Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:64])[CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:23][CH2:22]1)=[O:20])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:78]1[C:83](=[O:84])[CH2:82][CH2:81][C:79]1=[O:80])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:80]=[C:79]1[CH2:81][CH2:82][C:83](=[O:84])[N:78]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH2:23][CH2:22]1)=[O:20])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:64]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 86.4 %

Procedure:
To a solution of 2-[4-tert-butoxycarbonyl-4-({-4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]pentanedioic acid 1-tert-butyl ester (4.6 g) in THF (150 ml) was added TSTU (1.68 g). DIPEA (0.97 ml) was added. After stirring over night the mixture was concentrated in vacuo. The residue was crystallized from acetonitrile to afford the title compound as a solid (4.4 g, 87%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.[OH-].[Na+].Cl.O>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2
Reactant: CCOC(=O)CCn1c(-c2ccc(Cl)cc2N)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3N)n(CCC(=O)O)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a suspension of methyl 2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indole-6-carboxylate (1.05 g, 2.17 mmol) in tetrahydrofuran (11 ml) and methanol (11 ml) was added 4N aqueous sodium hydroxide solution (1.08 ml, 4.34 mmol), and the mixture was stirred for 2 hr. 2N Hydrochloric acid (2.2 ml) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2-amino-4-chlorophenyl)-1-(2-carboxyethyl)-3-cyclohexyl-1H-indole-6-carboxylate (949 mg) as a crude product. The obtained crude product was used for Step 4 without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][Zn]C.O>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C[Zn]C
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)cncc1Cl
Temperature: 60 °C
Yield: 90 %

Procedure:
To the solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (28 g, 105 mmol) in dioxane (300 mL) in a 1 L round bottom flask was added dimethylzinc (105 mL, 1.0 M in hexane) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) dichloromethane complex (1.3 g, 1.6 mmol). The resulting mixture was heated at 60° C. for 20 hours. After cooling, the reaction mixture was poured into cold water (500 mL) and extracted with dichloromethane (3×200 mL). After evaporation of the solvent, the crude product was filtered through a silica pad (10 cm) with 20% ethyl acetate in hexane (400 mL), and the solvent was evaporated. The oily ethyl 3-chloro-5-methylpyridine-4-carboxylate (20 g, 90% yield) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1nc2ccccc2s1
Solvent: CC(=O)OC(C)=O
Product: Clc1ccccc1C=Cc1nc2ccccc2s1

Procedure:
The synthetic sequence commences with the condensation of a 2-chloro-benzaldehyde with 2-methylbenzothiazole II in boiling acetic anhydride to give 2-(2'-chlorostyryl)benzothiazole III.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:5][CH:4]=1.[O:29]=[C:30]1[CH:34]([C:35](O)=[O:36])[CH2:33][CH2:32][NH:31]1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:35]([CH:34]5[CH2:33][CH2:32][NH:31][C:30]5=[O:29])=[O:36])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1CCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCNC5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (20.0 mg, 0.053 mmol; obtained from Example 5, Step D), 2-oxopyrrolidine-3-carboxylic acid (34.1 mg, 0.26 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (50.7 mg, 0.26 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (35.7 mg, 0.26 mmol), N-ethyl-N-isopropylpropan-2-amine (34.2 mg, 0.26 mmol), and THF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (2 days). Water (10 mL) was added and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (22.3 mg, 86.2%). LRMS (APCI neg) m/e 488 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[CH:23]=[C:22]1B(O)O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CS(=O)(=O)NCc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cncc(CNS(C)(=O)=O)c2)cc2ccc(Cl)cc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A flask is charged with N-(5-bromo-pyridin-3-ylmethyl)-methanesulfonamide (Example 163a, 530 mg, 2 mmol), N-Boc-6-chloro-indole-2-boronic acid (525 mg, 3.0 mmol), s-Phos (41 mg, 0.10 mmol), finely crushed potassium phosphate (849 mg, 4.0 mmol) and toluene (20 mL), and the mixture is degassed for 15 min. Pd2 dba3 (37 mg, 0.04 mmol) is added and the mixture is stirred at 85° C. for 1 h. The mixture is cooled to room temperature, diluted with DCM and silica gel (10 g) is added. The mixture is concentrated in vacuo and the residue is purified by silica gel flash chromatography eluting with a 0 to 90% ethyl acetate-heptane gradient to give 6-chloro-2-[5-(methanesulfonylamino-methyl)-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester. MS (ESI) m/z 436.1 and 437.9 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:30])[NH:10][C@@H:11]([CH2:24][C:25]2[NH:29][CH:28]=[N:27][CH:26]=2)[C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>CO.O>[NH:29]1[C:25]([CH2:24][C@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:30])[C:12]([NH:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:13])=[CH:26][N:27]=[CH:28]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)Nc1c(C)cc(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H]2O[C@@H]2C(=O)O)c(C)c1
Yield: 67.8 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18b (51.6 mg, 0.1 mmol); LiOH (5 mg, 0.2 mmol); MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL): yielded 29 as a white solid (26.2 mg, 54.2%). 1H NMR (MeOD-d4, 400 MHz): δ 7.62 (s. 1H); 6.93 (s, 1H); 6.87 (s, 2H); 4.84-4.82 (m, 1H); 3.53-3.49 (d, 1H); 3.38-3.35 (d, 1H); 3.25-3.22 (m, 2H); 2.25 (s, 3H); 2.07 (s, 6H). 13C NMR (MeOD-d4, 100 MHz): 174.40, 172.62, 170.80, 168.89, 136.54, 135.74, 135.11, 133.43, 131.25, 128.18, 117.26, 54.20, 53.82, 53.69, 52.80, 29.34, 19.55, 16.86. ESI-HRMS (m/z): [M−H+] calcd. for C19H22N4O5: 385.1517, observed: 385.1516. HPLC Method 2: Rt=16.4 min, purity=95.4%.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCOc1ccc(C=O)cc1
Yield: 38.9 %

