Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Oc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCO[C@@H]1CN(c2cc[nH]c(=O)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 5.4 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 4-chloro-2-hydroxypyridine (46 mg, 0.36 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMSO (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 6.3 mg of the title compound as a pale yellow amorphous solid (5%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:55][S:56]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1)(=[O:58])=[O:57]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.45 g, 0.66 m mol) in DCM (1.68 mL), cooled to 0° C., was slowly added triethylamine (0.185 mL, 1.33 mol) followed by methanesulfonyl chloride (0.13 mL, 1.66 mmol) and 4-dimethylaminopyridine (0.81 mg, 6.60 pmol). The mixture was stirred at rt overnight. After 16 hrs, a precipitate formed. The organic layer was re-dissolved in DCM and washed with water (2×), dried over sodium sulfated, filtered and concentrated in vacuo to a solid. The crude product was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded, 3×12 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% 7N NH3 (MeOH) in DCM] to afford 220 mg (44%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.48 (br. s., 1H), 8.33 (s, 1H), 7.82 (d, J=8.08 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 7.06 (d, J=2.02 Hz, 1H), 6.96 (d, J=7.58 Hz, 1H), 4.74-4.80 (m, 1H), 4.51 (s, 2H), 4.09 (quin, J=7.20 Hz, 4H), 3.89 (s, 3H), 3.34 (s, 1H), 3.29 (br. s., 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.64 (br. s., 1H), 2.29 (d, J=11.37 Hz, 2H), 1.69-2.00 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 756.19/757.23 (100/90) [MH+]. HPLC: tR=1.53 min (Micromass TOF: polar—3 min).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=O>C(Cl)(=O)C.ClCCl>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:12][C:13](=[O:15])[O:19][C:17](=[O:18])[CH2:16]1
Reactant: Cc1ccccc1C(CC(=O)O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: Cc1ccccc1C1CC(=O)OC(=O)C1
Reaction time: 12 h

Procedure:
To a solution of commercial 2-methylbenzaldehyde (18 g) and ethyl acetoacetate (39 g) in ethanol (30 ml) piperidine (3 ml) was added with stirring at rt. The mixture was kept at rt for 2 d. The precipitate was collected by suction filtration, washed with ethanol, and dried in vacuo to give 25.66 g of a yellowish solid (the bis-adduct of acetoacetate to the benzaldehyde). The powdered solid was added in portions to 40% NaOH (300 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (280 ml) to give a colourless precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(2-methylphenyl)glutaric acid (9.01 g) was obtained. The suspension of finely divided 3-(2-methylphenyl)glutaric acid in acetyl chloride (14.4 ml) was heated to reflux with stirring for 2 h. After cooling to rt petrol ether (50 ml) is added and the mixture is kept in the refrigerator for 12 h. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give a crude which is dissolved in dichloromethane (400 ml). Insolubles are removed by filtration and the filtrate is concentrated in vacuo to provide 3-(2-methylphenyl)glutaric anhydride (6.79 g) as colourless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[F:1][C:2]1[C:3]2[O:10][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccc(F)c2o1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A mixture of 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol), potassium carbonate (9.85 g, 71.4 mmol), and ethyl bromoacetate (4.30 ml, 39.3 mmol) in N,N-dimethylformamide (70 mL) was heated at 100° C. for 16 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate, 49/1→9/1) to afford ethyl 7-fluorobenzofuran-2-carboxylate (3.86 g, 52%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ7.56-7.54 (m, 1H), 7.47-7.42 (m, 1H), 7.28-7.14 (m, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=[N:19][CH:20]=3)[CH2:10][CH2:9]2)=CC=1>C(Cl)Cl.CO>[N:11]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:34]4[C:35]([Cl:45])=[C:36]([O:43][CH3:44])[CH:37]=[C:38]([O:41][CH3:42])[C:39]=4[Cl:40])=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)nc3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)cn3)c3ncccc23)c1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 105 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]pyridin-2-yl}-amide (Example 166) and stirring the reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.1 [M+H]+; TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:23][O:24][C@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][O:24][C@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([O:1][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[C:9]([NH:12][C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[CH:8]=[CH:7][CH:6]=2)[CH2:11]1)=[O:27]
Reactant: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H](C(=O)OC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1)c1ccccc1
Yield: 89.5 %

Procedure:
A mixture of Example 24B (1.03 g, 3.46 mmol), (R)-2-methoxy-2-phenylacetic acid (0.633 g, 3.81 mmol), 1,3-dicyclohexylcarbodiimide (1.14 g, 5.54 mmol), and 4-dimethylaminopyridine (0.846 g, 6.93 mmol) in dichloromethane (35 mL) was stirred at ambient temperature for 18 hr. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with 30% ethyl acetate/hexanes to afford 1.38 g (89% yield) of the title compound as a colorless syrup. MS (ESI+) m/z 446 (M+H)+, 463 (M+NH4).
