Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:20][N:21]([CH3:33])[C:22]1[CH:23]=[C:24]([NH:28][CH2:29][C:30]([OH:32])=O)[CH:25]=[CH:26][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[CH3:33][N:21]([CH3:20])[C:22]1[CH:23]=[C:24]([NH:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)=[O:32])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)c1cccc(NCC(=O)O)c1
Reactant: CCNCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccccn1)C(=O)CNc1cccc(N(C)C)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of ethyl-pyridin-2-ylmethyl-amine (41.1 mmol) and DIPEA (112 mmol) in DMF (200 mL) was cooled to −20° C. and added to a cold (−20° C.) solution of (3-dimethylamino-phenylamino)-acetic acid (37.4 mmol) and TBTU (48.6 mmol) in DMF (300 mL). The reaction mixture was stirred for 10 min at −20° C. Water (500 mL) and ethyl acetate (500 mL) were added, the layers were separated and the organic layer washed with water (4×200 mL). The combined aqueous layers were extracted with ethyl acetate (300 mL). The combined organic layers were washed with NaOH solution (1.0 mol/L, 100 mL) and brine (100 mL) and dried over Na2SO4. The solvents were removed in vacuo and the obtained solid was dissolved in ethanol. A solution of hydrogen chloride in ether was added at 0° C., the solvents were removed and the residue was crystallized from ethanol/ether to give 7.6 g product as white crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1([C:13]2[CH:14]=[N:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([NH:24][CH:25]([C:29]4[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[CH:10]1([C:13]2[CH:14]=[N:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([NH:24][CH:25]([C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:34])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)CCN
Reactant: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (31 mg, 0.27 mmol), (+/−)-4-(1-{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}butyl)benzoic acid (0.050 g, 0.13 mmol), hydroxybenzotriazole hydrate (0.020 g, 0.13 mmol), and triethylamine (76 ul, 0.55 mmol) in dichloromethane (1.3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.9 g, 201 mmol) (28 mg, 0.15 mmol) at rt. The mixture was stirred for 2 hours at ambient temperature. The reaction was diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 25 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, 1.48 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 2.5 mL of 37% formaldehyde solution and dropwise addition of 4 mL of 2.9 M sodium hydroxide solution. The reaction mixture was stirred for 25 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure before 20 mL water and 10 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 12j (1.09 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:20][NH:21][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
A slurry of methyl isophthalate (5.10 g, 0.028 mol) in CH2Cl2 (100 ml) at room temperature was treated with oxalyl chloride (6.0 ml) followed by DMF (3 drops). The resultant mixture was stirred under reflux (90 mins). The resultant mixture was cooled to room temperature, the solvent removed by evaporation and the residue azeotroped with CH2Cl2. The resultant mixture was dissolved in THF (100 ml), cooled to 0° C. and treated with a solution of methylamine (2M, 28 ml,56 mmol) in THF. The mixture was allowed to warm to room temperature overnight, solvent removed by evaporation and resultant mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer separated and washed with sat aq NaHCO3, sat aq brine, and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product (white solid, 4.60 g, 79%). 1H NMR (CDCl3) δ 3.00 (d, 3H), 4.00 (s, 3H), 6.30 (s, br, 1H), 7.50 (t, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H). LRMS m/z=211.1 (M+18)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.[H-].[Na+].I[CH3:25]>C(#N)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([CH3:25])[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1
Reactant: CI
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(OC)nc(C2(C)C(=O)Nc3c(F)cccc32)n1
