Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(C(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.20 g, 0.45 mmol) and triethylamine (0.13 mL, 0.90 mmol) in 5 mL of CHCl3 was cooled to 0° C. and treated with 4-tert-butylphenylsulfonyl chloride (0.10 g, 0.45 mmol). The reaction mixture was warmed to room temperature and treated with saturated aqueous NaHCO3. The organic phase was separated from the aqueous phase. The aqueous phase was extracted with additional CHCl3, and the combined organic extracts were dried MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate). The chromatography product was crystallized from hot heptane/ethyl acetate to give the title compound as a white solid 0.20 g 70%), mp=142-143° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[CH:17][NH:18]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.O>CN(C=O)C>[CH3:29][S:28][C:24]1[N:25]=[C:26]([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=4)[CH:20]=3)[CH:16]=[CH:17]2)[CH:27]=[CH:22][N:23]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (60% in mineral oil, 40 mg, 0.98 mmol) was added to a mixture solution of 6-(3-nitrophenyl)-1H-indole (117 mg, 0.49 mmol) in DMF (2 mL) at room temperature. 10 minutes later, 4-chloro-2-(methylthio)pyrimidine (68 μL, 0.59 mmol) was added. After stirring at room temperature for 30 minutes, water was added. Thus produced solid was filtered and dried. The target compound (102 mg) was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19]([OH:21])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Reactant: Nc1ccccc1
Product: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccccc1
Yield: 92.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.283 mmol) and aniline (28 mL, 0.311 mmol) to give 112 mg of the title compound (92%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (s, 1H), 9.99 (s, 1H), 7.55 (d, 2H, J=7.6 Hz), 7.30 (t, 2H, J=7.6 Hz), 7.21 (s, 1H), 7.17 (s, 1H), 7.05 (t, 1H, J=7.6 Hz), 4.92~5.02 (m, 1H), 3.25 (dd, 1H, J=17.8, 5.9 Hz), 2.50~2.66 (m, 3H), 2.28~2.42 (m, 1H), 0.86 (d, 3H, J=6.9 Hz).
Reaction SMILES: C[Al](C)C.C1(O)CCCC1.[CH3:11][C:12]1[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[N:15]=[C:14]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[O:23])[N:13]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:11][C:12]1[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[N:15]=[C:14]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([OH:32])=[O:31])(=[O:27])=[O:26])=[O:23])[N:13]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2c(n1)CCC2
Agent: C[Al](C)C
Agent: Cl
Agent: OC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)nc2c1CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To 20 ml of dry toluene was added 2.4 ml of 2 M trimethylaluminum in toluene under a nitrogen atmosphere. Subsequently, 0.82 g cyclopentanol in 1 ml toluene was added via syringe and the mixture stirred at ambient temperature for 15 minutes. After addition of 1.56 g of methyl 2-[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoate to the mixture, the reaction was heated to 80° for 3.5 hours. The mixture was then cooled in ice while B 40 ml of 5% aqueous hydrochloric acid was added. Ethyl acetate was then added and shaking of the two phase mixture resulted in the crystallization of the product which was collected and dried to yield 1.5 g of 2-[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoic acid, cyclopentyl, ester, m.p. 183°-184°. The product showed characteristic absorptions at 3120, 1725, 1720 cm-1 in the infrared spectrum and at 1.7-2.35, 2.50, 2.95, 5.4, 7.6, 8.4, 8.5 and 13.0 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[N:17](S(C)(=O)=O)[C:16]([C:29]1([CH3:32])[CH2:31][O:30]1)=[CH:15]2>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[C:21]([F:22])([F:24])[F:23])[NH:17][C:16]([C:29]([OH:30])([CH3:31])[CH2:32][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15]2
Reactant: Fc1ccc(S)cc1
Reactant: CC1(c2cc3cc(Cl)c(C(F)(F)F)cc3n2S(C)(=O)=O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(CSc1ccc(F)cc1)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluoro-phenyl thiol (55 mg, 0.425 mmoL) was treated with NaH (60%, 17 mg, 0.425 mmoL) in THF (2 mL) at 0° C. After 10 min., 5-chloro-1-methanesulfonyl-2-(2-methyl-oxiranyl)-6-trifluoromethyl-1H-indole, the epoxide derivative compound prepared as in Example 72 (100 mg, 0.425 mmoL) in THF (1 mL) was added into the reaction via syringe. The reaction was slowly warmed to room temperature. THF was removed and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, then concentrated to yield a crude white solid. The crude material was purified using column chromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield the title compound as a white solid.