Procedure:
The title compound (0.6 g, 39%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and 4-[2-bromoethoxy]benzaldehyde (1.37 g, 6 mmol) in the presence of K2CO3 (1.38 g, 10.0 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C.O>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:12])([F:1])[F:13])=[N:4][N:5]=[C:6]2[CH2:11]1
Reactant: ClCCCBr
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.90 g) in DMF (10 mL) was added K2CO3 (2.35 g) and 1-bromo-3-chloropropane (1.70 mL) at rt. The reaction mixture was heated at 80° C. for 3 h, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as transparent liquid (0.68 g, 30.00%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]#[N:12].C([O:15]CCO)C>C([O-])(O)=O.[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]([NH2:12])=[O:15]
Reactant: CCOCCO
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: NC(=O)Cc1c(Cl)cccc1Cl

Procedure:
Alternative Conditions. To a solution of sodium (169 mg, 7.35 mmol) dissolved in 2-ethoxyethanol (7.0 mL) was added 2,6-dichlorophenylacetonitrile (1.40 g, 7.53 mmol) and (IV) (502 mg, 3.66 mmol), and the mixture was then stirred at reflux for 30 minutes. The resulting solution was diluted with aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The solvents were removed under reduced pressure, then chromatography of the residue on silica gel, eluting with 2-3% MeOH/CH2Cl2, gave firstly a mixed fraction, which on crystallisation from CHCl3 /light petroleum gave 2,6-dichlorophenylacetamide (165 mg): mp (MeOH/CH2Cl2) 211.5-213° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.8 h

Procedure:
A 100-mL round-bottom flask was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of 3-(methylthio)-6-nitro-1-phenyl-1H-indazole (3.5 g, 12.28 mmol, 1.00 equiv) in ethyl acetate (30 mL), Palladium carbon (2.2 g), bubbled with H2 (gas). The resulting solution was stirred for 48 min at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 3-(methylthio)-1-phenyl-1H-indazol-6-amine as brown oil. MS: 256 (MH+)
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2occc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc2occc2c1

