Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[O:35]1[C:39]2([CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[O:35]1[C:39]2([CH2:44][CH2:43][CH:42]([O:34][C:31]3[CH:32]=[CH:33][C:28]([N:4]4[C:5](=[O:27])[C:6]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]6[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=6)=[CH:15][CH:14]=5)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]4[CH2:1][CH3:2])=[CH:29][CH:30]=3)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g), 1,4-dioxaspiro[4.5]decan-8-ol (2.82 g), diisopropyl azodicarboxylate (1.9 M in toluene, 3.2 mL), triphenylphosphine (4.67 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow amorphous solid (5.13 g, 98%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH2:10][CH3:11].[CH2:18]([O:25][C:26]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53]Br)=[CH:47][C:27]=1[C:28]([NH:30][C:31]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:25][C:26]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:15]2[CH2:16][CH2:17][N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]2)=[CH:47][C:27]=1[C:28]([NH:30][C:31]1[CH:40]=[C:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CCCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Potassium carbonate (0.14 g) and 1-propylpiperazine dihydrochloride (0.12 g) were added to an acetone (1.6 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.080 g), followed by heating to reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.081 g of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow oily substance.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[C:28](OC)(=O)[CH2:29]CC.C(C1C(NC2C=C(NC(=O)OC(C)(C)C)C=CC=2)=NC(SC)=NC=1)=O>>[CH2:28]([C:11]1[C:10](=[O:13])[N:9]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=2)[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1)[CH3:29]
Reactant: CCCC(=O)OC
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Agent: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Product: CCc1cc2cnc(SC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O

Procedure:
This compound (720 mg, 1.75 mmol, 31% yield) obtained as an off-white solid was prepared according to procedure described for Intermediate 51, using methyl butanoate (1.89 mL, 16.65 mmol) and tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (2.00 g, 5.55 mmol) as the starting materials. m/z (ESI, +ve ion) 413.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, s), 7.47-7.55 (2H, m), 7.39-7.46 (1H, m), 7.29 (1H, d, J=1.4 Hz), 6.92 (1H, dd, J=7.8, 1.0 Hz), 6.57 (1H, br. s.), 2.66 (2H, q, J=7.4 Hz), 2.19 (3H, s), 1.50 (9H, s), 1.23-1.31 (3H, m).
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:22]=[C:15]3[C:16]([O:18]C(=O)[NH:20][C:14]3=[CH:13][CH:12]=2)=[O:17])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23]C1C=CC(S(Cl)(=O)=O)=CC=1C(O)=O>>[Cl:23][C:14]1[CH:13]=[CH:12][C:11]([S:8](=[O:10])(=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:22][C:15]=1[C:16]([OH:18])=[O:17].[CH:1]1([NH:7][S:8]([C:11]2[CH:22]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([NH2:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CCCCC3)cc2c(=O)o1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Product: Nc1ccc(S(=O)(=O)NC2CCCCC2)cc1C(=O)O
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)ccc1Cl

Procedure:
5-(N-Cyclohexylsulfamoyl)-isatoic anhydride, which is to be used as the starting material, can be obtained, for example, in a manner analogous to that described in Example 1, using 2-chloro-5-chlorosulfonylbenzoic acid as the starting material, the product being obtained via 2-chloro-5-(N-cyclohexylsulfamoyl)-benzoic acid with a melting point of 168°-175° and 5-(N-cyclohexylsulfamoyl)-anthranilic acid with a melting point of 204°-206°. It melts at 232°-233°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (95.97 g, 233.8 mmol) in methylene chloride (800 mL), was added trifluoroacetic acid (33.87 mL, 455.9 mmol), and the mixture was stirred at room temperature overnight. Sat. sodium bicarbonate (500 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate, and evaporated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (64.36 g, 88% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9](Cl)=[N:8]2)=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:8]2)=[O:4]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(OC)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nc(NC(C)C)c1nnc(OC)n12
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A mixture of 4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester (80 mg), isopropylamine (24 mg) and sodium bicarbonate (45 mg) in DMF (2 mL) was stirred at 23° C. for 17 hrs. The mixture was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. Trituration with EtOAc/hexanes afforded 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester as a light yellow solid. MS (M+H)+=316.3.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.CCOCC>C(O)C>[C:2]1([CH2:1][CH2:8][CH:9]([OH:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(O)CCc1ccccc1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
Benzylacetone (7.5 mL, 50 mmol) was dissolved in ethanol (50 mL) and cooled to 0° C. Sodium borohydride (1.89 g, 50 mmol, 1 equiv.) was added. The mixture was stirred and allowed to warm to room temperature overnight. All of the starting material was gone by tlc analysis, so the mixture was poured into water (50 mL) and ether (50 mL). The layers were separated and the aqueous layer was extracted with ether (2×25 mL). The organic layers were combined and concentrated. The resulting aqueous residue was poured into ether (50 mL). The organic layer was removed, dried (MgSO4), and concentrated to provide 1c (6.86 g; 91%). 1H nmr (300 MHz, CDCl3): 7.38-7.15 (5H, m); 3.85 (1H, m(6), J=6.17 Hz); 2.82-2.61 (2H, m); 1.79 (2H, q, J=7.12 Hz); 1.421 (1H, s); 1.236 (3H, d, J=6.09 Hz). IR (neat film, cm-1): 3250 (b); 2900 (b). EIMS (m/e): 150 (M+).
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:17][OH:18]>>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([O:18][CH3:17])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Product: C=CC(=O)N1Cc2ccccc2SC(OC)C1

