Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([SH:40])[CH3:39].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([CH2:14][S:40][CH2:38][CH3:39])([OH:13])[C:15]([F:16])([F:17])[F:18]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 19.1 %

Procedure:
To 66 mg (0.14 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 and 93 mg (0.29 mmol) Cs2CO3 in 0.6 ml DMF are added 16 μl (0.22 mmol) of ethyl mercaptan in DMF. The mixture is stirred vigorously for 20 hours and water is added. The aqueous layer is extracted with ethyl acetate, the organic phases washed with brine and dried over sodium sulphate. After removal of the solvent thin layer chromatography on silica gel (ethyl acetate) yields 14 mg of the title compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[CH2:16][CH2:17][CH2:18][CH:9]([C:10]=23)[C:8]1=[O:19].C(Br)C#C>CN(C)C=O.O>[CH2:3]([C:9]12[CH2:18][CH2:17][CH2:16][C:11]3[C:10]1=[C:15]([CH:14]=[CH:13][CH:12]=3)[NH:7][C:8]2=[O:19])[C:2]#[CH:1]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC12CCCc3cccc(c31)NC2=O
Reaction time: 0.25 h

Procedure:
Potassium tert.-butoxide, 4.94 g (0.044 mol), was added to a solution of 6.92 g (0.04 mol) of rac-2a,3,4,5-tetrahydro-benz[cd]indol-2(1H)-one in 50 ml of dimethylformamide. After stirring for 15 minutes under nitrogen, 5.23 g or 3.9 ml of propargyl bromide was added and stirring was continued for 30 minutes. The mixture was diluted with water and ice and the precipitate was collected by filtration, washed with water and sucked dry. The solids were dissolved in methylene chloride and the solution was dried and evaporated. Crystallization of the residue from ethyl acetate gave crude product of rac-2a,3,4,5-tetrahydro-2a-(2-propynyl)benz[cd]indol-2(1H)-one with m.p. 174-177° which was recrystallized from ethyl acetate to melt at 177°-180°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=2)[CH2:24]1)=[O:12]
Reactant: FC(F)(F)c1ccc(C2CCCNC2)cc1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (44 mg, 0.22 mmol) was dissolved in DCM (4 ml). 3-(4-Trifluoromethylphenyl)piperidine HCl (51 mg, 0.19 mmol) and triethylamine were added. The mixture was stirred for 1 h, 1 M HCl (2 ml) was added, and the phases were separated. The organic phase was absorbed on silica and the mixture purified by flash chromatography using heptane/EtOAc as eluent. The fractions containing the first eluting diastereomer were collected to yield 21 mg of A11.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([O:14][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:5]=2)=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1cc(O)ccc1C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(OCc2ccccc2)ccc1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 178.5 %

Procedure:
A suspension of 1.1 g (5.64 mmol) of 2-acetylamino-4-hydroxy-benzoic acid (preparation: Recl. Trav. Chim. Pays-Bas, 72, p195, 1953), 1.6 ml (13.53 mmol) of benzyl chloride, 3.9 g (28.18 mmol) of potassium carbonate in DMF (15 ml) was stirred at 80° C. for 17 h under argon. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and water. The layers were separated, the aqueous layer once extracted with CH2Cl2, the organic layers combined, washed with brine, dried over MgSO4 and concentrated in vacuo, to give 1.89 g (85.75%) of the desired 2-acetylamino-4-benzyloxy-benzoic acid benzyl ester as an off-white solid. ISP mass spectrum, m/e: 376.5 (M+1 calculated for C23H21NO4: 375.42).
Reaction SMILES: [O:1]=[C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])[CH2:3][CH2:4]C1C=CC=CN=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37]CCC(NN)=O.ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1>>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37][CH2:4][CH2:3][C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])=[O:1]
Reactant: NNC(=O)CCSCc1ccco1
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCSCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide (13) was prepared in the manner 8-chlorodibenz[b,f]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6) was prepared, as described above in Example 6, from 3-[(2-furanylmethyl)thio]propanoic acid, hydrazide (12), prepared as described above in Example 12, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, on a 10 mmol scale. The yield was quantitative. Analysis calculated for C22H20N3O4SCl (M.W. 457.94): C, 57.70; H, 4.40; N, 9.18; Cl, 7.74; S, 7.00. Found: C, 57.59; H, 4.36; N, 9.01; Cl, 7.95; S, 7.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Reaction time: 0.45 h
Yield: 92.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4010 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.0902 g, 0.0023 mol) in DMF (2 mL) and after stirring for 27 min, benzyl bromide (0.26 mL, 0.0022 mol) is added. After stirring for 2.5 h at room temperature, the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 100/0) to give 0.5158 g (91%) of the title compound. An aliquot (0.0625 g) is recrystallized from ethyl acetate/heptane to give 0.0415 g of product; mp 196.5-197° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; 1H NMR (CDCl3) δ2.24, 2.58, 2.87, 5.31, 6.99, 7.16, 7.29, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.18; H, 5.19; N, 4.58.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71]C=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.N1CCCC1>>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]([N:52]4[CH2:54][CH2:67][CH2:72][CH2:71]4)=[O:41])[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Solvent: C1CCNC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)N3CCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with pyrrolidine (0.13 mL) in a similar manner as described in Example 24-(i) to give the titled compound (550 mg) as a colorless powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:18]([C:1]([C:26](=[O:28])[CH3:27])([C:16](=[O:21])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19])(=[O:19])[CH3:17]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)C(CCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO)(C(C)=O)C(C)=O

