Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[N:10]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A mixture of 3-benzyl-6-chloropyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (1.24 g) and potassium carbonate (0.36 g) in DMF (20 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.8 g, 53%).
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:78][CH3:79])=[C:39]([C:41]([CH3:77])([CH3:76])[CH2:42][C:43]([OH:75])([C:71]([F:74])([F:73])[F:72])[CH2:44][NH:45][C:46]2[CH:54]=[C:53]([CH3:55])[CH:52]=[C:51]3[C:47]=2[CH:48]=[N:49][N:50]3[C:56]2[CH:57]=[C:58]([C:62]([N:64]([CH3:70])[C@H:65]([C:67](O)=[O:68])[CH3:66])=[O:63])[CH:59]=[CH:60][CH:61]=2)[CH:40]=1.N.O1CCOCC1>CN(C=O)C.CO>[NH2:4][C:67](=[O:68])[C@@H:65]([N:64]([CH3:70])[C:62](=[O:63])[C:58]1[CH:59]=[CH:60][CH:61]=[C:56]([N:50]2[C:51]3[C:47](=[C:46]([NH:45][CH2:44][C:43]([OH:75])([C:71]([F:74])([F:73])[F:72])[CH2:42][C:41]([C:39]4[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=4[O:78][CH3:79])([CH3:77])[CH3:76])[CH:54]=[C:53]([CH3:55])[CH:52]=3)[CH:48]=[N:49]2)[CH:57]=1)[CH3:66]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(=O)O)c1)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(N)=O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
N,N-Diisopropylethylamine (0.044 mL, 0.25 mmol) and HATU (20.1 mg, 0.053 mmol) were added to a solution of N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-N-methyl-L-alanine (32.4 mg, 0.05 mmol) in DMF (1 mL) and the solution stirred at room temperature under nitrogen for 10 min. Ammonia in dioxan (5M, 1.01 mL, 5.05 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with methanol and purified by mass directed autopreparation (System B) and product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was separated, combined with a second dichloromethane extract, washed twice with water, dried through a hydrophobic frit and evaporated to give the title compound (11 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>ClC(Cl)C>[CH2:19]([O:18][C:16]([C:12]1[NH:11][C:15]([CH:3]=[O:4])=[CH:14][CH:13]=1)=[O:17])[CH3:20].[CH2:19]([O:18][C:16]([C:12]1[NH:11][CH:15]=[C:14]([CH:3]=[O:4])[CH:13]=1)=[O:17])[CH3:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C=O)c[nH]1
Product: CCOC(=O)c1ccc(C=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7 %
Yield: 50 %

Procedure:
To a solution of dimethylformamide (21 mL, 0.27 mol) in 75 mL of dichloroethane was added a solution of phosphorus oxychloride (25 mL, 0.27 mol) in 75 mL of dichloroethane at 0° C. The mixture was stirred at room temperature for 30 minutes and cooled to 0° C. To the mixture was added a solution of ethyl pyrrole-2-carboxylate (25 g, 0.18 mol) in 50 mL of dichloroethane dropwise. The resulting mixture was stirred at room temperature for 30 minutes and then at 40° C. for 1 hour. The mixture was poured into ice and basified to pH 11 with 5 N sodium hydroxide solution. The mixture was extracted with ethyl acetate and the extract washed with water, brine and dried over anhydrous sodium sulfate. The two products were separated by column chromatography (1:3 ethyl acetate:hexane) to give 15 g (50% yield) of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester and 2 g (7% yield) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H-NMR (5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester) (300 MHz, dimethylsulfoxide) δ 13.02 (br s, 1H, NH), 9.69 (s, 1H, CHO), 6.95 (d, 1H), 6.86 (d, 1H), 4.27 (q, 2H, CH3), 1.28 (t, 3H, CH3). MS m/z 167 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][N:11]1[C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1.C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:16]([C:15]2[N:11]([CH3:10])[N:12]=[C:13]([CH3:19])[CH:14]=2)=[O:17])[CH:3]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.6 %

Procedure:
To a solution of 3-amino-4-methylphenol (930 mg, 7.5 mmol) in N,N-dimethylacetamide (10 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1370 mg, 8.7 mmol) in N, N-dimethylacetamide (5 mL), and the mixture was stirred at 0° C. for 20 min. To the mixture were added ethyl acetate/tetrahydrofuran, saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted 4 times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 63%) as a white solid. To a suspension of lithium aluminum hydride (1130 mg, 24 mmol) in tetrahydrofuran (35 mL) was slowly added dropwise a solution of N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 4.8 mmol) in tetrahydrofuran (10 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 5 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (570 mg, 52%) as a white solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][CH:26]([C:30]1([CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]1=[O:43])[C:27](O)=[O:28].Cl.[CH2:49]([O:56][NH2:57])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>C(Cl)Cl>[CH2:49]([O:56][NH:57][C:27](=[O:28])[CH:26]([CH2:25][CH2:24][N:15]1[C:14](=[O:13])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:23])[C:30]1([CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]1=[O:43])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(CCc2ccccc2)C1=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
CDI (82 mg, 0.51 mmol) is added to a solution of α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (202 mg, 0.424 mmol) and CH2Cl2 (3.2 mL) at room temperature, and the solution is stirred for 1 hour at room temperature. O-Benzylhydroxylamine hydrochloride (98 mg, 0.614 mmol) and 4-methylmorpholine (84 uL, 0.76 mmol) are added in succession, and the solution is allowed to stir overnight at room temperature. Aqueous workup (CH2Cl2, MgSO4) and purification by column chromatography (2% acetene/CH2Cl2) gives 120 mg (49%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cccc(Cl)c1C(=O)O
Product: COC(=O)c1c(N)cccc1Cl

