Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]3[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=4[N:10]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21

Procedure:
((R)-7-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (30E) (0.111 mmol, crude oil) prepared according to the procedure described in Example 30, Steps A-E was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.122 mmol, 0.032 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31A) as a clear oil that was used directly onto the next step. EST-MS: m/z 647.3 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH3:4].[Cl:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:23][O:24][CH2:25][CH3:26])[N:19]([CH2:20][C:21]#[CH:22])[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:23][O:24][CH2:25][CH3:26])[N:19]([CH2:20][C:21]3[O:1][N:2]=[C:3]([CH3:4])[CH:22]=3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CC(Cl)=NO
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(C)no1

Procedure:
N-Hydroxyethanimidoyl chloride (prepared as described in Part D of Example 1, 2.10 g, 22.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline prepared as described in Part D of Example 3, 5.39 g, 18.0 mmol) and triethylamine (3.70 mL, 27.0 mmol) in dichloromethane (60 mL). The solution was heated at reflux for 16 hours and then was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate) to provide 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g) as a white solid.
Reaction SMILES: O.[Na].Cl[CH2:4][CH2:5][CH:6]([C:14]1[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)=[N:16][N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(OCC)(=[O:37])C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2([OH:37])[C:14]3[N:15]([N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=3)[CH2:4][CH2:5]2)=[CH:12][CH:11]=1
Reactant: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Sodium hydrate (containing mineral oil at 40%, 15 mg) was added to a solution of 3-[3-chloro-1-(4-fluorophenyl)propyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazole (86 mg) in DMF (1 mL), and the reaction solution was stirred at room temperature for 13 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]([C:22]([O:24]CC)=[O:23])([C:17]([O:19]CC)=[O:18])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]([C:17]([OH:19])=[O:18])([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2onc(-c3ccc(Cl)cc3)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(C(=O)O)CCc2onc(-c3ccc(Cl)cc3)c2C1
Yield: 102.2 %

Procedure:
7.7 g of diethyl 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5,5-dicarboxylate were treated with 2.74 g of potassium hydroxide in 16 ml of water and 65 ml of ethanol at 20° C. for 3 days. After removal of the ethanol by evaporation and acidification with 2N hydrochloric acid, the product was taken up in ethyl acetate. There were obtained 6.7 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5,5-dicarboxylic acid as a buff colored solid of melting point 200°-202° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[CH3:27][O:28][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: COc1cccc(C2CCc3cc(O)ccc3O2)c1
Product: COc1cccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1

Procedure:
2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-methoxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.32 (t, 1H, J 15.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 8.4 Hz), 7.01 (s, 1H), 7.00 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.92 (d, 1H, J 8.7 Hz), 6.90 (dd, 1H, J 8.4, 2.6 Hz), 5.12 (dd, 1H, J 10.0, 2.3 Hz), 3.77 (s, 3H), 2.93-2.97 (m, 1H), 2.71-2.77 (m, 1H), 2.15-2.20 (m, 1H), 1.99-2.05 (m, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]([CH3:27])([CH3:26])[CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:22][C:13]1[C:12]2=[N:11][N:10]([CH2:23][CH2:24][CH3:25])[C:9]([CH2:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:27])[CH3:26])=[C:21]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
Methanesulfonyl chloride (232 μL, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3 hours at 0° C., the solution was stirred for 2 days at ambient temperature. To the solution was added 2 M aqueous sodium carbonate. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid. The crude product was purified by IFC (silica gel, elution with 10% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to provide a white foam that was crystallized from acetonitrile, isolated by filtration, and dried to yield 600 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white solid, mp 130-139° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:35][C:24]4([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:35][C:24]4([CH2:27][NH:26][CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:36])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC2(CNC2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.23 %

Procedure:
(Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.13 g) was dissolved in DCM (1.5 mL). The reaction mixture was cooled to 0° C. and CF3COOH (1.5 mL) was added. The reaction mixture was allowed to warm to room temp. where it was stirred for 4 h. The reaction mixture was concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.100 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (Yield 95.23%). 1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.52-8.5 (m, 3H), 8.32 (s, 1H), 7.44-7.42 (d, 1H, J=10.4 Hz), 5.97-5.94 (d, J=10.4 Hz, 1H), 4.37-3.93 (m, 8H); LCMS calcd for C18H16F6N5O [M+H]+ 432.34. found 432.29 at retention time 2.256 min.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([OH:60])[CH2:5][C:4]1=[O:61])[CH3:2].[CH2:62]([NH2:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:69][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([OH:60])[CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(Oc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCc4ccccc4)C(Oc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-phenoxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (87 mg). The mixture is stirred at r.t. for 30 minutes, and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C([Mg]Cl)(C)C.C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=1
Reactant: COB(OC)OC
Reactant: FC(F)(F)COc1ccc(Cl)cc1Br
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1OCC(F)(F)F
Temperature: -70 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a mixture of 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 10.4 mmol) and tetrahydrofuran (60 ml), cooled to −70° C., was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 5.7 ml). After warming to 0° C., the mixture was stirred for 1 hour. After cooling to −70° C., the mixture was treated with trimethylborate (1.2 g, 11.4 mmol). After stirring at room temperature for 12 hours, the mixture was treated with hydrochloric acid (2 M, 20 ml). After stirring for 40 minutes, the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane (50 ml). Filtration and drying of the solid under reduced pressure gave 5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenylboronic acid (1.6 g, 61% yield). 1H NMR (acetone-d6) δ 4.86 (q, 2H, J=8.5 Hz, CH2), 7.12 (d, 2H, J=4.6 Hz, OH), 7.20 (d, 1H, J=8.8 Hz, Ar), 7.49 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.76 (d, 1H, J—2.7 Hz, Ar).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH:29][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 49 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (49%). M+(LC/MS(ESI)): 446.4.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH2:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)O
Reaction time: 6 h

