Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2]>O.NN.C(O)C>[NH2:7][CH2:6][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)OCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CN)CC(CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
3 g (6.4 mmol) of benzyl 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4 -methylvalerate were dissolved in 39 ml (12.8 mmol) of a 0.33M solution of hydrazine hydrate in ethanol. The solution was stirred at room temperature overnight. The solvent was removed by evaporation and traces of hydrazine were removed by treatment with toluene followed by evaporation. The residue was taken up in 50 ml of dichloromethane and stirred at room temperature for 45 minutes in the presence of 5 ml of glacial acetic acid. The solid was removed by filtration and the filtrate was evaporated to give 2.56 g of benzyl 2(RS)-[[(RS) -(aminomethyl)(ethoxy)phosphinyl]methyl]-4-methylvalerate in the form of a gum.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:12][C:13]1C=C[C:16](S(O)(=O)=O)=[CH:17][CH:18]=1.C1C[O:26]CC1>>[I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH:16]2[CH2:17][CH2:18][CH2:13][CH2:12][O:26]2)[N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Product: CCOC(=O)c1cn(C2CCCCO2)nc1I
Yield: 98 %

Procedure:
A solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (27 g, 101.8 mmol), 3,4-DHP (25.71 g 305.6 mmol) and PTSA (1.94 g 10.18 mmol) in THF (100 mL) was heated at 60° C. for 5 h. Solvent was evaporated under vacuum and the residue redissolved in DCM (500 mL) was added. The solution was washed with sat.NaHCO3 (200 mL×2), dried, concentrated to afford crude ethyl 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (35 g, yield: 98%). The crude material was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[SH:8].[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][Cl:28])[CH2:21][CH2:20]2)[CH:16]=[C:15]([CH:29]([F:31])[F:30])[N:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[ClH:28].[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][S:8][C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[N:5][N:4]=3)[CH2:23][CH2:24]2)[CH:16]=[C:15]([CH:29]([F:30])[F:31])[N:14]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1nnc(S)n1C
Reactant: CC(C)(C)c1nc(C(F)F)cc(N2CCN(CCCCl)CC2)n1
Product: Cc1nnc(SCCCN2CCN(c3cc(C(F)F)nc(C(C)(C)C)n3)CC2)n1C
Product: Cl
Yield: 31.5 %

Procedure:
0.5 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3.87 mmol) were reacted with 1.34 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine (3.87 mmol) to yield 0.58 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=[N:36][N:35]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:34]3[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=[N:36][N:35]=3)[CH:11]=2)[CH:28]=1)([CH3:31])[CH3:30]
Reactant: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
5% Pd/C was wetted carefully with methanol under N2, then a solution of 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (100 mg, 0.17 mmol) in methanol (5 ml) was added. The reaction system was vacuumed and filled with hydrogen three times, and the reaction was stirred under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give product 5′-isopropyl-2′-methoxy-5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-2,4-diol (49 mg, 71%). M.p.: 174-176° C.; 400 MHz 1H NMR (CDCl3) δ: 10.58 (s, 1H), 7.60 (s, 1H), 7.28 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 4.73 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 3.38 (t, J=5.6 Hz, 2H), 3.10 (s, 3H), 2.99-2.87 (m, 1H), 2.28 (pent, J=6.4 Hz, 2H), 1.27 (d, J=7.2 Hz, 6H); LCMS: 399 [M+H].
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]([CH2:19][CH3:20])([CH2:14][C:15](=O)[CH2:16]Br)[C:11]([NH2:13])=[O:12])[CH3:9].[CH:21]([NH2:23])=[S:22]>>[C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]([CH2:19][CH3:20])([CH2:14][C:15]1[N:23]=[CH:21][S:22][CH:16]=1)[C:11]([NH2:13])=[O:12])[CH3:9]
Reactant: CCC(CC)(CC(=O)CBr)C(N)=O
Reactant: NC=S
Agent: O=C(O)CC(=O)O
Product: CCC(CC)(Cc1cscn1)C(N)=O

Procedure:
a reaction of diethyl (3-bromo-2-oxo-propyl)acetamide malonate with thioformamide to give diethyl (4-thiazolylmethyl)acetamide malonate and
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OC1CCCC1
Temperature: 69 °C
Yield: 100.3 %