Procedure:
2-Amino-6-chlorobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-amino-6-chlorobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:12]>C1C=CC=CC=1.CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (500 mg, 3.594 mmol) in benzene (8 mL) and MeOH (2 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0° C., and the mixture was stirred overnight at room temp. The reaction mixture was quenched by the addition of AcOH, and the resulting mixture was concentrated in vacuo. The residue was chromatographed on silica-gel with n-hexane-EtOAc (1:3, v/v) as eluent to give 269.8 mg (49%) methyl 2-hydroxypyridine-5-carboxylate as a white crystalline powder. IR (KBr) 3062, 1657, 1654, 1612, 1435, 1300, 1113, 775, 642 cm−1; 1H-NMR (400 MHz, CDCl3) δ3.87 (s, 3H), 6.58 (d, J=9.8 Hz, 1H), 7.99 (dd, J=2.4, 9.8 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H); MS (FAB) m/z 154 (M++1); Anal. Calcd. for C7H7NO3.1/4H2O: C, 53.33; H, 4.80; N, 8.89. Found: C, 53.58; H, 4.65; N, 8.87.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:17]=1>>[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[C:23]([CH2:2][C:3]3[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=3)=[C:22]([OH:27])[CH2:21]2)[CH:17]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(=O)[nH]c(CCl)n1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(C)cc(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 19 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6-methylpyrimidin-4(3H)-one (Example B(54), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 19%.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[C:22]([C:24]1([CH3:28])[CH2:27][NH:26][CH2:25]1)#[N:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([N:26]3[CH2:27][C:24]([CH3:28])([C:22]#[N:23])[CH2:25]3)=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC1(C#N)CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC(C)(C#N)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 47.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (15 mg, 0.077 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (9 mg, 47.3%). 1H NMR (400 MHz, DMSO-d6) δ 0.79 (dd, J=6.69, 2.91 Hz, 3 H) 0.96 (dd, J=9.09, 6.57 Hz, 3 H) 1.41-1.73 (m, 3 H) 2.26-2.44 (m, 1 H) 3.85 (dd, J=15.66, 9.85 Hz, 1 H) 4.06 (d, J=9.35 Hz, 2 H) 4.61 (s, 1 H) 4.88 (dd, J=19.20, 6.82 Hz, 1 H) 5.03 (d, J=11.12 Hz, 1 H) 5.07-5.18 (m, 1 H) 7.99 (t, J=3.16 Hz, 1 H) 8.25 (t, J=2.65 Hz, 1 H) 12.40 (br. s., 1 H). [M+H] calc'd for C19H20FN5O2, 370; found, 370.5
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11](=[O:43])[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH3:9].[F:44][C:45]([F:50])([F:49])CCO>>[F:44][C:45]([F:50])([F:49])[CH2:9][CH2:8][O:10][C:11](=[O:43])[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Reactant: OCCC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCCC(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
4.0 M HCl in 1,4-dioxane (196 μL, 786 μmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid ethyl ester (50.0 mg, 98.2 μmol) in 3,3,3-trifluoropropan-1-ol (336 mg, 3.0 mmol), and the resulting mixture was stirred at 70° C. for 3 hours. The mixture was concentrated in vacuo to yield a white solid, which was purified by preparative HPLC (C18 column chromatography using 40-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (18 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H24ClF3N4O5, 577.14. found 577.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.CO.C(O)(=O)C>[Br:15][C:16]1[C:17]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1cccs1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)[N-]C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ncc(Br)c(-c2ccc(Cl)s2)n1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-chlorothiophene (0.467 mL, 5 mmol) in anhydrous tetrahydrofuran (5 mL) with treated with a solution of lithium diisopropylamide (2 M in THF, 2.75 mL, 5.5 mmol) at −40° C. under a nitrogen atmosphere. After 15 min, the reaction was allowed to warm up to −10° C. and held at that temperature for 20 min. The reaction was then cooled back down to −40° C. and 5-bromo-2-chloropyrimidine (1.06 g, 5.5 mmol), dissolved in anhydrous THF (10 mL) was added to the reaction slowly. After 2 h, a mixture of 1:1 methanol/acetic acid (2 mL) was added to the reaction. After 15 min, a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.36 g, 6 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (5 mL) was added to the reaction mixture which was stirred for an additional 5 min. The reaction was then diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 5 to 20% ethyl acetate in hexanes to obtain a yellow solid. Yield=0.6 g. MS (M+H)+ 311/313.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH2:63][CH3:64])[C:60](O)=[O:61])=[O:57]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:60]([C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH2:63][CH3:64])=[O:61])=[O:18])=[CH:12][CH:11]=2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC[C@H](NC(=O)OC)C(=O)O
Reactant: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Product: CC[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1