Temperature: 60 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (5.0 g) is introduced as initial charge in 225 ml of acetonitrile, sodium hydride (0.73 g, 60% in mineral oil) is added and the mixture is after-stirred until a thick suspension is formed. After adding iodomethane (7.0 g), the mixture is heated to 60° C. and stirred for 11 hours at 60° C. The organic solvent is largely distilled off in vacuo. 2-Propanol is added to the partially crystalline residue and the product is filtered off. This gives the intermediate as a solid in an HPLC purity of 93% (3.46 g, 64% of theory). The structure can be confirmed by NMR spectroscopy.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:21])([CH3:20])[C:7]=2[CH:22]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:20])([CH3:21])[C:7]=2[CH:22]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1oc1cccnc21
Temperature: 178 °C
Yield: 54.6 %

Procedure:
Mixture of 8-methoxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b] fluoren-5-one (Compound GT15-4, 25 mg) and pyridine hydrochloric acid salt (492 mg) was stirred and heated at 178° C. overnight. The reaction mixture was cooled, and added with water. The mixture was neutralized with saturated aqueous solution of sodium bicarbonate and extracted with DCM. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (DCM/MeOH) to obtain the title compound (13 mg, 54%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[O:16][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A cooled (0° C.) solution of (S)-4-benzyl-3-((S)-2-cyclopropyl-2-hydroxy-acetyl)-oxazolidin-2-one (4.137 g, 15.026 mmol) in dichloromethane (60 mL) was subsequently treated with 2,6-lutidine (3.5 mL, 30.052 mmol) and triisopropylsilyl trifluoromethanesulfonate (6.1 mL, 22.539 mmol). After stirring at room temperature for 1 h, the reaction was quenched with pH 4 buffer (phthalate). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (5.28 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.40-0.49 (m, 2H), 0.53-0.62 (m, 1H), 0.63-0.71 (m, 1H), 1.02-1.18 (m, 21H), 1.20-1.34 (m, 1H), 2.66 (dd, J=13.1, 10.5 Hz, 1H), 3.49 (dd, J=13.1, 3.4 Hz, 1H), 4.17-4.27 (m, 2H), 4.63-4.73 (m, 1H), 5.58 (d, J=5.1 Hz, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:31])[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]([SH:30])=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][O:25]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:30][C:27]3[CH:28]=[CH:29][C:20]([O:19][CH2:18][C:17]([OH:31])=[O:16])=[C:21]4[C:26]=3[O:25][CH2:24][CH2:23][CH2:22]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)on2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp 131-133° C.; MS m/z 446 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:15](OC(=O)C)=[O:16].CO>CCOCC>[CH:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(=O)OC=O
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: CO
Solvent: CCOCC
Product: O=CNc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (0.96 g, 4.44 mmol) was suspended in ether (50 ml). Acetic formic anhydride (1.0 g, 11.36 mmol) was added dropwise and the reaction mixture was stirred for 16 hours. The white precipitate was collected by filtration and triturated with ether (50 ml). There was thus obtained (4-formamidophenylsulphonyl)nitromethane (0.98 g, 90% yield), m.p. 192°-193° C. (after recrystallisation from aqueous methanol); microanalysis, found: C, 39.3; H, 3.1; N, 11.4%; C8H8N2O5S requires: C, 39.3; H, 3.3; N, 11.5%.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:30])=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.C(O[CH:37](OCC(C)(C)C)[N:38]([CH3:40])[CH3:39])C(C)(C)C>O1CCCC1>[CH3:37][N:38](/[CH:40]=[N:29]\[C:27](=[O:28])[C:24]1[CH:23]=[C:22]([CH3:30])[C:21]([C:19]2[CH:18]=[N:17][C:12]3[NH:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]4)[C:11]=3[N:20]=2)=[CH:26][N:25]=1)[CH3:39]
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(=O)/N=C\N(C)C)cc4C)nc32)CC1
Temperature: 85 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide (0.412 g, 1.00 mmol), dimethylformamide dineopentylacetal (1.5 mL) and tetrahydrofuran (10 mL) were combined and heated at 85° C. for 3 h. Reaction was concentrated under a stream of nitrogen placed in reaction vessel. Crude product was used directly for next step (0.467 g, 1.00 mmol, 100% yield). MS (ESI) m/z 466.6 [M+1]+
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:42]2[N:41]=[C:40]([Cl:43])[N:39]=[C:23]([NH:24][CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]=2[N:21]=[CH:20]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>CO.O>[Cl:43][C:40]1[N:39]=[C:23]([NH:24][CH2:25][CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:22]2[N:21]=[CH:20][N:19]([C:42]=2[N:41]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 11.2 %

Procedure:
