Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O[C@:13]([CH3:28])([CH2:26][CH3:27])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=O>>[CH2:26]([C@@:13]1([CH3:28])[O:10][C:9](=[O:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:14]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=1)[CH3:27]
Reactant: CC[C@@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CC[C@@]1(C)OC(=O)C(c2ccc(F)cc2)=C1c1ccc(S(C)(=O)=O)cc1

Procedure:
Using the procedures described in Example 1, Step 4 and Step 5, replacing phenylacetic acid with p-fluorophenylacetic acid and replacing 2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone with (2R)-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]butan-1-one from Step 4, the title compound was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[I-:29].[Na+]>CC(C)=O>[I:29][CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCI
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane (1.05 g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8 g, 12 mmole) and the mixture was stirred for 36 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed with 10% sodium thiosulfate solution and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 1.04 g=81%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=1.[H-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.64 mmol), and 4-chloropicolinamide (110 mg, 0.71 mmol) in DMF (2 mL) was added NaH (80 mg, 1.3 mmol, 60% dispersed in mineral oil). The reaction mixture was microwaved at 120° C. for 1.5 hours, then cooled to rt, diluted with water (20 mL), and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%).
Reaction SMILES: [CH:1]1([P:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:33][S:34](O)(=[O:36])=[O:35].[OH-].[Na+:39]>CO>[CH:24]1([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([S:34]([O-:36])(=[O:35])=[O:33])[C:15]=2[O:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1.[Na+:39]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added 2-dicyclohexylphosphino-2′6′dimethoxybiphenyl (5.13 g, 12.5 mmol) and CH2Cl2 (5 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (32.5 mL, 625 mmol) was added dropwise. The solution slowly turned yellow in color. The solution was heated to 40° C. in a preheated oil bath and was allowed stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜50 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜200 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×300 mL) and concentrated under reduced pressure to give a light yellow solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (2) as a light yellow solid (6.35 g, 99%). Mp=165° C. (turned red, dec.) 1H NMR (400 MHz, CD3OD) δ: 7.88 (d, 1H, J=8.8 Hz), 7.60 (m, 1H), 7.36 (m, 2H), 7.22 (m, 1H), 6.76 (d, 1H, J=8.8 Hz) 3.70 (s, 3H), 3.39 (s, 3H), 1.14-2.01 (m, 22H). 13C NMR (125 MHz, CD3OD) δ: 161.3, 157.1, 143.3, 142.9, 137.9, 137.8, 133.7, 133.6, 133.3, 133.2, 131.9, 130.0, 129.3, 128.0, 127.9, 127.8, 105.9, 61.6, 56.1, 50.0, 37.0, 36.9, 34.8, 34.6, 31.7, 31.6, 31.5, 31.2, 31.0, 30.8, 30.7, 28.9, 28.8, 28.7, 28.4, 28.34, 28.31, 28.2, 27.8, 27.7. 31P NMR (162 MHz, CD3OD) δ: −8.02. IR (neat, cm−1): 3453, 2925, 2849, 1577, 1462, 1448, 1400, 1229, 1191, 1099, 1053, 736. Anal. Calcd for C26H34NaO5PS: C, 60.92; H, 6.69. Found: C, 60.40; H, 6.85. 1H NMR (d4-MeOH/D2O) is shown in FIG. 7. 31P NMR (d4-MeOH) is shown in FIG. 7.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:16][CH3:17])(=[O:15])[CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O.[CH:18](OC)=O.[NH2:22][C:23]([NH2:25])=[S:24]>C(OC)(C)(C)C.CO>[O:13]=[C:11]1[C:10]([CH2:9][CH2:8][C:7]([O:16][CH3:17])=[O:15])=[CH:18][NH:25][C:23](=[S:24])[NH:22]1
Reactant: NC(N)=S
Reactant: COC=O
Reactant: COC(=O)CCCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)CCc1c[nH]c(=S)[nH]c1=O