Procedure:
In a procedure similar to Grode and Cardellina D-erythro-sphingosine (4, 2 mg, 6.7 μmol, Sigma) in acetic anhydride (1 ml) and pyridine (2 ml) was stirred at 25° C. for 4.5 h, at which time no starting material could be observed by TLC. The solvent was removed by a stream of nitrogen to give 133: white solid; silica TLC Rf 0.86 (3:12:2:2 CHCl3/1-BuOH/AcOH/H2O, phosphomolybdic acid), 0.65 (9:1 CHCl3/MeOH, phosphomolybdic acid); FABMS m/z 580, 426, 366, 306, 264; CIMS m/z 468, 454, 426, 424, 394, 366, 364, 306, 264, 144, 85, 84, 83, 61.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCCCC(N1CC(O)(C2C=CC(C)=CC=2)C[C@H]1C(O)=O)=O)(=O)C>>[OH:26][C:17]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: Cc1ccc(C2(O)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)cc1
Agent: CC(=O)SCCCC(=O)N1CC(O)(c2ccc(C)cc2)C[C@H]1C(=O)O
Product: Cc1ccc(C2(O)CN[C@H](C(=O)O)C2)cc1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline form part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(4-methyl)phenyl]-L-proline. This amino acid is then reacted with 4-acetylthiobutyroyl chloride according to the procedure of Example 1 (c) to yield 1-[4-(acetylthio)-1-oxobutyl]-4-hydroxy-4-[(4-methyl)phenyl]-L-proline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>CN(C=O)C.O>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]2[CH:37]=[C:36]3[C:41]([C:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)=[N:33][CH:34]=[N:35]3)=[CH:40][CH:39]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: CN1CCN(CCCN)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(CCCNc2ccc3c(C4CCNCC4)ncnc3c2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminopropyl)-1-methylpiperazine (0.1 mmol), Et3N (0.1 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 12b, in DMF (1 mL) was stirred at 130° C. for 3 h. It was then diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h, then concentrated in vacuo.
Reaction SMILES: [CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][OH:16])[N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].ClC(Cl)(Cl)[C:57]([N:59]=C=O)=[O:58].C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl.CO>[C:57](=[O:58])([O:16][CH2:15][CH2:14][C:11]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[N:9]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:51][CH2:52][CH2:53][CH3:54])[C:12]=1[Cl:13])[NH2:59]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CCO)c1Cl
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CCOC(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a 0° C. solution of N,N-dibutyl-4-chloro-5-(2-hydroxyethyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamide (Example 170, 20 mg, 0.026 mmol) in CH2Cl2 (0.5 mL) was added trichloroacetyl isocyanate (4 μl, 0.031 mmol). After stirring at 0° C. for 30 min, K2CO3 (2 mg, 0.014 mmol) and MeOH (0.5 mL) were added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford a colorless oil. The oil was dissolved in MeOH (3.0 mL) and water (3.0 mL) and K2CO3 (120 mg, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then partitioned between EtOAc and H2O. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (10 mg, 44%) as a white solid. 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 8.73 (br s, 1H), 8.13-8.04 (m, 4.5H), 8.02-7.95 (m, 2H), 7.78-7.64 (m, 3H), 7.23-7.08 (m, 4H), 7.02-6.88 (m, 0.5H), 4.94-4.89 (m, 1H), 4.67-4.41 (m, 1H), 4.25 (t, J=6.5 Hz, 2H), 4.18-4.05 (m, 1.5H), 4.01-3.71 (m, 1.5H), 3.65-3.46 (m, 4H), 3.37-3.34 (m, 2H), 3.02 (t, J=6.5 Hz, 1.5H), 2.92-2.77 (m, 1.5H), 1.68-1.53 (m, 2H), 1.31-1.25 (m, 3H), 1.20-1.17 (m, 1H), 0.99 (t, J=7.4 Hz, 2H), 0.94-0.86 (m, 3H), 0.78-0.73 (m, 2H), 0.68 (t, J=6.4 Hz, 1H); MS(ESI+) m/z 813.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]1[O:14][CH2:13]1.[C:15](O)(=[O:17])[CH3:16]>>[OH:17][CH2:15][CH2:16][N:1]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:13][CH2:12][OH:14]
Reactant: CC(=O)O
Reactant: COC(=O)c1cccc(N)c1
Reactant: C1CO1
Product: COC(=O)c1cccc(N(CCO)CCO)c1