Procedure:
To a mixture of 6-chloro-2-cyclopentyloxy-nicotinonitrile (1.32 g, 5.92 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.43 g, 7.10 mmol) in DMF (10 mL) was added potassium carbonate (1.22 g, 8.88 mmol). The resulting mixture was heated at 69° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give white solid, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (2.30 g, quantitative) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.70 (s, 1H), 7.60-7.46 (m, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.95 (br. s., 1H), 1.87-1.50 (m, 6H), 1.52-1.30 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH2:8]/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:10](=[C:9](/[NH2:8])\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: C#CC(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)/C=C/C(C(=O)OCC)=C(\C)N
Temperature: 90 °C

Procedure:
Ethyl propiolate (39.2 g, 41 mL, 400 mmol) was added to ethyl 3-aminocrotonate (51.75 g, 400 mmol) and the mixture heated at 90° C. for 90 minutes to give a dark red oil. The mixture was allowed to cool, to give the product as a dark orange solid, 87.0 g (96%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)ccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of the compound of Example 49B (2.25 g, 6.14 mmol) in dry THF (25 mL) was treated with sodium hydride (295 mg of 60% in oil, 177 mg, 7.37 mmol) followed by stirring at room temperature for 1 h. The solution was then treated with SEM-Chloride (1.20 mL, 1.13 g, 6.76 mmol) followed by stirring at room temperature for 18 h. The mixture was quenched by addition of water and the mixture was diluted with ethyl acetate. The mixture was extracted with water and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 20-75% ethyl acetate in hexanes. These procedures afforded the product (2.24 g, 73%) as a heavy oil, which solidified after setting for several days. This mixture of both regioisomeric SEM derivatives was not separated for use in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:21][CH:20]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:34])([CH3:33])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)=O.O>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:33])([CH3:34])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC(C)(C)C)cc3)c(C)cc21
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)c(C)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A solution of 6-(4-tert-butoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 194, 0.23 g, 0.5 mmol) in 1,4-dioxane (1 mL) was treated with formic acid (3 mL) and the resulting reaction mixture was stirred at ambient temperature for 6 h. Water was added and the reaction mixture was extracted with ethyl acetate(×2). The combined organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title compound (0.15 g, 74%).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14].CS(O)(=O)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][CH:16]([O:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12])[CH3:17])[CH3:14]
Reactant: C=COCC
Reactant: O=C1N[C@H](c2ccccc2)[C@@H]1O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0° C. was added 5 mL of ethyl vinyl ether and 20 mg (0.2 mmol) of methane-sulfonic acid. The mixture was stirred at 0° C. for 20 min, diluted with 20 mL of saturate aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrate to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([CH2:14][CH2:15][NH3+:16])[CH2:9][CH2:10][C:11]([O-:13])=[O:12]>C(O)(=O)C>[C:1]1(=[O:6])[N:16]([CH2:15][CH2:14][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: [NH3+]CCCCCC(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O

Procedure:
The symmetrical anhydride of 6-Maleimidocaproic acid (Compound 24, FIG. 5) was prepared by the reaction of maleic anhydride and e-Amino-n-caproic acid in the presence of acetic acid to give 6-Maleimidocaproic acid (Compound 23) which was then converted to Compound 24 using dicyclohexyl carbodiimide (DCCl).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.CCN(CC)CC.O.[NH2:20][NH2:21]>C1COCC1.O>[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]2[NH:20][N:21]=[CH:9][C:5]=12
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(Cl)c2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Amino-4,6-dichloro-pyrimidine-5-carbaldehyde (5 g, 26.04 mmol) is dissolved in THF (125 ml), Et3N (4.13 ml, 29.6 mmol) is added followed by hydrazine monohydrate (1.19 g, 26.04 mmol) in water (15 ml) and the reaction mixture is stirred at room temperature for 1.5 hours. The organic solvent is removed in vacuo and a further 30 ml of water is added to the reaction mixture. The resulting precipitate is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][OH:45]>C(#N)C.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([CH2:43][CH2:44][OH:45])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a solution of Compound (2) (13 mg, 26 μmol) in ACN (1 mL) was added potassium carbonate (7.3 mg, 52 μmol) followed by 2-bromoethanol (5.6 μL, 79 μmol). The mixture was then stirred at 80° C. for 16 h (monitored by LCMS). The mixture was cooled to RT, diluted with EtOAc (3 mL), washed with water (1 mL) and brine (2 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude mixture was purified by preparative HPLC to give Compound (3) (4.86 mg, 34%) as a white powder. ESI-MS m/z calculated for [M+H]+: 539.18; found: 539.12; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.52 (brd, J=9.0 Hz, 2H), 7.47 (s, 1H), 7.12-7.02 (m, 6H), 5.79 (brd, J=4.3 Hz, 1H), 4.21-4.00 (m, 1H), 3.85-3.62 (m, 3H), 3.18 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.51-2.27 (m, 1H), 1.06 (ddd, J=11.3, 6.9, 3.1 Hz, 3H), 0.62-0.44 (m, 1H).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nccs1
Yield: 85247 %