2-Chloro-N-(2,2-diphenylethyl)-adenosine 2',3',5'-triacetate (2.0 g,3.29 mmol) was dissolved in methanol (120 ml) and the solution was stirred at room temperature with 2M aqueous sodium carbonate solution (10 ml). After 2h the mixture was diluted with water (350 ml) and extracted with ethyl acetate (2×10 ml). The extract was washed with water (100 ml) and dried (MgSO4) then evaporated to leave a froth (1.42 g). A sample (0.42 g) was purified by column chromatography on flash silica eluting with ethyl acetate:cyclohexane (3:1). Evaporation of appropriate fractions gave an oil which was treated with ether (20 ml) to give a solid, which was collected by filtration, washed with ether and dried in vacuo to give the title compound (0.177 g) as a solid [α]D -39° (CHCl3 c=1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([NH:14][O:15][C:16](=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[NH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:12]2[N:13]=[C:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][N:14]=2)[CH:24]=[CH:25][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)ONC(=N)c1cccc(NC(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1nc(-c2cccc(NC(=O)OC(C)(C)C)c2)no1

Procedure:
A suspension of 3-tert-butyloxycarbonylamino-N-(3-carbomethoxypropionyloxy) benzamidine (8.25 g, 22.6 mmol) in toluene (120 mL) was added to a 250-mL round bottomed flask equipped with a magnetic stirrer and a reflux condenser, and the contents heated to reflux for 5 h. The reaction was then cooled, and the resulting solution concentrated under vacuum. This afforded a quantitative yield of methyl 3-[3-(3-tert-butyloxycarbonylaminophenyl)-1,2,4-oxadiazol-5-yl]propionate as a yellow solid. m.p. 90-91° C.; 1H NMR (CDCl3) δ (ppm) 7.97 (s, 1H), 7.72 (d, 1H,J=7.6 Hz), 7.61 (d, 1H,J=7.6 Hz), 7.39 (m, 2H), 6.57 (bs, 1H), 3.73 (s, 3H), 3.26 (t, 2H,J=7.3 Hz), 2.94 (t, 2H,J=7.3 Hz), 1.53 (s, 9H); m/z=346 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: BrCCCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (4-bromobutoxy)benzene (1.37 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from dichloromethane-hexane to provide 0.85 g of alpha-oxo-4-[[(4phenoxy)butyl]oxy]benzeneacetic acid methyl ester, mp 57°-59°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]=[CH:12][N:11](C(OC(C)(C)C)=O)[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH:21]([N:24]1[C:29]2=[N:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([N:24]1[C:29]2=[N:30][C:31]([C:2]3[C:7]([CH3:8])=[N:6][C:5]([C:9]4[NH:13][CH:12]=[N:11][N:10]=4)=[CH:4][CH:3]=3)=[CH:32][N:33]=[C:28]2[NH:27][CH2:26][C:25]1=[O:43])([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2ncn(C(=O)OC(C)(C)C)n2)ccc1Br
Reactant: CC(C)N1C(=O)CNc2ncc(B3OC(C)(C)C(C)(C)O3)nc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 100 °C
Yield: 41 %

Procedure:
7-Bromo-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), bis(pinacolato)diboron) (1 equiv), potassium acetate (3 equiv) and bis(1,1′-bis(diphenylphosphino)ferrocene)palladium (0.01 equiv) were combined in dioxane, degassed with nitrogen and heated to 95° C. under nitrogen. Dilution with ethyl acetate, filtration through Celite, concentration, trituration with ethyl acetate and hexanes, filtration and drying gave the boronate ester in 60% yield. tert-Butyl 3-(5-bromo-6-methylpyridin-2-yl)-1H-1,2,4-triazole-1-carboxylate (1 equiv), 1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.2 equiv), tetrakis(triphenylphosphine) palladium(0) (0.05 equiv), sodium carbonate (3 equiv) were combined in (3:1) dimethyl acetamide and water. The mixture was degassed and heated to 100° C. overnight. Standard ethyl acetate/water work up and subsequent trituration in ethyl acetate gave the desired product in 41% yield.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:43][CH2:42]1>C(#N)C.C(N(CC)CC)C>[C:47]1([CH:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:46][CH2:45]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: NCCCCN1CCC(c2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCN1CCC(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 1.60 g (6.89 mM) of 1-(4-aminobutan-1-yl)-4-phenylpiperidine and 1.3 ml (9.33 mM) of triethylamine in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol/ethyl acetate 20-50-80%) to provide the title compound as red-purple solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][NH:17]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][N:17]2[C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2ccc(Cl)cc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 6-chloroindoline (D36) to give (E19) (1.54 g, 73%) m.p. 204°-5° C.