Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:7]CC[CH2:4][N:3]1[CH2:8][CH2:9][C:10](=[O:12])[CH3:11].[C:13](O)(C(O)=O)=O.[CH2:19]([OH:21])[CH3:20]>>[OH:21][CH:19]1[CH2:7][CH2:2][N:3]([CH2:8][C:9](=[CH2:13])[C:10](=[O:12])[CH3:11])[CH2:4][CH2:20]1
Reactant: CCO
Reactant: O=C(O)C(=O)O
Reactant: CC(=O)CCN1CCCCC1O
Product: C=C(CN1CCC(O)CC1)C(C)=O
Reaction time: 0.08 h

Procedure:
3-[(4-Hydroxypiperidino)methyl]-4-(4-(hydroxypiperidino)butan-2-one (1 g.) was dissolved in 8 ml. of ethyl alcohol and added to a cooled solution of oxalic acid anhydrous (0.9 g.) in 5 ml. of ethyl alcohol. After standing at 0° C. for five minutes, the resultant precipitate was filtered. The filtrate was stripped of solvent under reduced pressure and the residual oil taken up in a small volume of water, saturated with potassium carbonate and then extracted with ether. The ether solution was dried over anhydrous sodium sulphate, filtered and the filtrate stripped of ether. The residual oil, approximately 0.1 g., was characterized including a proton nuclear magnetic resonance spectrum in deuterated dimethylsulfoxide. There were two vinylic protons, at 5.9 and 6.1 ppm downfield from the reference tetramethylsilane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].[NH2:22][C:23]([NH2:25])=[O:24].[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=O.Cl>C(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[CH:9]2[C:27]([C:26]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:30])[NH:25][C:23](=[O:24])[NH:22]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CSc2ccc([N+](=O)[O-])cc2C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(=O)NC1c1cc([N+](=O)[O-])ccc1SCc1ccc(OC)cc1

Procedure:
A mxiture of 5-nitro-2-(p-methoxybenzylthio)benzaldehyde (1.0 mmol), urea (1.5 mmol) and ethyl acetoacetate (1.5 mmol) in ethanol (2 ml) is heated with a catalytic amount of hydrochloric acid to yield the compound 2a.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:28]([CH:35]([CH3:39])[C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36](=[O:37])[CH:35]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH3:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(Oc1ccccc1)C(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)C(C)Oc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenoxypropionyl chloride.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13]O)=[CH:11][S:10][C:9]1=[N:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C=O)C.O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13][N:40]=[N+:41]=[N-:42])=[CH:11][S:10][C:9]1=[N:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)N=c2scc(CO)n2CCCNC(C)=O)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N=c2scc(CN=[N+]=[N-])n2CCCNC(C)=O)c(OC)c1
Reaction time: 2 h