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O>CN(C)C=O>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: NNC(=O)C(N)=O
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Solvent: CN(C)C=O
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
The reaction of 320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide can be carried out, in a manner analogous to that described in Example 1, but using 5 ml of N,N-dimethylformamide as solvent. 102 mg (27% of the theoretical yield) of 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide of m.p. 186-189° are likewise obtained.
Reaction SMILES: [H-].[Na+].[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:4].[CH3:18]I>C1COCC1>[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:18])[CH3:4]
Reactant: CC(=O)SCCCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of NaH (0.57 g, 60%, 14.25 mmol) in 20 ml of THF at 0° C. was added S-3-(tert-butoxycarbonylamino)propyl ethanethioate (1.25 g, 5.36 mmol) under Ar. After stirring at 0° C. for 30 min, MeI (1.0 ml, 16.06 mmol) was added to the mixture. Stirring was continued at 0° C. for 2 h then RT overnight. The mixture was concentrated, redissolved in 120 ml of EtAc/Hexane (1:2), washed with 1 M NaH2PO4 NaCl (conc.), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1:7) to afford 1.121 g (85%) of the title compound. 1H NMR (CDCl3) 3.69 (t, 2H, J=7.3 Hz), 2.41 (t, 2H, J=7.3 Hz), 2.39 (s, 3H), 2.03 (s, 3H), 1.76 (m, 2H), 1.47 (s, 9H); 13C NMR 173.21, 153.39, 83.28, 43.67, 31.84, 28.26, 28.19, 27.11, 15.65; MS m/z+270.0 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14]([Cl:22])=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CN1C=C(C(=O)O)[C@H](c2ccc(F)cc2)NC1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C=C(C(=O)Cl)[C@H](c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 mL dichloromethane and 1 drop of DMF was added 150 mg of (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. To this mixture was added 70 μl oxalyl chloride. When the bubbling stopped another drop of oxalyl chloride was added but as no bubbling was observed the solution was stirred at room temperature for 30 minutes after which the solvent was removed in vacuo to afford crude (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid chloride (not shown in Scheme H). This acid chloride was taken up in propionitrile and added to a solution of 125 mg 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine, 3 ml propionitrile, and 0.1 ml di-iso-propylethylamine. The solution was stirred at room temperature for 18 hours, then diluted with ethyl acetate and aqueous pH 2 buffer. The layers were separated and the organic layer dried over Na2SO4, filtered and the solvent removed in vacuo to give (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide, which was used directly in the next step without further purification.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:17][C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=3[Cl:6])=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 2-chloro-4-trifluoromethyl phenol (0.29 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl) 3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.61 g of desired compound (melting point: 113.0°-114.0° C.).
