Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(O)(C)C.[OH-].[NH4+:51]>C(Cl)Cl>[NH2:51][CH2:45][C@@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:13]2)=[O:11])=[N:5]1
Reactant: [NH4+]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CN)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 26 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), and ammonium hydroxide (1 mL) was microwaved at 130° C. for 15 min. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (11.4 mg, 26%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H40Cl2F2N6O3+H [(M+H)+]: 677.2580. found: 677.2576.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]4)=[O:22])[C@@H:17]([CH3:31])[CH2:16]3)=[C:11]3[CH:32]=[N:33][CH:34]=[CH:35][C:10]=23)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:26]1([F:30])[CH2:27][CH2:28][CH:23]([C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[N:13]=[N:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:46](=[O:47])[O:48][CH3:49])=[CH:8][CH:7]=4)=[C:10]4[CH:35]=[CH:34][N:33]=[CH:32][C:11]=34)[CH2:16][C@@H:17]2[CH3:31])=[O:22])[CH2:24][CH2:25]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN(c2nnc(-c3ccc(CN)cc3)c3ccncc23)CCN1C(=O)C1CCC(F)(F)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NCc1ccc(-c2nnc(N3CCN(C(=O)C4CCC(F)(F)CC4)[C@@H](C)C3)c3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-(4-(1-(4-(aminomethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 51 (120 mg, 250 μmol) was dissolved in DMF (3 ml) and N,N-diisopropylethylamine (0.300 ml, 1.72 mmol). Methyl chloroformate (0.0211 ml, 275 μmol) was added and the reaction stirred at RT for 2 hours. The reaction was the taken up in ethyl acetate (80 ml) and washed with aqueous K2CO3 (10%), water, and brine. The organic phase was dried (MgSO4) and evaporated to give an orange oil. The residue was chromatographed over silica with a gradient of dichloromethane with 2.5% triethylamine and 0-5% methanol. The product (S)-methyl (4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)phenyl)methylcarbamate 52 was isolated as a yellow solid. LC/MS m/z=539 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.Cl[C:34]([C:36]1[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=1)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][C:34]([C:36]2[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=2)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[O:35])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (191 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (120 mg, 1.50 mmol, 3.00 equiv), and tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (158 mg, 0.50 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (20:1) to give 100 mg (30%) of product as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2S[CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:35]C=C(C(OC)=O)N=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:35][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)[CH2:18][CH2:17]1)=[O:13]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: COC(=O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1

Procedure:
Methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}-1,3-oxazole-4-carboxylate 9 was prepared, according to the procedure described for compound 7, using methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate. Yield: 410 mg, 45%.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:15]([C:17]1[C:18]2[C:23]([CH:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)#[N:16]>C1(C)C=CC=CC=1>[CH:29]1[C:30]2[C:25](=[CH:24][C:23]3[C:18]([C:17]=2[C:15](=[NH:16])[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1c2ccccc2cc2ccccc12
Reactant: C1CCNCC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N=C(c1c2ccccc2cc2ccccc12)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of MeMgBr in ether (3.3 mL, 3.0 M, 9.9 mmol) was added to a solution of piperidine (1.11 g, 13.1 mmol) in toluene (50 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 9-cyanoantracene (2.00 g, 9.9 mmol) was added. The mixture was allowed to warm to room temperature and the mixture was stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 98%. The mixture was quenched with an aqueous NH4Cl solution (1%, 150 mL). The organic phase was separated from the aqueous phase and the latter was extracted with CH2Cl2 (250 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure resulting in a sticky residue. Pure product 1.76 g (62%) was obtained by rinsing the residue with ligroin. The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 8.4 (s, 1H), 7.9 (m, 4H), 7.4 (m, 4H), 5.8 (bs, 1H), 4.0 (bt, 2H), 2.7 (bt, 2H), 1.8 (bm, 2H), 1.5 (p, 2H), 1.2 (bm, 2H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm): 163.3, 130.7, 129.4, 126.6, 125.8, 125.3, 124.6, 123.8, 123.5, 46.5, 41.8, 25.0, 23.8, 22.8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].C[Si](C)(C)Cl.[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>>[S:13]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])([CH3:16])(=[O:15])=[O:14]
Reactant: O=C1NCCCN1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Product: CS(=O)(=O)N1CCCNC1=O

Procedure:
This compound was produced as described in Example 35 C from 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 49 parts by weight of trimethylchlorosilane and 30 parts by weight of mesylchloride. The reaction product was recrystallized from acetone at low temperature and thereafter from acetone/ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-])=O)=[CH:28][CH:27]=2)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])=[CH:12][CH:13]=2)([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:21])[F:19])=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(C(c2ccc(Nc3ccccc3[N+](=O)[O-])cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ccc(C(c2ccc(Nc3ccccc3N)cc2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 94.9 %