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.10 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg, tris(dibenzylideneacetone)dipalladium(0) 3 mg and cesium carbonate 0.24 g was added 5-bromobenzofuran 0.18 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=30:1] to give tert-butyl 2-((benzofuran-5-yl)amino)-4-phenylbenzoate. Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 2-((benzofuran-5-yl)amino)-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent of reaction mixture was removed under reduced pressure, and the obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=30:10:1] to give 2-((benzofuran-5-yl)amino)-4-phenylbenzoic acid 42 mg.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18]([OH:25])([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:26])C.COCCOC.[OH-].[K+].[Na+].[Cl-]>C(OCC)C.O>[OH:26][C@H:12]1[CH2:13][CH2:14][C:15](=[CH:16][CH2:17][C:18]([OH:25])([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCCCCC(C)(O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: CCCCCC(C)(O)CC=C1CC[C@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A mixture of 250 mg. 9β,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester (as mixture of the two 15-epimers), 20 ml. 1,2-dimethoxyethane, 0.3 g. KOH and 5 ml. water is stirred for 12 hours at room temperature, diluted with 40 ml. diethyl ether and saturated with NaCl. The organic phase is separated, washed twice with 15 ml. amounts of H2O and dried over MgSO4. Solvent is removed to obtain, as oily residue, 9α,15-dihydroxy-15-methyl-12-prostenoic acid as mixture of the 15-epimers.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([N:27]([CH3:37])[C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.O.C(OCC)C>[CH3:26][O:25][C:23]1[N:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([N:27]([C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:29])[CH3:37])[N:22]=1
Reactant: COc1nc(OC)nc(N(C)C(=O)Oc2ccccc2)n1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Reaction time: 96 h
Yield: 79.9 %

Procedure:
To 0.22 g of 2-(5-methyl-1H-tetrazol-1-yl)benzenesulfonamide (compound of Example 2, 0.32 g) and 0.32 g of phenyl (4,6-dimethoxy-1,3,5-triazin-2-yl)(methyl)carbamate in 4 ml of dry acetonitrile was added at room temperature 0.2 ml of DBU. The reaction mixture was allowed to stand for four days, then diluted with 4 ml of water, several ice chips and 4 ml of diethyl ether. After stirring this solution for one minute, the ether layer was removed by pipet and the remaining mixture was acidified by dropwise addition of 1N HCl. The resulting precipitate was filtered, washed with water and dried to give 0.32 g of a white solid, m.p. 180°-182° C. (d).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OS(O)(=O)=O>>[CH2:2]1[CH:1]2[CH:6]([C:10]3[C:9]([C:7]2=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(C1=CCCCC1)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C2CCCCC12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cyclohex-1-enylphenyl ketone (9.7 g) was slowly added to a concentrated H2SO4 solution (100 ml) at room temperature and the resulting mixture was placed into a pre-heated oil bath (110° C.) for 20 minutes. The hot mixture was poured into ice-water (400 ml) and extracted with CH2Cl2 (4×40 ml). The organic phase was washed with 5% NaHCO3 solution (2×30 ml) and water (30 ml). After drying over Na2SO4 and evaporation the yield was 9.6 g.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH-].[Na+]>CO>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH:8]([F:10])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CC(F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of methyl1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylate(1.2 g, 4.85 mmol) in MeOH (5 ml) was added 1 N NaOH (5 ml) and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, quant) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (br s, 9H), 2.78–2.83 (br s, 3H), 4.37 (s, 2H), 6.73–6.76 (m, 3H), 7.17 (m, 1H).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: N#Cc1cccnc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1-c1cccs1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
To an oven-dried, N2-purged, 50-mL, round-bottomed flask containing a magnetic stir bar were added cesium fluoride (1.34 g, 8.80 mmol), bis(tri-t-butylphosphine)palladium (66.0 mg, 0.13 mmol), and 2-chloro-3-cyanopyridine (559 mg, 4.00 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. Neat 2-(tri-n-butylstannyl)thiophene (2.38 g, 2.02 mL, 6.38 mmol) was added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 25% ethyl acetate, 75% hexanes=product Rf˜0.4) to give ˜750 mg of the title compound as a beige solid that was used without further purification for the next step. MS (ESI−) m/z 186.7 (M+H)+; 1H NMR (CDCl3) δ 7.19 (dd, J=5.1, 4.0 Hz, 1H), 7.23-7.27 (m, 1H), 7.56 (dd, J=5.1, 1.0 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.27 (d, J=4.1 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH2:7][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc(O)cc2O1
Yield: 96 %

Procedure:
A solution of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (19.0 g, 0.081 mol) in acetic acid is hydrogenated over 10% Pd/C (4.5 g) at 50 psi H2 for 16 hr at ambient temperatures. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to give a residue. The residue is dissolved in EtOAc, washed with saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to give a solid residue. Crystallization of the solid from CCl4 affords the title compound as an off-white solid, 17.2 g (96% yield), mp 78-80° C., identified by NMR and mass spectral analyses.