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a suspension of potassium tert-butoxide (7.29 g, 64.9 mmol) in t-butylmethyl ether (100 mL) was added a solution of dimethyl pentanedioate (5.2 g, 32.5 mmol) and methyl formate (1.950 g, 32.5 mmol) in t-butylmethyl ether (50 mL). The mixture was stirred overnight and concentrated to dryness afford the yellow oil. The oil was dissolved in methanol (80 mL), to which thiourea (2.72 g, 35.7 mmol) was added. The mixture was heated to reflux overnight. The result mixture was concentrated and dissolved in water, adjust pH to 3 with AcOH. The solution was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (2.1 g, 9.80 mmol, 30.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]3)[C:25]([Cl:27])=[CH:26][C:19]=2[N:18]=1.ClC1C=C(C=CC=1)C(OO)=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:43])=[O:9])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([F:36])([F:35])[F:37])[CH2:32][CH2:33]3)[C:25]([Cl:27])=[CH:26][C:19]=2[N:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide (298 mg, 0.52 mmol), m-chloroperoxybenzoic acid (127 mg, 0.74 mmol) and DCM (20 mL) was stirred at rt overnight. The mixture was basicified to pH ˜8-9 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from DCM/Et2O gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][OH:11]
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1NCCO
Temperature: 85 °C
Yield: 90.8 %

Procedure:
2-(4-Bromo-2-nitrophenylamino)ethanol (3.20 g, 12.3 mmol) was stirred in EtOH (100 mL) and water (50 mL), and iron powder (3.45 g, 61.6 mmol) and ammonium chloride (731 mg, 13.5 mmol) were added. The mixture was heated at 85° C. for 2 h, then filtered through a pad of celite and rinsed with EtOH (500 mL). The filtrate was concentrated and purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (2.58 g, 91%) as a yellow oil: ESI MS m/z 231 [M+H]+.
Reaction SMILES: CO[C:3]1C(O)=C[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]1[O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23]CCOCCOC1.BrCC1OCCO1.C([O-])(O)=O.[Na+]>CCOCC.CN(C=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=[C:31]([O:32][CH3:15])[C:30]=1[O:29][CH2:28][CH:27]1[O:23][CH2:24][CH2:25][O:26]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COc1cc(O)c(OC)c([N+](=O)[O-])c1
Agent: BrCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCC1OCCO1
Temperature: 140 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a mixture of 2,5-dimethoxy-3-hydroxynitrobenzene (2.0 g, 8.43 mmol), 18-crown-6 (2.97 g, 8.43 mmol) and bromomethyl dioxolane (4.22 g, 25.3 mmol) was added DMF (60 ml). The solution was then heated for a total of 1.5 h in the CEM microwave at 140° C., initial voltage=300 W. The solution was poured on to a mixture of sat. NaHCO3 and Et2O, the layers separated and the aqueous extracted with Et2O. The combined organic layers were washed with water (4×50 ml), 1M HCl (50 ml) and brine (2×50 ml), dried over MgSO4 filtered and evaporated. Hexanes were added to the solid residue and the resulting suspension stirred for 1 h. The product was isolated by filtration and dried in a vacuum oven to afford the title compound (1.45 g, 57%). m/z 286 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].Cl.[OH:26][C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[O:29][N:28]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O1CCOCC1.CN(C=O)C.C(O)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH:21][C:32]([C:30]1[O:29][N:28]=[C:27]([OH:26])[CH:31]=1)=[O:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=C(O)c1cc(O)no1
Reactant: CCOC(=O)C(C)(C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCCCO
Product: CCOC(=O)C(C)(C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(O)no1
Temperature: 65 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
(R)-4-Amino-5-biphenyl-4-yl-2,2-dimethyl-pentanoic acid ethyl ester (72.1 mg, 221 μmol, 1.0 eq.), 1-butanol (5 mL) and 4 M of HCl in 1,4-dioxane (2 mL) were combined and stirred at 65° C. overnight. To this was added a mixture of 3-hydroxyisoxazole-5-carboxylic acid (28.6 mg, 221 μmol, 1.0 eq.), EDCI (39.2 μL, 221 μmol, 1.0 eq.) and HOBt (29.9 mg, 221 μmol, 1.0 eq.) that had been combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was then quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (50 mg, 95% purity). MS m/z [M+H]+ calc'd for C25H28H2O5, 437.20; found 437.4.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1B(O)O.OP([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])=[CH:3][CH:4]=[CH:5]2)=[N:9]1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Cn1cc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3cn(C)nc23)c(C)c1
Temperature: 69 °C
Reaction time: 156 h
Yield: 60.4 %

Procedure:
A mixture of 7-bromo-2-methyl-2H-indazole (6: R=Me; 2.01 g, 9.53 mmol), 2,4,6-trimethylphenyl boronic acid (1.70 g, 10.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.657 g, 0.569 mmol), 70 mL of DMF, and 33 mL of a 2 M aqueous K2HPO4 solution was stirred at 69° C. for 6.5 d. The mixture was partitioned between 350 mL of diethyl ether and 350 ML of water. The organic layer was washed with 350 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a pale yellow oil. Column chromatography (0→33% EtOAc/hexanes) afforded of impure 2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole (5: R=Me, Ar=2,4,6-trimethylphenyl; 1.44 g) as a white solid that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]CCOC)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[C:28]1(C)C(C)=CC=CC=1>>[CH3:28][N:4]1[S:5](=[O:12])(=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:2]([OH:1])=[C:3]1[C:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:16]
Reactant: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: Cc1ccccc1C
Reactant: Nc1ccccn1
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 6 h
Yield: 96 %

Procedure:
2-Methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (28 g., 0.089 mole) and 2-aminopyridine (9.26 g., 0.098 mole) were combined with 500 ml. of xylene in a 1 liter flask equipped with an addition funnel and a reflux, variable take-off distillation head. The stirred reaction mixture was heated to reflux and the xylene distilled at the rate of approximately 100 ml./hour, while maintaining the pot volume almost constant by the addition of fresh xylene. After 6 hours, the head temperature, which had been relatively constant at 134° C., rose to 142° C. and reflux rate slowed. The reaction mixture was then cooled in an ice-bath and the precipitated solids recovered by filtration, with hexane for transfer and wash, and dried at 45° C. in vacuo to yield piroxicam (28.5 g., 96%; m.p. 167°-174° C.).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][S:6][CH:7]1[C:11]2[C:12]([O:21][CH3:22])=[C:13]3[C:18](=[C:19]([OH:20])[C:10]=2[C:9](=[O:23])[N:8]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[N:17]=[CH:16][CH:15]=[CH:14]3.O.CO.[Li+].[OH-]>C1COCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C:9](=[O:23])[C:10]3[C:19]([OH:20])=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:21][CH3:22])[C:11]=3[CH:7]2[S:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:30][CH:29]=1
Reactant: COC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O

Procedure:
A solution of 23 (150 mg, 0.329 mmol) in 3.29 mL of a 1:2:3 solution of H2O:MeOH:THF was stirred with LiOH. H2O (69 mg, 1.65 mmol) for 1 hour when LCMS demonstrated complete conversion of starting materials to product. The reaction mixture was dried under reduced pressure and the residue was suspended in water and the pH was adjusted to 11 with aqueous 1N NaOH solution. The aqueous layer was washed with EtOAc twice. The pH of the aqueous layer was then adjusted to 5 using 1N HCl and the product was extracted with CH2Cl2 under continuous extraction conditions. The organic layer was dried in vacuo to yield the product 24 as an orange solid. 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 1H), 2.25-2.45 (m, 4H), 4.04 (s, 3H), 4.43 (d, 1H, J=15 Hz), 5.32 (dd, 1H, J=3, 14 Hz), 5.49 (s, 1H), 7.03 (t, 2H, J=9 Hz), 7.35 (dd, 2H, J=5, 8 Hz), 7.57 (dd, 1H, J=4, 8 Hz), 8.52 (dd, 1H, J=2, 8 Hz), 8.98 (dd, 1H, J=2, 5 H); 13C NMR (75 MHz, CD3OD) δ 21.4, 33.6, 41.9, 61.8, 61.9, 112.3, 115.7, 116.0, 123.1, 125.0, 126.5, 130.4, 130.5, 131.8, 131.8, 139.3, 142.6, 148.3, 149.6, 162.4 (d, J=245 Hz), 167.2, 175.3; 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 441.4 [M−H]−, 883.1 [2M−2H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:43][CH3:44])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]([CH2:26][C@H:27]([OH:42])[C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH2:34][N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[C:32]=2[CH:41]=1)C(=O)OC(C)(C)C)[CH3:17])=[O:5])[CH3:2].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:43]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH:18][CH2:26][C@H:27]([OH:42])[C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH2:34][N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[C:32]=2[CH:41]=1)[CH3:17])=[O:5])[CH3:44]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N(C[C@H](O)c3ccc4c(c3)N(S(C)(=O)=O)CCO4)C(=O)OC(C)(C)C)c[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc4c(c3)N(S(C)(=O)=O)CCO4)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