Procedure:
The compound (3.45 g) obtained in the above (2) and triethylamine (976 mg) were dissolved in DMF (35 ml), and thereto was added dropwise methanesulfonyl chloride (0.75 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours, and thereto was added sodium azide (627 mg), and the mixture was further stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol (98:2)] to give the title compound (3.48 g) as oil.
Reaction SMILES: C([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(OC(C)(C)C)=O.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:21][C:19](=[O:20])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of BOC-O-benzyl-D-serine (5.05 g, 17.12 mmol) in MeOH (100 mL) at −78° C., was added SOCl2 dropwise. The reaction mixture was warmed to 0° C. and stirred for ˜4 hours and then concentrated. The residue was taken up in EtOAc and washed with 10% Na2CO3 (3×80 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. To the crude material in EtOAc (100 mL) at 0° C. was bubbled HCl gas for approximately 10 minutes, and the reaction was capped and the mixture stirred at 0° C. for 30 minutes before it was concentrated in vacuo. The crude material was diluted with 50 mL of a 1:1 solution of saturated NaHCO3/10% Na2CO3 and extracted with EtOAc (4×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give O-benzyl-D-serine methyl ester (3.13 g, 14.96 mmol) which was used without further purification. LCMS (ES) m/z 210.1 (M+H)+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:43])[CH2:27][NH:28][CH2:29][C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:43])[CH2:27][N:28]1[CH2:29][C:30]2([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:2]1=[O:4])([CH3:14])[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CC2(CCCCC2)N(c2ccccc2)C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
136 mg (0.46 mmol) of triphosgene are added to 10 ml of dichloro-methane. The medium is cooled to 0° C. and a solution of 580 mg (1.37 mmol) of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexyl-methyl)amino]acetamide and 260 μl (1.49 mmol) of diisopropylethylamine in 10 ml of dichloromethane are added drop by drop. The mixture is allowed to rise to room temperature and is stirred for one night. The medium is then poured into water and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20) and 485 mg of N-(2,6-diisopropylphenyl)-2-(2-oxo-1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid after having been precipitated in dichloromethane and heptane, filtered and dried. M.p. 107-9° C., yield=79%.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH:7](O)([CH3:9])[CH3:8].C1C=CC=CC=1.OS(O)(=O)=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC.O>[CH:7]([O:5][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)O
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: C/C=C/C(=O)OC(C)C
Yield: 56.9 %

Procedure:
40.0 g (465 mmol) of crotonic acid (Fluka 28010), 25.1 g (418 mmol) of isopropanol (Merck 1.09634.2500), 200 mL of benzene, 4.2 g of conc. H2SO4 and 2.1 g of para-toluene sulfonic acid was charged to a 500 mL flask equipped with a magnetic stirrer bar and Dean-Stark water separator. The mixture was refluxed until water formation ceased. 200 mL of ether was added to the mixture, and then washed with several portions of NaHCO3 (aq., sat.) until the the acid was neutralized. Organic phase was separated, dried with MgSO4 and filtered. Solvent was removed under reduced pressure and the remainder distilled at 95° C. to give 30.5 g of isopropylcrotonate. Yield 57%. 1H-NMR (CDCl3): 6.95 (dq, 1H), 5.82 (d, 1H), 5.05 (sept, 1H), 1.88 (d, 3H), 1.25 (d, 6H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Fe]>[CH2:1]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1ccccc1
Reactant: C=CCCCCCCC
Agent: [Fe]
Product: CCCCCCCCCc1ccccc1O

Procedure:
The alkylation reaction, example 11 from DE-A-1 271 682 was reworked analogously. In a 1 liter three-neck flask equipped with a thermometer, a magnetic stirring mechanism and a reflux condenser, 252.5 g (2.0 mole) nonene, 235.3 g (2.5 mole) phenol and 5.0 g catalyst from Example 2 and Example 3 were heated to 90° C. After 3 hours reaction time, the catalyst was filtered off. The filtrate was fractionated using a 10 cm Vigreaux column. In the boiling range from 159° C. to 181° C. the alkylation product nonyl phenol was obtained.
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]([O:14][NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:28]C(C)([O-])C.[K+]>>[Cl:3][C:4]1[C:5]([O:14][N:15]([CH3:28])[C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(NOc1ncc(C(F)(F)F)cc1Cl)c1cccc2ccccc12
Agent: [K+]
Solvent: CI
Product: CN(Oc1ncc(C(F)(F)F)cc1Cl)C(=O)c1cccc2ccccc12
Reaction time: 48 h