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([Cl:44])[CH3:43])=[O:40]>C(Cl)Cl>[Cl:44][CH:42]([O:41][C:39](=[O:40])[O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][P:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:43]
Reactant: O=P(OCCOCCOCCOCCO)(OCc1ccccc1)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCOCCOCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of dibenzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl phosphate (500 mg, 1.1 mmol) and pyridine (200 mg, 205 μl, 2.53 mmol) in methylene chloride (6 mL) at −78° C. was added slowly 1-chloroethyl chloroformate (178 mg, 134 μl, 1.24 mmol) in methylene chloride (2 mL). After addition, the reaction mixture was allowed to stir at −78° C. for 1.5 h. Then the cold bath was removed and the reaction mixture was warmed up to room temperature. 1H-NMR showed the completion of the reaction. The reaction mixture was concentrated in vacuo. The residue was reconstituted with diethyl ether. The solids in the ethereal solution were filtered off and washed thoroughly with diethyl ether. The filtrate and washing solutions were combined and concentrated to give carbonic acid 2-(2-{2-[2-(bis-benzyloxy-phosphoryloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester 1-chloro-ethyl ester as clear light-yellow thick oil. The crude product was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F

Procedure:
Intermediate (a), N-Boc-(R)-2-(4-methoxy-3-trifluoromethylbenzyl)morpholine (23 mg, 0.06 mmol), was deprotected using trifluoroacetic acid, (20% v/v solution in dichloromethane, 1 mL total) over 2.5 hrs. The reaction mixture was poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and dichloromethane: methanol (1:1 v/v, 2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine, example 2 as a white solid (15 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.035 g, 0.09 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.012 mL, 0.09 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD78. ESI-MS m/z [M+H]+ found 583.5, calculated 583.2.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([C:24]([CH3:26])=[CH2:25])[CH2:8][CH2:9]/[C:10](/[CH3:23])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][C:16](OC(C)C)=[O:17])([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+].O.S(=O)(=O)(O)O>CCCCCC>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][CH:7]([C:24]([CH3:26])=[CH2:25])[CH2:8][CH2:9]/[C:10](/[CH3:23])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC(=O)OC(C)C)O[Si](C)(C)C(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: C=C(C)C(CC/C(C)=C/CCC(C)=CCO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
24.5 ml of sodium dihydro-bis(2-methoxyethoxy)-aluminate (70% solution in toluene, "Vitride") are slowly added dropwise at 0° to a solution of 32.6 g of isopropyl (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienoate in 80 ml of hexane. After stirring at room temperature for 2 hours a further 2.5 ml of "Vitride" are added dropwise. The reaction mixture is stirred for a further hour and then treated cautiously with 20 ml of water, whereupon the mixture is poured into ice-water. After adding 70 ml of 50% sulphuric acid the mixture is extracted twice with hexane. The combined extracts are washed with 2N sulphuric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 80:20:0.1, whereby (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrien-1-ol is obtained as a colourless oil. NMR (80 MHz, CDCl3); 5.45 (t, J=7.1 olefin. H); 5.15 (m, 1 olefin. H); 4.95-4.75 (m, 2H-C(12)); 4.2 (d, J=7, 2H-C(1)); 4.05 (t, J=6.5, H-C(10)); 2.2-1.3 (m, 4CH2, 3CH3); 0.9 (s, SiC(CH3)3); 0.05 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30].O>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH:8][C:29](=[O:30])[C:28]([O:32][CH2:33][CH3:34])=[O:31])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Reactant: CCOC(=O)C=O
Agent: CCN(CC)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred solution of 5-bromo-N3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine (5.15 mmol, 1.8 g) and N,N-diethylisopropylamine (9.30 mmol, 2 mL) in CH2Cl2 (20 mL) was added ethyl glyoxylate (5.41 mmol, 0.74 g) at 0° C. The suspension was warmed up naturally and stirred overnight. Water was added to dissolve the precipitation. The combined organic layers from extraction were combined, dried, concentrated, and then subjected to a silica gel column chromatography by using CH2Cl2/MeOH (9:1) as eluents, furnishing ethyl ({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(oxo)acetate in 52% yield (1.20 g).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.CCN=C=NCCCN(C)C.[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36].CN(C=O)C>[Cl-].[Na+].O>[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:4]([C:6]3[O:7][C:8]4[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=4[C:10]=3[CH3:11])=[O:5])=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36]