Procedure:
The above-mentioned 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.20 g), methanol (0.1 ml) and stannic chloride (0.31 g) were reacted in the same manner as in Experimental Example 13 to give 4-acryloyl-2-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.19 g). This compound (0.18 g) and 4-benzyl piperidine (0.19 g) were reacted in the same manner as in Experimental Example 5 to give 4-[3-[1-(4-benzyl)piperidinyl]propionyl]-2-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.25 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (156 mg, 0.5 mmol) according to the general procedure M. Obtained as a light yellow foam (213 mg, 79%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.O.S(=O)(=O)(O)[OH:27]>CCOCC.C(OCC)(=O)C>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:10](=[O:27])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: C(CCCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-phenylbutylidene)-1-benzylpiperidine (from the Step C) (4.37 g) in anhydrous ether (150 mL) under nitrogen with stirring was add 1M borane solution in TEF (45 mL). The reaction was stirred for 3 h when water (2 mL) was added dropwise. The mixture was stirred a further 30 min and was then cooled in an ice bath. A solution of chromic anhydride (2.5 g), concentrated sulfuric acid (5.44 mL) and water (125 mL) was added dropwise with vigorous magnetic stirring over 5 min. After another 5 min, the ice bath was removed. After 1.5 h at rt, 0.5N sodium hydroxide and ether (400 mL each) were added and the mixture was stirred until the residue dissolved. The layers were separated and the aqueous layer was extracted twice with ether. The combined ether layers were washed with an aqueous EDTA solution, water and brine (100 mL each), dried over sodium sulfate and concentrated under reduced pressure to give a colorless gel. Flash chromatography on silica gel with 30-50% ethyl acetate in hexanes with 3% (v/v) TEA gave the title compound (1 g) as a colorless gel. Rf: 0.43 (30% ethyl acetate in hexanes with 3% (v/v) TEA). 1H NMR (500 MHz, CDCl3): δ7.25-7.33 (m, 7 H), 7.16-7.22 (m, 3 H), 3.51 (s, 2 H), 2.89-2.93 (m, 2 H), 2.63 (t, J=7.6 Hz, 2 H), 2.46 (t, J=7.2 Hz, 2 H), 2.38 (tt, J=11.5 and 3.9 Hz, 1 H), 1.99-2.03 (m, 2 H), 1.92 (tt, J=7.2 and 7.6 Hz, 2 H), 1.76-1.81 (m, 2 H), 1.65-1.72 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5[C:24](=[O:36])[N:25]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]([CH3:29])[C:27]=5[CH3:28])=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:51]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 72.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.413 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (154 mg, 0.619 mmol) and Cs2CO3 (268 mg, 0.826 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford a pale yellow solid (192 mg, 73%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:3]1.[C:23]1([C:29]2[NH:30][C:31]3[C:36]([C:37](=O)[CH:38]=2)=[CH:35][C:34]([CH:40]=[CH2:41])=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:23]1([C:29]2[CH:38]=[C:37]([O:1][C@H:2]3[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:3]3)[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH:40]=[CH2:41])[CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCC[Si](C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
To a solution of 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate 3 (1.0 g, 3.02 mmol) in THF (30 mL) was added 2-phenyl-6-vinylquinolin-4(1H)-one 2 (0.78 g, 3.17 mmol) and PPh3 (1.19 g, 4.52 mmol). The flask was then cooled to 0° C. and diethylazodicarboxylate (0.713 mL, 4.52 mmol) was added slowly. The mixture was then warmed to RT and stirred overnight (16 h). At this time, the starting material to product ratio was 2:1. The reaction was re-cooled to 0° C., and additional PPh3 (1.19 g, 4.52 mmol) and diethylazodicarboxylate (0.713 mL, 4.52 mmol) were added. After stirring for an additional 19 h, only a small amount of starting material remained. Silica gel was then added to the reaction and the mixture was filtered through silica gel with EtOAc as the eluent. The crude mixture was then purified on silica (5-40% EtOAc/hexanes) to yield 0.85 g (50% yield) of 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.43 (m, 1H), 8.13-8.09 (m, 2H), 7.92 and 7.91 (2 br s, 2H), 7.56 (m, 3H), 7.12 and 7.11 (2 br s, 1H), 6.92 (br dd, J=17.5 Hz, 10.5 Hz, 1H), 6.02 (d, J=17.5 Hz, 1H), 5.58 (d, J=10.5 Hz, 1H), 5.53 and 5.49 (2 br s, 1H), 4.64 and 4.54 (2 app t, J=7.5 Hz, 1H), 4.27 (app t, J=7 Hz, 2H), 4.07 (m, 1.5H), 3.89 (br d, J=13 Hz, 0.5H), 2.81 (m, 1H), 2.55 (m, 1H), 1.47 and 1.45 (2 s, 9H), 1.04 (m, 2H), 0.07 and 0.06 (2 s, 9H). LRMS (CI, [M+H]) Calc'd=561.4. found=561.4. HRMS (APCI, [M+H]+) Calc'd for C32H41N2O5Si: 561.2779. found: 561.2749.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:66]([CH2:68][NH2:69])[OH:67]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([NH:69][CH2:68][CH2:66][OH:67])=[O:30])[C:20]([C:31]([CH3:32])([CH3:34])[CH3:33])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCCO
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)NCCO
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-yl)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were successively added Et3N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring for 10 min at 60° C., ethanolamine (1.3 μL, 0.022 mmol) was added, and the mixture was stirred for another 4 h at 60° C. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(4-(2-hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) m/e (M+H+) 506.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[C:16](=O)([O:18]CC)[NH2:17]>[Cl-].[Zn+2].[Cl-]>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:16](=[O:18])[N:17]=1
Reactant: CCOC(N)=O
Reactant: Nc1sccc1C(=O)c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=c1nc(-c2ccccc2Cl)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 10.0 g of 2-amino-3-(o-chlorobenzoyl)thiophene, 14.26 g of ethyl carbamate and 0.86 g of zinc chloride is heated at 200°C for 30 minutes. After cooling, the reaction mixture is well washed with chloroform, then with water, and filtered to give crude crystals of 4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[CH3:12][C:13]([O:15][C:16]1[C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:13]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:23])(=[O:14])[CH3:12]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1ccc(OC)c(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(OC)c(NC(=O)c2ccccc2OC(C)=O)c1
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
2,5-Dimethoxyaniline (10.0 g, 65.3 mmol) was dissolved in pyridine (100 ml), and a solution of O-acetylsalicyloyl chloride (13.0 g, 65.3 mmol) in ethyl acetate (50 ml) was added thereto over 15 minutes under ice cooling. Thereafter, the mixture was stirred for 15 minutes at the same temperature as above. After adding water (10 ml) to the reaction mixture to stop the reaction, ethyl acetate (500 ml) was added and the reaction mixture was washed with 3 N hydrochloric acid (500 ml), water (500 ml), 2% sodium hydrogen carbonate solution (500 ml), and water (500 ml) in order. After drying it over Glauber's salt, the ethyl acetate layer was concentrated under reduced pressure and dried under vacuum to obtain the titled compound (19.8 g) as pale yellow syrup. The compound was used in the subsequent step without purification. The titled compound purified by preparative thin layer chromatography had the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:34]([CH:30]5[O:31][CH2:32][CH2:33][NH:28][CH2:29]5)=[O:35])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CNCCO1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=C(C1CNCCO1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 8 %