Procedure:
Iodomethane (0.82 g) was added to a stirred solution of the product from Example 13 (Compound 1012) (1.93 g) and potassium tert-butoxide (0.61 g) in tetahydrofuran (50 ml). The reaction mixture was stirred for 48 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was separated and extracted with 3 portions of ethyl acetate. The combined organic phases were dried, filtered and evaporated to give a residue which was purified by silica gel chromatography (ethyl acetate/petrol) to give the title compound, m/z (EI) 380 (M+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(/C=C/c3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2/C=C/c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
Under an argon atmosphere, to a mixture of (E)-5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-styrylpyrazin-2-amine (7b) (500 mg, 1.24 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy) phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11b (563 mg, 864 μmol, 69.7%) as a yellow solid. Rf=0.29 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.24 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.66 (s, 2H), 6.81-6.91 (m, 3H, includes AA′BB′), 6.99-7.04 (AA′BB′, 2H), 7.28-7.40 (m, 7H, includes AA′BB′), 7.82 (d, 1H, J=16 Hz), 8.11-8.19 (AA′BB′, 2H), 8.91 (s, 1H), 10.66 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.8, 17.9, 25.5 (6C), 42.0, 119.7 (2C), 120.3 (2C), 122.5, 127.1 (2C), 128.2 (2C), 128.5, 128.7 (2C), 128.9, 129.0, 130.3 (2C), 133.8, 136.0, 137.8, 142.8, 143.9, 148.0, 154.0, 156.7, 170.6; IR (KBr, cm−1) 471, 521, 638, 691, 746, 781, 806, 839, 914, 968, 1007, 1080, 1103, 1169, 1263, 1325, 1371, 1391, 1414, 1439, 1472, 1510, 1566, 1605, 1659, 2857, 2886, 2930, 2055, 3028, 3057, 3217; HRMS (ESI+) m/z 674.3203 ([M+Na]+, C38H49N3NaO3Si2+ requires 674.3205).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[C:24]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH:24]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccsc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 244A (0.070 g, 0.15 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.090 mL, 0.18 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (m, 3 H) 4.58 (m, 1 H) 5.74 (s, 1 H) 7.07 (m, 1 H) 7.18 (m, 1 H) 7.28 (m, 3 H) 7.37 (s, 1 H) 7.55 (m, 2 H) 7.66 (m, 1 H) 7.96 (d, J=6.62 Hz, 1 H) 8.07 (s, 1 H) 16.30 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].C1C=CC2N(O)N=[N:34][C:32]=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:34][CH3:32])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)NC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Boc-Gly-Pro-Nleu-OH (0.77 g, 2 mmol), HClNH2CH3 (0.27 g, 4 mmol.) and HOBt (0.35 g, 2.5 mmol) were dissolved in DMF and the solution was chilled to 0° C. on a water-ice bath. Triethylamine (0.7 ml) was added slowly while stirring the solution. After 5 minutes, EDC (0.46 g, 2.4 mmol.) was added to the solution and the stirring continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 150 ml chloroform. The chloroform solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the Boc-Gly-Pro-Nleu-NHCH3. TLC Rf=0.44 (developing solvents: CMA, 85:15:3). This product was used directly in next step without further purification and characterization. 30 ml solution of 30% TFA in DCM was used to remove the Boc group. The deprotection was allowed to proceed 30 minutes. Then, the DCM and TFA was removed under reduced pressure and benzene 3×20 ml was added and distilled to remove trace TFA. The TFA salt of Gly-Pro-Nleu-NHCH3 was dissolved in 50 ml and the solution was chilled to 0° C. Triethylamine was added slowly to neutralize the peptide. After a while, acetic anhydride (2ml) was added and the acetylation was allowed to proceed 40 minutes. The DCM was removed and the resulting mixture was dissolved in 100 ml chloroform. The chloroform solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was approximately 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the final product Ac-Gly-Pro-Nleu-NHCH3 (0.6 g, 88%). Analytical HPLC profile, single peak, RT=10.5 min. (10-50% B in 30 min.). FAB-MS, observed (M+H)+ =341. 1 -NMR (500 MHz, DMSO-d6, 28° C., assignment by TOCSY) δ 8.04 (m, C-terminal NH), 7.93 (m, Gly-NH), 7.71 (m, C-terminal NH), 7.48 (m, C-terminal NH), 4.94 (d, Pro-α), 4.81 (m, Pro-α), 4.68 (m, Pro-α), 4.50 (m, Pro-α), 4.29-3.52 (sets of bands, Nleu-α, Gly-α), 3.52-3.42 (m, Pro-δ), 3.36 (m, Pro-δ), 3.29-2.86 (sets of bands, Nleu-β), 2.59 (m, C-terminal N-CH3), 2.53 (m, C-terminal N-CH3), 2.31-2.03 (sets of bands, Pro-β), 1.96 (m, Pro-β, Pro-γ), 1.92-1.61 (m, acetyl-CH3, Pro-β, Nleu-g, Pro-γ), 0.86 (dd, Nleu-δ), 0.75 (m, Nleu-δ).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]([CH3:15])[CH2:9]1)=O)(C)(C)C.CC1CNCCCN1.[Cl:24][S:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30]([CH3:38])=[CH:31][N:32]=[CH:33]2)(=[O:27])=[O:26]>>[ClH:24].[CH3:15][CH:10]1[CH2:9][NH:8][CH2:14][CH2:13][CH2:12][N:11]1[S:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30]([CH3:38])=[CH:31][N:32]=[CH:33]2)(=[O:26])=[O:27]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: CC1CN(C(=O)OC(C)(C)C)CCCN1
Agent: CC1CNCCCN1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCCNCC3C)c12
Product: Cl
Yield: 15.2 %