Reactant: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(O)c4c3C)cc2)cc1)C(C)C
Temperature: 65 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To 70 mg (0.3 mmol) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 115 mg (2 eq) EDCI, 109 mg (1 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of DMF. The mixture was stirred at 65° C. overnight. The reaction mixture was poured into brine, and extracted with dichloromethane. The organic solution was washed with 2N HCl and water. Removal of the solvents under vacuum gave crude product, which was purified by column chromatography on silica gel to give 20 mg (10% yield) of (S)-2-{4′-[(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)[C@@H](N)CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 100 °C

Procedure:
7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C. until there is no further reaction and after cooling it is evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[CH2:32]([O:31][C:29]([CH2:28][O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(=NO)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-hydroxyimino-1-(4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (500 mg) in N,N-dimethylformamide (10 ml) was treated with sodium hydride (72 mg, 60% w/w in mineral oil) at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and then at ambient temperature for 30 minutes. Ethyl bromoacetate (301 mg) was added, and the reaction mixture was stirred for 2 hours. The reaction was quenched with aqueous hydrochloric acid and the mixture was diluted with ethyl acetate. The organic phase was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and brine. The organic solution was dried over magnesium sulfate and concentrated to give crude 5-ethoxycarbonylmethoxyimino-1-(4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine. This product was taken on without further purification (700 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:24]=4)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:40][CH2:41][CH2:42][OH:43])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[O:30])=[CH:27][CH:28]=4)[CH:22]=3)=[N:9]2)=[CH:37][CH:38]=1
Reactant: OCCCBr
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Yield: 63 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-ol (60 mg; 0.12 mmol; 1.0 eq.), 3-bromo-1-propanol (24 mg; 0.18 mmol; 1.5 eq.) and cesium carbonate (77 mg; 0.24 mmol; 2.0 eq.) in DMF (1.2 mL) was stirred at RT O/N. The reaction mixture was then diluted with DCM and washed with brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white powder (43 mg, 64%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[O:34].ClC([O-])=O>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH2:37][O:38][CH3:39])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: COCCOC(=O)Cl
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Yield: 54.5 %

Procedure:
At RT, triethylamine (260 mL, 1.87 mmol) was added to a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (300 mg, 0.94 mmol) in THF (9 mL). The mixture was cooled to −70° C. external temperature and 2-methoxyethyl chloroformate (0.1 mL, 0.89 mmol) was added dropwise. Once the addition of the chloroformate was complete, the reaction was quenched with H2O, and extracted three times with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2-10% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-2-methoxyethyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 14) (205 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.41 (m, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.25-4.01 (m, 6H), 3.88-3.85 (m, 1H), 3.49-3.47 (m, 2H), 3.23 (s, 3H), 2.49 (s, 3H), 2.26-2.17 (m, 1H), 2.07-2.01 (m, 1H) ppm. LC/MS: m/z 423.3 (M+H)+ at 2.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]([NH:28]/[N:29]=[C:9]2\[C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16]3[C:11]\2=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)CC1CCCCC1
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC2CCCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-cyclohexylacetohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.01-1.07 (m, 2H), 1.18 to 1.39 (m, 7H), 1.60-1.72 (m, 5H), 1.81 (d, 2H), 1.92-1.94 (m, 1H), 2.27 (d, 1H), 2.69 (d, 1H), 3.70 (t, 2H), 3.87 (s, 3H), 6.42 (s, 1H), 6.62 (d, 1H), 7.52 and 7.74 (d for isomers, 1H), 12.39 and 13.99 (br s for isomers, 1H).