>[NH2:1][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]3[CH:30]=[N:29][NH:28][C:15]3=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
A solution of THF (20 mL) saturated with NH3 (g) at −20° C. was added over 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) in a closed vessel. It was stirred at room temperature for 2 days and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 7 mg of the title compound (yield: 9%)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:34][CH3:35])=[C:23]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:24]=1>C(O)(C)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:34][CH3:35])=[C:23]([S:25]([N:28]2[CH2:29][CH2:30][N:31]([C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[C:5]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:6]4[CH3:11])[CH2:32][CH2:33]2)(=[O:26])=[O:27])[CH:24]=1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCNCC1
Solvent: CC(C)O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(c2ncnc3c2nc(-c2cnn(C)c2)n3C)CC1
Yield: 49 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 1-(5-chloro-2-methoxyphenylsulfonyl)piperazine (43.6 mg, 0.15 mmol, Oakwood Products, Inc.), and triethylaminem (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The resulting precipitate was collected by vacuum filtration, washed with ethanol (2 mL), water (2 mL) and diethyl ether (2 mL) and dried under reduced pressure, to give 29.6 mg (49% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.70 (dt, 2H), 7.27 (d, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.31-3.25 (m, 4H). MS (EI) for C21H23ClN8O3S: 503.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]([O:31][CH3:32])([O:29][CH3:30])[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]([O:31][CH3:32])([O:29][CH3:30])[CH3:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reactant: COC(C)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)OC
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (0.2234 g, 0.68 mmol), 60% NaH (1.460 g, 36.5 mmol), and 1-bromo-2,2-dimethoxypropane (7.760 g, 42.4 mmol) in THF (20 mL) was heated at 80° C. for 3 d and then cooled to rt. The reaction mixture was then quenched with water, extracted with ethyl acetate (3×), and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude product (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2,2-dimethoxypropoxy)methyl)piperidine-1-carboxylate was directly used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1>CS(C)=O>[OH:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), (S)-pyrrolidin-3-ol hydrochloride (163 mg, 1.32 mmol, 3.00 equiv), DIEA (227 mg, 1.76 mmol, 4.00 equiv), toluene (4 mL), in DMSO (2 ml). The resulting solution was stirred at 100° C. for 7 hrs. Then the reaction was quenched by the addition of water. The resulting solution was extracted with 5×15 mL of dichloromethane and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (70:1). This resulted in 176 mg (crude) of (S)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH2:43]>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH-:43]
Reactant: NCc1ccccn1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [NH-]Cc1ccccn1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 206 μl (2 mmol, 216 mg) of 2-picolylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.29) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 1:1 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (188 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[C:6]=1[CH3:13].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:11][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(OCCO)ccnc1CO
Solvent: ClCCl
Product: Cc1c(OCCO)ccnc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.9 g of the 4-(2-hydroxyethoxy)-2-hydroxymethyl-3-methylpyridine prepared above was dissolved in 200 ml of dichloromethane to obtain a solution. 24 ml of thionyl chloride was dropwise added to this solution at 0° C. The obtained mixture was stirred at a room temperature for 2 hours and distilled under a reduced pressure to remove the dichloromethane and excess thionyl chloride. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue to obtain a mixture. This mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 10.9 g of 2-chloromethyl-4-(2-hydroxyethoxy)-3-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][N:30]=[C:31]=[O:32]>C(#N)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)NS(=O)(=O)c1ccc(NC(=O)NCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
A solution of methyl 4-aminophenylsulfonylcarbamate (50 mg, 0.2 mmol), N,N-diisopropylethylamine (35 L, 0.2 mmol), 3,4-dichlorobenzylisocyanate (30 L, 0.2 mmol) in acetonitrile was stirred under an N2 atmosphere for 19 h. The mixture was concentrated and the residue purified by reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give methyl 4-(3-(3,4-dichlorobenzyl)ureido)phenylsulfonylcarbamate. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=431.01; tR=2.9 min.