Reaction SMILES: C(OC(=O)NCC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34]C=C(F)C=2)=[C:24]([Cl:37])[CH:23]=1)(C)(C)C.C(OC([N:47]1CC[CH2:49][C@H:48]1C(O)=O)=O)(C)(C)C>>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([NH2:10])[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:49]=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1

Procedure:
The procedure of (1-5) of Example 1 was repeated except for using 414 mg of (2S)-pyrrolidine-1,2-dicarboxylic acid-1-t-butylester instead of 2-t-butoxycarbonylamino-ethanoic acid and 368 mg of the compound obtained in (145-2) to obtain the title compound (200 mg, 35%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH3:39][N:40]([CH3:50])[C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([N:40]([CH3:50])[CH3:39])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CN(C)c1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1
Yield: 37 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-(dimethylamino)phenylboronic acid gave 276 as an off-white solid (34 mg, 37% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 7.37-7.34 (m, 1H), 7.30 (s, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.82 (dd, J=8.3, 2.6 Hz, 1H), 3.69 (s, 3H), 3.13-3.04 (m, 4H), 2.97 (s, 6H), 2.58 (d, J=6.5 Hz, 2H), 1.80 (d, J=12.5 Hz, 2H), 1.52-1.39 (m, 1H), 1.32 (qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+) m/z 455 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])(=[O:40])=[O:41])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To an ice-cold solution of 4-(3,4-dichlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.65 g, 8.6 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) in dichloromethane (80 mL) was slowly added a solution of 2-nitrobenzene-1-sulfonyl chloride (2.1 g, 9.5 mmol) in dichloromethane (10 mL). The mixture was stirred for 2 hours and then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (3.39 g, 80%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd, J=8, 1.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.3, 2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.73 (s, 1H), 4.77 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H), 4.18 (dd, J=4.9, 4.9 Hz, 1H), 3.82 (dd, J=13.2, 4.5 Hz, 1H), 3.81 (s, 3H), 3.63 (dd, J=13.1, 5.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc(F)cc2s1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 6-fluoro-2(3H)-benzothiazolone (47.58 g) in 100% sulfuric acid (760 ml) was cooled at 0° to 5° C., and 98% fuming nitric acid (d=1.52; 18.79 g) was dropwise added thereto, followed by stirring at the same temperatur for 60 minutes. The reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzothiazolone (48.48 g) as pale brown crystals. m.p., 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N1C=CN=C1)([N:35]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:30])[NH2:35])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(N)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
N-(2,6-dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (52.6 mg) was dissolved in anhydrous THF (1 mL), carbonyldiimidazole (36.1 mg) was added and the mixture was stirred at room temperature under N2 for 2 h. Ammonium hydroxide (29% aqueous solution, 135 μL) was added and the mixture was stirred for an additional 22 h. The mixture was then extracted with EtOAc. The extract was washed with 1N HCl, sat. NaHCO3 and brine, dried (MgSO4) and evaporated. The residue was purified through a silica gel column using toluene/EtOAc (1:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-(2-carbamoylphenyl)-L-phenylalanine methyl ester (48.1 mg). ESMS: m/z 471 (MH+).
Reaction SMILES: C(OC([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:20]([N:22]2[C:33]4[C:25](=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]([C:34]([O:36][CH2:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:35])[CH2:27]5)[CH:24]=[CH:23]2)=[O:21])[CH2:13]3)[CH:10]=[CH:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH:10]1[C:11]2=[C:12]3[C:16](=[CH:17][CH:18]=[C:19]2[NH:8][CH:9]=1)[NH:15][CH:14]([C:20]([N:22]1[C:33]2[C:25](=[C:26]4[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]([C:34]([O:36][CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:35])[CH2:27]4)[CH:24]=[CH:23]1)=[O:21])[CH2:13]3
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)OCCc1ccc([N+](=O)[O-])cc1)C4)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCc1ccc([N+](=O)[O-])cc1)C1Cc2c(ccc3c2ccn3C(=O)C2Cc3c(ccc4[nH]ccc34)N2)N1

Procedure:
5 grams of 16 are placed in a flask. 100 mL of trifluoroacetic acid is added, and the mixture is stirred. After an hour, the acid is evaporated on a rotary evaporator and 100 mL saturated sodium bicarbonate solution and 100 mL of water are added. The mixture is agitated or sonicated for ˜½ hours, then filtered and washed with water and then methanol, and dried in vacuo. The material may be recrystallized. It is dissolved in a minimum amount of warm DMF, and then approximately a threefold portion of methanol is added and the solution is sonicated a few minutes. A cream to brown material crystallizes out. This is washed with methanol, and dried in vacuo. The yield approaches theoretical values.1H NMR (DMSO-d6) δ: 11.96 (s, NH, 1H), 11.71 (s, NH, 1H), 8.30 (br s, aromatic proton, 1H), 8.27 (br s, aromatic proton, 1H), 8.19 (d, aromatic protons, J=8.5 Hz, 2H), 7.66 (d, aromatic protons, J=8.3 Hz, 2H), 7.34 (m, aromatic protons, 2H), 7.08 (s, aromatic proton, 1H), 7.03 (s, aromatic proton, 1H), 4.60 (m, aliphatic protons, 4H), 3.68 (t, J=8 Hz, aliphatic protons, 2H), 3.40 (t, J=8 Hz, aliphatic protons, 2H), 3.24 (m, aliphatic protons, 4H). Combustion Analysis: Found: C, 63.55%; H, 4.42%; N, 11.95%. Calculated, for ½ mole sodium bicarbonate contaminant: C, 63.43%; H, 4.45%; N, 12.13%.