Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]>C(O)(=O)C.ClCCl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc(OC)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of fuming nitric acid (12.1 ml; s.g. 1.5) in glacial acetic acid (120 ml) was added in one portion to a stirred solution of 4-ethyl-2-methoxyphenol (41.7 g) in dry dichloromethane (800 ml). After 1 minute the solution was washed with water (3×300 ml), and the organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give an orange crystalline residue. This was recrystallised from a mixture of methanol and water to give 4-ethyl-2-methoxy-6-nitrophenol (31.3 g), m.p. 59°-61° C.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=2[C:6]1=O)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30]([NH2:32])=[NH:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=4[C:6]=3[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: Cc1ccc2c(c1)NC(=O)CC(=CN(C)C)C2=O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method I, 4-((dimethylamino)methylene)-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-g) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-42 (57%): HRMS Calcd. for C21H20N4O3: 377.1613, Found 377.1613.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CO1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC(O)CSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
4-Mercaptopyridine (93 mg) was added to a suspension of sodium hydride 60% (12 mg) in DMF (2 ml) under nitrogen. After stirring for 15 minutes 4-(4-bromo-2-fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline (100 mg) (from Example 5) was added and the mixture was stirred for 3 hours at ambient temperature. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 7 with 1N HCl. The organic layer was separated, washed with water, followed by brine, dried (MgSO4) and evaporated to give 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-pyridylsulphanyl)propoxy]-6-methoxyquinazoline (20 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=O)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:35]1([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][N:47]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:48][C@H:49]([OH:59])[C@@H:50]([NH2:58])[CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][N:47]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:48][C@H:49]([OH:59])[C@@H:50]([NH:58][C:18](=[O:20])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:12][C:10]([O:9][CH3:8])=[O:11])[CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(N2CCCC2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(N2CCCC2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
12.3 ml (88 mmol) of triethylamine are added to a solution of 3.3 g (17.6 mmol) of N-methoxycarbonyl-(L)-tert-leucine, 6.7 g (35.2 mmol) of EDC and 4.8 g (35.2 mmol) of HOBT in 90 ml of DMF (degassed under vacuum) and the whole is stirred at RT for 20 min. After that, 4 g (8.8 mmol) of 1-[p-(pyrrolidin-1-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 8d), dissolved in 20 ml of DMF, are added and the mixture is stirred at RT for 16 h. The reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate/water. The organic phase is separated off and subsequently washed consecutively with water, 5% sodium bicarbonate solution (twice), water, dilute brine and brine, with the title compound thereby being obtained. The solvent is removed and the residue is recrystallized from ether in an ice bath, with the title compound thereby being obtained.
Reaction SMILES: [N:1]([C:4](N=[N+]=[N-])=[O:5])=[N+]=[N-].[C:9]([O:13][C:14](OC([O-])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CO.[OH-].[OH-].[Pd+2]>[C:14]([C:4]([NH2:1])=[O:5])([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15]
Reactant: [N-]=[N+]=NC(=O)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(N)=O
Yield: 82.2 %

Procedure:
A solution of 19b (550 mg, 3.1 mmol)and t-butyldicarbonate (1.36 g, 6.2 mmol) in 50 mL of MeOH was placed in a Parr bottle with 20% Pd(OH)2 (200 mg) and hydrogenated under 50 psi of H2 for 6 hr. The reaction mixture was filtered through Celite in a sintered glass funnel and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography to give 370 mg (55% yield) of Boc-amino ketone 19c.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:18][CH2:19][CH3:20])=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([Br:21])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:21][C:5]1[CH:4]=[N:3][C:2]2[N:18]([CH2:19][CH3:20])[C:12]3[N:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: CCNc1nc(F)ccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1c2nc(F)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of the 2-chloro-N-{2-(ethylamino)-6-fluoro-3-pyridinyl}-5-bromo-3-pyridinecarboxamide (73.5 g, 216 mmol) in pyridine (435 mL) at 50° C. was added drop-wise a 1 M solution of NaHMDS in THF (520 mL, 520 mmol). After 10 min, the reaction was allowed to cool to room temperature, then poured over ice water (2 L). The resulting solid was filtered, rinse with water and then hexane. The solid was dried under reduced pressure to give the title compound (50.6 g, 69% yield) as a dark green solid.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:6](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.O>CO>[Cl:4][CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(Cl)(c2ccccc2F)C(Cl)n2cncn2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1ccc(C(c2ccccc2F)C(Cl)n2cncn2)cc1
Yield: 96.4 %