To a solution of tert-butyl [2-(7-diethylcarbamoyl-1H-indol-3-yl)-(1R)-1-methylethyl]-[(2R)-2-hydroxy-2-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethyl]carbamate (48.4 mg, 0.077 mmol) in methylene chloride (3 mL) is added trifluoroacetic acid (250 μL) under nitrogen atmosphere, and the mixture is stirred at room temperature for 18 hours, and to the mixture is added trifluoroacetic acid (1 mL). The mixture is stirred at room temperature for 3 hours, and thereto are added trifluoroacetic acid (1 mL) and thioanisole (50 μL). The mixture is stirred at room temperature for one hour. The pH value of the reaction solution is adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is distilled off. The residue is dissolved in chloroform:methanol (2:1, 75 mL), and the insoluble materials are removed by filtration. The solvent is removed by distillation, and the crude product is purified by preparative TLC (a saturated ammonia solution in chloroform) and prepartive HPLC (trifluoroacetic acid-acetonitrile-water) to give the desired 3-{(2R)-2-[(2R)-2-hydroxy-2-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamino]propyl}-1H-indole-7-carboxylic acid diethylamide trifluoroacetate (6.6 mg, 0.0103 mmol, yield: 13%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:45]=[N+:46]=[N-:47].[Na+].[N-]=[N+]=[N-]>CN(C=O)C.O>[N:45]([C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@H:11]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](I)[C@@H]1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](N=[N+]=[N-])[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound 87 (30 mg) was dissolved in DMF/water 1:1 (2 ml) and followed by sodium azide (26 mg, 10 equiv.). The reaction mixture stirred at 80° C. overnight. LCMS confirms conversion of starting material to product substituted with azide.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=O.[CH2:12]([C:19]1[C:20]([NH2:31])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C:19]1[NH:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]2[C:3](=[O:5])[C:2]([CH2:6][C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[N:31][C:20]=12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(=O)Cc1cccs1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Product: O=c1c(Cc2cccs2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized from method C using 2-oxo-3-(thiophen-2-yl)propanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. 1H NMR (300 MHz, dmso) δ 8.85 (s, 1H), 7.99 (d, J=6.8, 2H), 7.63-7.02 (m, 10H), 6.94 (dd, J=3.5, 5.1, 1H), 4.62 (s, 2H), 4.58 (s, 2H), 2.69 (contaminate); exact mass calculated for C24H20N3OS+ m/z+398.13, found m/z+398.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[C:10](O)=[O:11])([OH:3])=[O:2].[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:25][OH:26]>>[CH3:25][O:26][C:10]([C:9]1[CH:8]=[CH:7][N:6]([CH3:13])[C:5]=1[CH2:4][C:1]([O:3][CH3:14])=[O:2])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cn1ccc(C(=O)O)c1CC(=O)O
Reactant: CO
Product: COC(=O)Cc1c(C(=O)OC)ccn1C

Procedure:
2-Carboxymethyl-1-methyl-1H-pyrrole-3-carboxylic acid (17.67 g) prepared as described by Bottaccio, Giorgio; Campolmi, Stefano; Carletti, Vittorio; Marchi, Marcello. EP105664, para-toluenesulfonic acid (9.17 g) and methanol (250 ml) were refluxed under argon for 48 hours. The solvent was evaporated and the residue washed with ethanol to yield the title compound as a white solid (15.75 g)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
To a solution of (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (271 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. The crude material was triturated with 2:2:1 water/CH3CN/DMSO and the resultant white solid filtered off. Repetitive concentration and trituration of the filtrate in the same manner gave cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide (F) (230 mg, 60%) as a white solid. The (F) compound was stirred in 1M HCl/ether (10 mL) for 1 h and concentrated to give the HCl salt of Ex. 7 (250 mg): 1H NMR (400 MHz, CD3OD) δ 7.50 (br s 2 H), 7.35-7.25 (m, 2 H), 7.22-7.05 (m, 4 H), 4.43 (s, 2 H), 2.92 (d, 2 H), 2.41 (m, 1 H), 2.23 (m, 1 H), 1.93 (m, 2 H), 1.60 (m, 6 H); mass spectrum m/z 366 [(M+H)+; calcd for C22H25N3OF: 366].