Procedure:
The product from Example 114C (0.040 g, 0.056 mmol) and (S)-2-(methoxycarbonylamino)butanoic acid (0.011 g, 0.067 mmol) were processed as in Example 81A to give the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.90 (t, J=7.37 Hz, 3 H) 1.29-1.37 (m, 2 H) 1.39-1.47 (m, 4 H) 1.47-1.58 (m, 1 H) 1.61-1.72 (m, 1 H) 1.75-2.06 (m, 6 H) 2.08-2.20 (m, 1 H) 3.39-3.50 (m, 1 H) 3.52 (s, 3 H) 3.56-3.64 (m, 1 H) 3.69-3.77 (m, 1 H) 3.79-3.90 (m, 1 H) 4.14-4.21 (m, 1 H) 4.24 (s, 1 H) 4.31 (dd, J=7.81, 4.23 Hz, 1 H) 4.43 (dd, J=7.92, 4.34 Hz, 1 H) 4.56 (s, 4 H) 6.64 (dd, J=9.27, 4.39 Hz, 2 H) 6.91 (t, J=8.89 Hz, 2 H) 7.17 (dd, J=8.51, 2.55 Hz, 4 H) 7.27-7.36 (m, 3 H) 7.42 (d, J=6.94 Hz, 2 H) 7.51 (dd, J=8.51, 3.74 Hz, 4 H) 9.95 (d, J=2.93 Hz, 2 H); MS ESI− m/z 858.6 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N+:19]([O-])([O-:21])=[O:20].[Na+].[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O>CCOCC.Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [La+3]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(SC2CCCc3cccnc32)ccc1O
Reaction time: 24 h
Yield: 31.9 %

Procedure:
15.0 g (58 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 90 ml of ether were added dropwise to a stirred solution of 4.96 g (58 mmol) of sodium nitrate and 0.25 g (58 mmol) of lanthanum nitrate in 60 ml of 5.5N hydrochloric acid at 0° to 5° C. in an ice-bath. Stirring was then continued under nitrogen for 24 hours, after which water was added and the mixture was extracted with chloroform. Removal of solvent left a yellow oil which was purified by flash chromatography (Kieselgel 60; 10% ethyl acetate in dichloromethane) to obtain 5.6 g (20%) of 8-(4-hydroxy-3-nitrophenylthio)-5,6,7,8-tetrahydroquinoline as yellow crystals (from ethanol).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1.Cl>CCCCCC.O.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([Cl:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reactant: Cc1nnnn1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cn1nnnc1CC(=O)c1ccc(Cl)cc1N
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (1.6M, 20.8 ml) was added slowly to a stirred mixture of 1,5-dimethyltetrazole (3.26 g) and dry tetrahydrofuran (70 ml) at 0° under nitrogen. The mixture was stirred at 0° for 0.5 hour and then 7-chloro-1H-3,1-benzoxazine-2,4-dione (2.17 g) was added in portions at 0° to 5°. The mixture was stirred at room temperature for 3 hours, then poured into water (200 ml) and acidified with 5N hydrochloric acid to pH 6 to 7. The mixture was extracted with dichloromethane (4×70 ml). The extracts were combined, dried over anhydrous magnesium sulphate and evaporated to give the novel compound 1-(2-amino-4-chlorophenyl)-2-(1-methyl-1-H-tetrazol-5-yl)ethanone as an oil that was used in the next stage without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([Cl:17])=[O:13])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Nitrophenylacetic acid (15.0 g, 82.8 mmol) was dissolved in 330 mL of dichloromethane. Three drops of DMF were added, followed by dropwise addition of oxalyl chloride (14.4 mL, 165.6 mmol). The reaction was allowed to stir at ambient temperature for 3 hours, at which time the reaction was concentrated under reduced pressure to afford (2-nitrophenyl)acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#N)=[CH:12][C:11]=2[O:19][CH3:20])=[C:4]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=1.S(=O)(=O)(O)[OH:28].[C:32]([O-])(O)=[O:33].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:33][CH3:32])=[O:28])=[CH:12][C:11]=2[O:19][CH3:20])=[C:4]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The product from step (vii) (0.329 g) was added in one portion to a mixture of sulfuric acid (2 ml) and MeOH (4 mL). The resulting solution was stirred at 70° C. for 2 h. The mixture was allowed to cool and poured into saturated aqueous NaHCO3 (20 mL). The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to afford a colourless gum that was triturated with hexane (5 mL). The solid was collected by filtration to give the title compound as a colorless solid 0.089 g.