Procedure:
5.4 g of sodium methylate are added to a solution of 17.8 g (0.0503 mol) of 1,2-dichloro-1-(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethane in 125 ml of methanol. After the reaction mixture has been refluxed for one hour, 100 ml of water are added to the solution, which is then extracted several times by shaking with methyl tert-butyl ether. The organic phase isolated is washed twice with water, dried over sodium sulfate and evaporated down, 15.5 g (97%) of 1-chloro-1-(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethane being obtained as a 1:1 E/Z mixture.
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:32](Cl)(=[O:34])[CH3:33].CS(C)=O>C1C=CC=CC=1>[C:32]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:34])[CH3:33]
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 92.5 %

Procedure:
Analogously to Example 19, 10.8 g of ethyl 4-benzhydrylaminobutyrate and 5.2 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 3.1 g of acetyl chloride. As reaction product one obtains 11.4 g (92.5% of theory) of ethyl N-acetyl-4-benzhydrylaminobutyrate as a viscous non-distillable oil. The saponification of this ester yields 9.2 g (88% of theory) of N-acetyl-4-benzhydrylaminobutyric acid (M.P. 173° to 174°).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:16]=[C:17]([NH2:19])[S:18][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Yield: 111.9 %

Procedure:
A suspension of 3-Bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10 grams, 35 mmol, obtained in above step) and thiourea (3.28 grams, 42 mmol) in isopropanol (100 mL) was refluxed for 1 hour. After completion of reaction, reaction mass was concentrated and resulted crude was triturated with diethyl ether (50 mL), solids were filtered and dried under vacuum to obtain the title compound (10 grams).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][N:8]3[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[C:6]([CH3:19])=[N:7]3)=[CH:13][CH:14]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccc(NCc3ccc(Cl)cc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Reductive amination: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 100 mg, 0.37 mmol) in tetrahydrofurane (1 mL) was added 4-chlorobenzaldehyde (185 mg, 1.32 mmol) and sodium triacetoxyborohydride (240 mg, 1.13 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (1 mL) and treated with aqueous NaOH solution (4 M, 0.6 mL). After 4 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C@H:27]([CH3:31])[C:28](O)=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OS([O-])(=O)=O.[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][N:10]([C:28](=[O:29])[C@H:27]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)[CH3:31])[CH2:11][CH:12]([O:13][CH3:14])[O:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(CNCCCC(=O)OC(C)(C)C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(CCCC(=O)OC(C)(C)C)C(=O)[C@@H](C)Nc1ccc(Cl)c(Cl)c1)OC
Temperature: 25 °C

Procedure:
A solution of 0.99 g (4.00 mmol) of 4-(2,2-dimethoxy-ethylamino)-butyric acid tert-butyl ester (intermediate 30) in 24 ml of DMF was treated with 1.03 ml (4.40 mmol) of (R)-2-(3,4-dichloro-phenylamino)-propionic acid (62% ee) (intermediate 31), 0.48 ml (4.40 mmol) of triethylamine and at 0° C. with 2.28 g (6.00 mmol) of HATU. Over night, the suspension was naturally warmed to RT, poured on aqueous 10% KHSO4 solution and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after purification with flash chromatography (SiO2, dichloromethane/Et2O 97.5:2.5 to 4:1) 1.37 g (74%) of the titled compound as light yellow viscous oil. MS: 463.17 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:13]([O:15]C)=[O:14])[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].O.[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(CC1CCC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N[C@@H](CC1CCC1)C(=O)O
Reaction time: 3 h

Procedure:
10.8 g (47 mmol) of methyl ethoxycarbonyl-3-cyclobutyl-DL-alaninate (synthesised in Step B) is dissolved in 20 ml of benzene in the 250 ml vessel of the titrator. 100 ml of water is added and the pH of the solution is adjusted to 7.5 with 1M NaOH under stirring. 40 mg of enzyme [Subtilisin Carlsberg, Protease, Type VIII (Sigma)] is added, the pH readjusted to 7.5 and kept at this value during titration. The enzymatic hydrolysis is complete in 3 hours. The phases are separated. From the aqueous phase pure ethoxy-carbonyl-3-cyclobutyl-L-alanine can be isolated. The benzene phase is washed with 2×10 ml of 5% NaHCO3 and 2×10 ml of water, dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The resulting yellowish oil is considered to be pure and used without further treatment in the next step.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]OS(C)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[C:20]([O:24][C:25](=[O:26])[NH:27][CH2:28][CH2:29][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C