Procedure:
20 g (34.7 mmol) of 2,2-bis[N-(2-nitrophenyl)-(4-aminophenyl)]hexafluoropropane synthesized above were dissolved in 200 ml of ethyl acetate. Thereto was added 1 g of 10% palladium carbon as a catalyst, and replacement with hydrogen was then carried out. After that, reaction was conducted at room temperature under a hydrogen pressure of 1.01 MPa (10 atm) for 18 hours with stirring vigorously. The obtained reaction solution was filtered with cerite to remove the catalyst, and ethyl acetate was removed under reduced pressure. The residue was re-crystallized by using a chloroform-hexane mixed solution, and ethanol-water mixed solution to obtain 17 g of 2,2-bis[N-(2-aminophenyl)-(4-aminophenyl)]hexafluoropropane (hereinafter pNPN-AF) in white solid (yeild: 95%).
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[C:8](N)[C:9](F)=[C:10](F)[C:11]=2F)[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)C.C(OC(NC1CCNC1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:4]=[C:5]1[C:18]([OH:20])=[O:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Agent: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 2.79 g (15 mmole) of 3-(t-butoxycarbonylamino)pyrrolidine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl[-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cccc(Cl)c2Cl)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cccc(Cl)c2Cl)n1
Yield: 42 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(2,3-dichloro-phenyl)-pyrimidin-2-ylamine and 4-chloroaniline provided the title compound (42% yield). 1H NMR (CD3OD) δ 6.19 (s, 1H, Ar), 7.29 (d, 2H, Ar), 7.31 (d, 2H, Ar) 7.4 (d, 1H, Ar) 7.55 (d, 2H, Ar).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[C:1]1([S:7][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To the solution of thiophenol (0.5 g, 0.463 mL, 4.5 mmol) in DMF (6 mL) was added potassium carbonate (0.94 g, 6.8 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-fluoro benzaldehyde (0.675 g, 0.574 mL, 5.4 mmol) was added and the reaction mixture stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (25 mL×2) then with brine (25 mL), dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain title compound (0.94 g, 96%).
Reaction SMILES: [H][H].[N+:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-])=O)([CH2:9]3)[CH2:7]1)[CH2:13]2)([O-])=O>>[NH2:3][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: [H][H]
Reactant: O=[N+]([O-])C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Product: NC12CC3CC(C1)CC(N)(C3)C2
Yield: 95 %

Procedure:
To an autoclave, 10 mmole of 1,3-dinitroadamantane obtained by the method of Example 16, 5% Pd-C (10 mole % of Pd relative to a substrate), 1 ml of dilute hydrochloric acid and 10 ml of methanol were charged. The mixture was stirred for 2 hours at 80° C. in an atmosphere of hydrogen at 30 atm. As a result, the conversion of 1,3-dinitroadamantane was 99%, and 1,3-diaminoadamantane (yield 95%) was formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11]([CH2:14][NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)([CH3:13])[O:10][C:9]2=[O:38])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[N:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54](Cl)=[O:55]>ClCCl>[C:35]([C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:25]2[O:24][C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][C:11]4([CH3:13])[O:10][C:9](=[O:38])[N:8]([C:5]5[N:6]=[CH:7][C:2]([NH:1][C:54]([C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][N:48]=6)=[O:55])=[CH:3][CH:4]=5)[CH2:12]4)=[O:37])=[CH:22][CH:21]=3)=[N:27][C:26]=2[CH:28]=1)#[N:36]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(N)cn5)C(=O)O4)cc3)oc12
Reactant: O=C(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(NC(=O)c6ccccn6)cn5)C(=O)O4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-{[3-(5-aminopyridin-2-yl)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (10 mg, INTERMEDIATE 23) and diisopropylethylamine (7 μl) in 4 ml of dichloromethane was added picolinoyl chloride (3 mg). The mixture was stirred at room temperature for 1 h. The sample was purified directly via column chromatography on a Biotage Horizon 12M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound (4 mg, 34%). Mass spectrum (ESI) 616.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 9.01 (s, 1H), 8.69 (d, J=3.9 Hz, 1H), 8.47 (d, J=8.4 Hz, 2H), 8.33 (d, J=8.3 Hz, 2H), 8.31 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.92 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.41 (bs, 1H), 6.65 (bs, 1H), 4.94 (bs, 1H), 4.04 (d, J=10.3 Hz, 1H), 3.99 (dd, J=14.2, 6.6 Hz, 1H), 3.83 (dd, J=14.4, 6.4 Hz, 1H), 3.47 (sept, J=7.0 Hz, 1H), 1.67 (s, 3H), 1.46 (d, J=6.9 Hz, 6H).
Reaction SMILES: [ClH:1].Cl.[C:3]1([O:13][C:14](=[O:37])[C@H:15]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[NH:16]C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)N)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>Cl.O1CCOCC1>[ClH:1].[C:3]1([O:13][C:14](=[O:37])[C@H:15]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:14]([O:13][CH2:3][C:12]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:37])[NH2:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](N)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)Oc1cccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 209.8 %