Procedure:
Using 1.07 g of 4-(tert-butoxycarbonyl)-hexahydro-2-methyl-1H-1,4-diazepine prepared by protecting the 4-position of hexahydro-2-methyl-1H-1,4-diazepine (2.8 g) synthesized in accordance with J. Med. Chem., 1990, 33, 142 and 1.21 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.27 g of the objective compound (white crystals).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O.CO>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g (1.45 mmol) of 7-benzylxanthine from Example 6b) in 60 ml of dimethylformamide was heated to 50° C. and treated in portions with 0.35 g (1.45 mmol) of sodium hydride, diluted with 20 ml of dimethylformamide and stirred at 50° C. for one hour. 1.36 ml (1.45 mmol) of 2-bromopropane were added to this suspension and the temperature was increased to 80° C. In the course of the reaction, a total of 4.91 ml (52.3 mmol) of 2-bromopropane were additionally added. After a total of 16 hours at 80° C., 10 ml of water and 2 ml of methanol were added, and the mixture was stirred for 10 minutes, treated with a further 70 ml of water and extracted three times using 70 ml of methyl tert-butyl ether each time. The organic phases were washed with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.4).
Reaction SMILES: N1C=CC=CC=1.CS([O:11][S:12]([CH3:15])(=[O:14])=[O:13])(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]([CH3:29])[CH:22]=[C:21]2[C:30]1[N:40]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38]O)=[C:32]2[CH:31]=1>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]([CH3:29])[CH:22]=[C:21]2[C:30]1[N:40]([S:41]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)(=[O:43])=[O:42])[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][O:11][S:12]([CH3:15])(=[O:13])=[O:14])=[C:32]2[CH:31]=1
Reactant: COc1cc2c(-c3cc4c(CO)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(COS(C)(=O)=O)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 1 h
Yield: 29.2 %

Procedure:
0.064 g of pyridine and 0.092 g of methanesulfonic anhydride are added to a solution of 0.13 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol in 5 cm3 of dichloromethane, at a temperature in the region of −10° C. The reaction medium is stirred at this same temperature for one hour, and then at room temperature for 24 hours. Ice and 15 cm3 of dichloromethane are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.044 g of methanesulfonic acid 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl ester is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14]CC)=[O:13].O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (1.0 g, 4.5 mmol) in THF (14 mL), MeOH (3 mL), and H2O (3 mL) was added lithium hydroxide monohydrate (0.68 g, 16 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (20 mL) and washed with DCM (25 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 0.9 g of pure 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 94%).