Procedure:
To a mixture of 2-trimethylsilylthiazole (135 g, 858 1 mmol) in toluene (1350 mL) add a solution of ethyl chloroformate (98.4 mL, 1.03 mol) in toluene (1350 mL) over 15 min. Stir the reaction at 22° C. for 2 h. Add the solution over aqueous sodium carbonate 25% (wt/wt) (5 L) and stir for 30 min. Separate the organic layer and re-extract the aqueous layer with methylene chloride (2×1 L). Combine the organic layers and evaporate the solvent to provide the title compound (134 g, 99%). ES/MS m/z 158 (M+1)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(C=O)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)cs1
Yield: 44 %

Procedure:
Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol), 4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g, 4.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol %) heated at reflux overnight (18 hrs) in dioxane (50 ml). The cooled solution was filtered through a plug of Celite®, concentrated and triturated with iso-hexane (3×20 ml). The resultant solid was purified via flash column chromatography on silica gel, eluting with 5% methanol in chloroform. The purified product was isolated as a yellow solid (0.85 g, 44%). δH [2H6] DMSO 10.10(1H, s), 9.30(1,bs), 8.90(1H, s), 8.50(2H, s&d), 8.45(1H, d), 8.20(1H, d), 7.40(5H, bm), 7.10(4H, 2d), 6.80(1H, d).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C@H:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[OH-].[Li+].Cl>O.CO.C1COCC1>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH:20][C@H:4]([C@H:5]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:6]3[S:7][CH:8]=[CH:9][N:10]=3)[C:3]([OH:38])=[O:2])(=[O:23])=[O:22])=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](OCc3ccc(C)cc3)c3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-propionic acid. The (2R,3S)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid methyl ester 1f (550 mg, 1.00 mmol) is dissolved in water/methanol/THF (5 mL/5mL/5mL) and then lithium hydroxide (1 g, excess) is added. The resulting mixture is stirred overnight at room temperature. The reaction is acidified with 1N HCl and then the product precipitates out of solution to form a white powder. The product is filtered and the desired product is obtained as a white powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[CH:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:50]([Cl:52])[Cl:51]>C(O)(=O)C>[NH3:1].[CH2:50]([Cl:52])[Cl:51].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[N:27]=[CH:26]4)[CH2:23][CH2:24]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N
Product: c1ccc2c(c1)ncn2C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (82 mg), 1-Piperidin-4-yl-1H-benzoimidazole (62 mg), and acetic acid (0.03 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (110 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (81 mg). 1H NMR (400 MHz, CDCl3): 7.98 (s, 1H), 7.80 (m, 1H), 7.42 (m, 1H), 7.30–7.20 (m, 4H), 6.87 (d, J=8.6 Hz, 2H), 4.18 (m, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 3.10–3.03 (m, 2H), 2.48 (m, 2H), 2.41 (br, 4H), 2.21–2.10 (m, 5H), 2.01–1.94 (m, 2H), 1.62–1.55 (m, 4H), 1.47–1.39 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:30])[CH2:29][C:23]2=[C:24]([CH3:28])[S:25][C:26]([CH3:27])=[C:22]2[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:30][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][C:22]2=[C:26]([CH3:27])[S:25][C:24]([CH3:28])=[C:23]2[CH2:29]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (443 mg, 1.85 mmol), HATU (878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (88) as a pale yellow solid (599 mg, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 2-amino-4-(3,4-dichlorophenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 6 & 7, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 74% yield.