Procedure:
To a solution of t-BOC-Gly-Ama-diEt (985.2 g, 2.96 mol) in 770 mL CH2Cl2, 770 mL trifluoroacetic acid (TFA) was added. The resulting mixture was stirred and after 6 hour a precipitate formed, which was collected after 8 hours. Recrystallization from CHCl3 gave 1025.1 g of TFA-Gly-Ama-diEt as a white solid: 1H NMR (DMSO-d6): δ 9.34 (d, 1H, NH), 8.13 (b.s., 3H, NH2 TFA salt), 5.17 (d, 1H, CH), 4.20 (m, 4H, CH2), 3.71 (d, 2H, CH2), 1.22 (t, 6H, CH3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O.Cl>[O:12]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: c1ccsc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1cccs1
Temperature: 25 °C

Procedure:
Thiophene (5.0 gm, 0.059 moles) and succinic anhydride (7.13 gm, 0.0713 moles) were taken up in dichloroethane (50 ml). Aluminium chloride (17.43 gm, 0.131 moles) was added at room temperature and the resulting mixture heated under reflux for 1 hr with stirring. The reaction mixture was cooled to room temperature, diluted with 30 ml of 1:1 mixture of water and Conc. hydrochloric acid. After stirring for 10 min the separated solid was filtered under suction, washed with water and dilute hydrochloric acid (50 ml). The solid was dried at room temp to give 9.8 gm (89%0 of the title compound, mp 103-107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:15])[CH:21]([C:22](=[O:23])[NH2:24])[C:19]#[N:20])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCC(N)=O
Reactant: CC(C)(C)OC(=O)c1ccc(N=C=S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=S)C(C#N)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
4-Isothiocyanato-benzoic acid t-butyl ester 2 (28.3 gm, 120.4 mmol) was taken into DMF (200 ml). To this KOH (6.74 gm, 120.4 mmol) and cyanoacetamide (10.21 gm, 120.4 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with 1N HCl, the precipitate obtained was filtered, washed with water, and dried under vacuum, to provide 32.10 gm of 4-(2-Carbamoyl-2-cyano-thioacetylamino)-benzoic acid t-butyl ester 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]([C:24]#[N:25])[OH:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O>[C:24]([CH:22]([OH:23])[C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17][CH:18]=1)(=[O:33])[NH2:25]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)C#N)cn2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)C(N)=O)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(cyano-hydroxy-methyl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (prepared as in Example 26, 100 mg, 0.22 mmol) and potassium carbonate (400 mg, 2.9 mmol) in dimethyl sulfoxide (6 mL) was cooled to 0° C. and then was treated dropwise with a 30% aqueous hydrogen peroxide solution (2 mL). The reaction was stirred at 0° C. for 1 h. The resulting mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded N-[5-(carbamoyl-hydroxy-methyl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (30 mg, 28%) as a white solid: (ES)+-HRMS m/e calcd for C21H25ClN4O5S (M+H)+ 481.1314, found 481.1307.
Reaction SMILES: Br.[N:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(N2CCCCC2)ns1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of piperidine-1-carboximidamide hydrobromide (2.00 g, 9.61 mmol) and perchloromethyl mercaptan (1.04 ml, 9.61 mmol) in methylene chloride (10 ml) was added dropwise a solution of sodium hydroxide (1.54 g, 38.4 mmol) in water (4 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give 500 mg (25.6%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=c1[nH]c2cc(Br)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of commercially-available 5-bromobenzo[d]oxazol-2(3H)-one (35-1, 500 mg, 2.336 mmol) in DCM (23 mLl) at RT was added chlorosulfonic acid (1565 μl, 23.36 mmol). The mixture became a solution that was stirred at RT. After 18 h, The solution was cooled to 0° C. and carefully quenched with ice chips and then partitioned between water (15 mL) and EtOAc (150 mL). The aqueous layer was extracted with 3×30 mL DCM. The combined organics were dried over Na2SO4, filtered, concentrated to give 35-2 as a white solid, which was carried forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)nc1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a (0° C.) cooled and stirred solution of 2-bromo-5-aminopyridine (2.0 g, 11.56 mmol, 1.0 eq) in DCM (25 mL) was added sequentially 2,6-difluorobenzoyl chloride (1.44 mL, 11.56 mmol, 1.0 eq) and pyridine (1.19 mL, 13.87 mmol, 1.2 eq). The resulting mixture was allowed to warm to room temperature and then stirred at the same temperature for 30 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]([CH3:22])[CH2:18][C:19](O)=[O:20].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][N:17]([CH3:22])[CH2:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cccc(NC(=O)OC(C)(C)C)c1

Procedure:
A 250 mL round bottom flask with stir bar was charged with tert-butyl 3-aminophenylcarbamate (5.315 g, 25.5 mmol), 2-(dimethylamino)acetic acid (2.94 g, 28.5 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (5.17 g, 27.0 mmol) and 4-dimethylaminopyridine (0.09 g, 0.737 mmol) in dichloromethane (100 ml). The solution was stirred at ambient temperature for 2 hours. The reaction mixture was washed into a separatory funnel with an additional 100 mL dichloromethane and washed with 100 mL saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered, and concentrated to provide the title compound. MS ESI+) m/e 294.0 (M+H)+.