Procedure:
According to the procedure for compound 398 using morpholine 2-carboxylic acid (25 mg, 0.11 mmol) afforded 3.6 mg (8% yield) of 483 as a solid.
Reaction SMILES: Br[C:2]1C=CC(C(NC(CC2C=CC([Cl:20])=CC=2Cl)C(O)=O)=O)=C(NS(C2C(F)=CC=CC=2F)(=O)=O)C=1.[NH2:36][C@@H:37]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=1[Cl:49])[C:38]([OH:40])=[O:39]>>[ClH:20].[CH3:2][O:39][C:38](=[O:40])[C@@H:37]([NH2:36])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=1[Cl:49]
Reactant: O=C(NC(Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: N[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Product: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Product: Cl

Procedure:
2-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionic acid. (S)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford title compound. HPLC: RT=10.26 min. MS (ESI−): mass calcd. for C22H15BrCl2F2N2O5S, 608.2; m/z found, 607 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 7.87 (d, J=1.8, 1H), 7.52-7.44 (m, 1H), 7.39 (d, J=1.6, 1H), 7.27-7.25 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 1H), 6.97 (t, J=8.7, 2H), 6.79 (d, J=7.7, 1H), 5.05-5.00 (m, 1H), 3.50 (dd, J=14.2, 5.5, 1H), 3.29 (dd, J=14.2, 8.1, 1H).