Procedure:
Methyl 3-aminobenzoate (3.8 g; 25 mmol) was reacted with 11 g (250 mmol; 10 equivalents) of ethylene oxide in 25 ml of 30% acetic acid, followed by post treatments. The crude product so obtained was purified by chromatography on a silica gel column (eluted with methylene chloride/2-4% methanol), whereby 5.95 g (24.9 mmol) of the title compound were obtained as a yellow oil (yield: quantitative).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9].[CH2:25]([NH2:28])[CH2:26]N.[CH3:29][N:30](C)C=O>>[NH2:30][CH2:29][CH2:26][CH2:25][NH:28][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9]
Reactant: CN(C)C=O
Reactant: NCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2ccccc12
Product: NCCCNc1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)O

Procedure:
A mixture of Example 61A (90 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was treated with ethylene diamine (1 mL), heated to reflux for 2 days, and dried under vacuum. The concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(−)) m/e 398 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.05 (m, 1H), 7.96 (dd, 1H), 7.70-7.82 (m, 3H), 7.65 (d, 1H), 7.21-7.51 (m, 4H), 6.73 (d, 1H), 6.57 (t, 1H), 3.01-3.26 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(C)CCN(C)C.C([N-]CC)C.[K+].[C:25](=[O:27])=[O:26]>C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:25]([OH:27])=[O:26]
Reactant: COc1cccc(OC)c1
Reactant: O=C=O
Agent: CC[N-]CC
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of 1,3-dimethoxybenzene (12.06 g.) and tetramethylethylenediamine (15 ml.) in triethylamine (20 ml.) was added to the potassium diethylamide reaction mixture and stirred for two hours. The entire mixture, a gray suspension, was poured into a 1-liter beaker containing crushed dry ice (456 g.) with the aid of 35 ml of added triethylamine and was allowed to warm to room temperature. The contents of the beaker were transferred into a 1-liter flask with the aid of some water. All volatile components were removed by a rotary evaporator. The solid remaining in the flask was partitioned between diethyl ether (30 ml.) and water, which was extracted with diethyl ether (four times, 30 ml.). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1. The resultant precipitate was collected by filtration, water-washed and air dried to give 10.99 g. (69% yield) of 2,6-dimethoxybenzoic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29]([O:32][CH2:33]Cl)[CH2:30][CH3:31]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOCCl
Reactant: O=c1[nH]c(=O)n(CC2CC2)c2ncn(Cc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC2CC2)c1=O
Reaction time: 1 h

Procedure:
1.12 g (8.1 mmol) of potassium carbonate were added at 60° C. to a solution of 1.5 g (5.06 mmol) of 7-benzyl-3-cyclopropylmethylxanthine from stage a) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 722 μl (6.58 mmol) of propoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 4 hours. 12 ml of water and 5 ml of methanol were added and the mixture was stirred at 50° C. for 2 hours. 60 ml of water were then added again, the mixture was extracted three times using methyl tert-butyl ether, and the combined organic phases were washed twice 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 (19.8/0.2).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[C:29]([F:50])=[CH:30][C:31]([OH:49])=[C:32]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])[CH:33]=1>>[Cl:27][C:28]1[C:29]([F:50])=[CH:30][C:31]([OH:49])=[C:32]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])[CH:33]=1
Reactant: CCCCCN1C(=O)C(c2cc(Cl)c(F)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(Cl)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-chloro-4-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (46%): MS (ES+) m/z 360 (M−17), 400 (M+23).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH3:15])[CH:14]=2)[CH:6]=[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:4]=1.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>O>[CH3:28][S:24]([C:3]1[N:8]=[C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH3:15])[CH:14]=2)[CH:6]=[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:4]=1)(=[O:26])=[O:23]
Reactant: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CCOCC2)n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of the above-prepared [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.63 mmol) in MeOH (10 mL) is added a solution of oxone (3.0 g) in water (10 mL). The reaction mixture is stirred at room temperature for 15 hours and most of the solvent is evaporated. The residue is partitioned between DCM and aqueous saturated NaHCO3. The organic layer is washed with brine, dried, filtered and evaporated. The residue is triturated in MeOH and the resulting white solid is collected by filtration to give [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].[I-].[C:9](=[N:12][O:13][N+]1(C)CCCCC1)([CH3:11])[CH3:10].[CH2:21]1OCCOCCOCCOCCOC1>O>[C:9](=[N:12][O:13][CH2:21][O:5][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])([CH3:11])[CH3:10]
Reactant: CC(C)=NO[N+]1(C)CCCCC1
Reactant: CC(O)C(=O)[O-]
Reactant: C1COCCOCCOCCOCCO1
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CC(C)=NOCOC(=O)C(C)O

Procedure:
1.1 g of sodium lactate, 3.5 g of N-[(isopropylideneamino)oxy]-N-methyl-piperidinium iodide and 0.1 g of 15-crown-5 in 10 ml of diglycol dimethyl ether are heated at 110° C. under nitrogen for 4 hours. The mixture is then poured into 50 ml of water and extracted three times with ethyl acetate. The organic phase is washed four times with water and subsequently evaporated. After chromatograhy of the residue on a 10-fold amount of silica gel with n-hexane/ethyl acetate (1:1) and evaporation of the eluate, there is obtained 0.35 g of L (-)-lactic acid [[(isopropylideneamino)oxy]methyl] ester; [α]D20 =-1.2° (c=1.50% in chloroform).