Procedure:
In 25 g of hydrochloric acid-dioxane solution (110 mg HCl/g) was dissolved 13.2 g of the above ester, and the solution was stirred at room temperature for 1.5 hrs. The reaction mixture was evaporated under reduced pressure to dryness, and anhydrous diethyl ether was added to the residue. The resulting mixture was allowed to stand for 24 hrs, and the colorless powders thus precipitated were collected to obtain 11.0 g (yield 95%) of Nε -benzyloxycarbonyl-L-lysine 1-naphthyl ester hydrochloride, m.p. 80°-82° C.
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:18]([O-])=O)=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C(O)C>CCOC(C)=O>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:18])=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1c[nH]c2cc(N)c(C(F)(F)F)cc12
Temperature: 62 °C

Procedure:
A microwave vial charged with 3-tert-butyl-6-nitro-5-(trifluoromethyl)-1H-indole (95 mg, 0.3319 mmol), SnCl2.2H2O (375 mg, 1.66 mmol) and ethanol (1 mL), was sealed and heated at 62° C. for 3 h. The reaction was cooled to room temperature, diluted with EtOAc and quenched with saturated NaHCO3 solution until the pH was 7. The reaction mixture was then filtered through a plug of celite. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel column chromatography using 0 to 40% EtOAc in hexanes to obtain 3-tert-butyl-5-(trifluoromethyl)-1H-indol-6-amine. LC/MS: m/z 257.3 (M+H)+ at 1.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][C:13]=1[OH:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.O1CCCC1>[CH2:4]([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[OH:28])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(O)c1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of lithium hydroxide hydrate (300 mg, 7.15 mmol) in water (15 cm3) was added dropwise to a stirred solution of benzyl 4-benzyloxy-3-hydroxybenzoate (1.177 g, 3.52 mmol) in tetrahydrofuran (35 cm3). The resulting emulsion was stirred overnight, by which time a clear, pale yellow solution had formed. More lithium hydroxide hydrate (300 mg, 7.15 mmol), water (25 cm3) and tetrahydrofuran (25 cm3) were added, and stirring was continued for 24 h. The tetrahydrofuran was removed under reduced pressure. Water (100 cm3) was added to the residual mixture, which was washed with diethyl ether (2×50 cm3), acidified to pH 1 with 5% HCl and extracted with dichloromethane (3×100 cm3). The combined extracts were washed with brine (50 cm3), dried (NaSO4) and evaporated to give 4-benzyloxy-3-hydroxybenzoic acid as a white solid (638 mg, 74%). The diethyl ether washings were extracted with 1 M potassium hydroxide (2×25 cm3). The combined extracts were acidified to pH 1 with 5% HCl and extracted with dichloromethane (3×100 cm3). The combined extracts were dried over MgSO4 and evaporated to give a further 119 mg of product (total yield 757 mg, 88%), m.p. 163-165° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][NH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:21][CH:20]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: COC(CN=C=O)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COC(CNC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
A solution containing 1.5 g of the compound prepared in stage A in 10 ml ofbenzene is added to a solution containing 1.4 g of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione in 5 ml of tetrahydrofuran.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[O:9][CH2:10][CH2:11][OH:12])=[CH:2]1.C(Cl)(=O)C(Cl)=O>CS(C)=O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[O:9][CH2:10][CH:11]=[O:12])=[CH:2]1
Reactant: OCCOc1cccc(-c2ccsc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: O=CCOc1cccc(-c2ccsc2)c1

Procedure:
The resulting alcohol compound was oxidized in a similar manner to that described in J. Org. Chem., 43, 2481 (1978) using oxalyl chloride and dimethylsulfoxide to give the captioned compound.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:7]1=[O:24])C.[ClH:26]>>[ClH:26].[CH3:11][C@H:10]1[N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:7](=[O:24])[C@@H:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)C[C@H]1C
Agent: Cl
Product: C[C@@H]1C[C@H](CCc2ccc3c(n2)NCCC3)C(=O)N1CC(=O)O
Temperature: 60 °C

Procedure:
A mixture of 11-11 (185 mg, 0.5356 mmol) and 6N HCl (10 mL) was heated at 60° C. for 1 h. Evaporative removal of the solvent gave 11-12 as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:37])[C@@H:5]([O:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[CH3:36][O:35][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:11][CH:12]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc(-c4nnn[nH]4)cc3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(-c4nnn[nH]4)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-methoxy-3-(4-{3-[4′-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionic acid ethyl ester (Step A) via the standard hydrolysis procedure C (NaOH). 1H-NMR (MeOD, 300.15 MHz): δ 8.09 (d, 2H, J=8.3), 7.70 (d, 2H, J=8.3), 7.62 (d, 2H, J=8.7), 7.18 (d, 2H, J=8.5), 7.05 (d, 2H, J=8.7), 6.86 (d, 2H, J=8.7), 4.23 (t, 2H, J=6.0), 4.17 (t, 2H, J=6.1), 3.83 (dd, 1H, J=8.3, 4.2), 3.36 (s, 3H), 2.99 (dd, 1H, J=14.1, 4.0), 2.84 (dd, 1H, J=13.9, 8.1), 2.26 (qn, 2H, J=6.3).