Procedure:
Added N-hydroxyphthalimide (1.12 g, 6.87 mmol) and triethylamine (0.96 mL, 6.87 mmol) to a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (1.37 g, 5.73 mmol) in DMF (20 mL). The solution was heated to 50° C. for 16 hours after which time it was cooled to room temperature. The solution was diluted with ethyl acetate, washed with water (2×), saturated K2CO3, dried over Na2SO4 and concentrated to an orange solid (747 mg, 43%) which was taken on without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]1[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[C:67]=1[C:68]([O:70][CH3:71])=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]1[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[C:67]=1[C:68]([O:70][CH3:71])=[O:69])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
(2S)-2-[(Benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (10.2 mg, 0.020 mmol) in DMF (2.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.6 mg, 0.0240 mmol). After five minutes methyl 2-(4-aminobutoxy)-6-hydroxybenzoate hydrochloride (8.27 mg, 0.030 mmol) and N,N-diisopropylethylamine (17.4 μL, 0.100 mmol) were added and the solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (8.9 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 8.07 (brs, 1H), 7.63 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.31–7.23 (m, 7H), 6.49–6.46 (m, 2H), 5.43 (t, J=6.1 Hz, 1H), 5.02 (s, 2H), 4.33–4.29 (m, 1H), 3.97–3.92 (m, 2H), 3.85 (s, 3H), 3.47–3.36 (m, 2H), 3.29–2.82 (m, 4H), 1.68–1.60 (m, 4H); LCMS found for C32H35BrN3O10S (M+H)+: m/z=734.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(C)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1nc(C(F)(F)F)nc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 5.83 g (50 mol) of chlorosulfonic acid and then 2.49 g (9.73 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-1,3-dimethylbenzene. The mixture was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distill off ethyl acetate to obtain a title compound as 3.3 g of a crystal. Yield: 96%
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([S:8][C:9]([CH3:35])([CH:33]=[N:37][OH:38])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=NO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), hydroxylamine hydrochloride (0.26 g), potassium carbonate (0.52 g) and methanol (8 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (0.25 g, yield 55%) as colorless amorphous crystals. MS: 543 (MH+).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([C:17]1[C:22](I)=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:10]([C:17]1[C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ncc(-c2ccccc2)c(Nc2ccccc2)n1
Yield: 49.7 %

Procedure:
Phenylboronic acid (240 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg) were added to a solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59, 331 mg, 1 mmol) in toluene (10 ml) and ethanol (2.5 ml). 2M aqueous sodium carbonate solution (10 ml) was added and the mixture was stirred and heated under reflux for 3 hours. Further portions of phenylboronic acid (240 mg, 2 mmol) and tetrakis(triphenylphosphine) palladium(0) (30 mg) were added and the mixture was stirred and heated under reflux for 20 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (2×50 ml) and saturated sodium chloride (50 ml) and dried. Volatile material was removed by evaporation and the residue was purified by bond elute chromatography, eluting with 10-25% ethyl acetate in isohexane, to give the product (140 mg). NMR (CDCl3): 6.85 (s, 1H), 7.1 (t, 1H), 7.3 (t, 2H), 7.4 (m, 2H), 7.5-7.6 (m, 6H), 8.05 (s, 1H); MS (MH+): 282, 284.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH2:30][C@H:31]([C:35]([C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38])=[O:36])[CH:32]([CH3:34])[CH3:33].Cl>C(Cl)Cl.CC#N>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:30][C@H:31]([C:35]([C:37]([C:40]([F:41])([F:42])[F:43])([F:38])[F:39])=[O:36])[CH:32]([CH3:33])[CH3:34])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: -16 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To a stirred solution of Boc—Val—Pro—OH (1.10 g, 3.5 mmole) in CH2Cl2 (20 ml) under argon, cooled to −17° C., was added NMM (0.40 ml, 3.68 mmole). After 5 minutes, 1 equivalent (0.45 ml, 3.5 mmole) of IBCF was added and a light suspension formed several minutes later. After 20 minutes NMM (0.4 ml, 3.68 mmol) was added followed by a suspension of H-Val-CF2CF3.HCl (0.88 g, 3.50 mol) in CH2Cl2 (10 ml) plus CH3CN (10 ml) dropwise (from an addition funnel) over ca. 15 minutes. The reaction was stirred at −14 to −18° C. for 1 hour and then the cooling bath was removed. The reaction was allowed to warm to room temperature (ca. 40 min.) and diluted with CH2Cl2 (100 ml). The organic phase was washed with 1 N HCl (3×75 ml), satd. NaHCO3 (2×75 ml), and brine (50 ml). Drying (Na2SO4) and concentration gave a colorless oil which was placed under high vacuum to give the desired product as a white foam (1.59 g, 88%). Elemental analysis; calculated for C22H34F5N3O5: %C=51.26; %H=6.65; %N=8.15. Found: %C=50.80; %H=6.57; %N=7.85.