Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C@H:10]([C:21]([OH:23])=[O:22])[CH2:11][NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[C:5]([Cl:26])[CH:4]=1.[OH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1.O.[OH-].[Li+].Cl>O1CCCC1.CN(C=O)C.O.CO>[Cl:26][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:31]([C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([OH:27])[CH:29]=2)=[O:32])[CH:25]=[CH:24][C:6]=1[C:7]([NH:9][C@H:10]([C:21]([OH:23])=[O:22])[CH2:11][NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8]
Reactant: NCc1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
A mixture of N-[4-(aminomethyl)-2-chlorobenzoyl]-3-benzoylamino-L-alanine (Example 363; 100 mg, 0.26 mmol), 3-hydroxybenzoic acid (40 mg, 0.29 mmol) and dicyclohexylcarbodiimide (60 mg, 0.29 mmol) in tetrahydrofuran/DMF (4:1; 2.5 mL) was stirred at room temperature overnight. Methanol (1 mL) and a solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (1 mL) were added and the solution was stirred at room temperature overnight. The solution was made acidic with 1 M HCl and extracted with ethyl acetate. The ethyl acetate was evaporated and the residue purified by HPLC to give N-[2-chloro-4-[[(3-hydroxyphenyl)carbonyl]aminomethyl]benzoyl]-3-benzoylamino-L-alanine (12.2 mg, 9%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CN2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.2 g (41 mmol) of 4-nitrobenzaldehyde and 3.8 g (40.6 mmol) of azetidine-hydrochloride are dissolved in 120 ml of ethanol. 2.6 g (41 mmol) of sodium cyanoborohydride are added at 0° C. The mixture is slowly heated to ambient temperature and then stirred for 18 hours. Then the solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and washed with water. The solvent is eliminated in vacuo and after chromatography of the residue on silica gel (ethyl acetate/methanol/NH4OH=95:5:0.5) a light brown oil is obtained.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.S(Cl)([Cl:15])=O>>[S:1]1[C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
1.0 g of benzo[b]thiophene-2-carboxylic acid was reacted with 2 ml of thionyl chloride under reflux overnight, and then excess thionyl chloride was distilled off under reduced pressure to obtain benzo[b]thiophene-2-carbonyl chloride as a solid product.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:39]=[CH:38][C:12]2[N:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[O:31][N:30]=5)=[O:27])=[CH:21][CH:20]=4)[N:16]=[C:14]3[S:15][C:11]=2[CH:10]=1.O.[OH-].[Li+].Cl>C1COCC1>[C:34]([C:32]1[O:31][N:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]3[N:16]=[C:14]4[N:13]([CH:18]=3)[C:12]3[CH:38]=[CH:39][C:9]([O:8][CH2:7][CH2:6][NH:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:10][C:11]=3[S:15]4)=[CH:24][CH:23]=2)[CH:33]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)CNCCOc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCNCC(=O)O)ccc34)cc2)no1

Procedure:
A mixture of [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester (1 equivalent) and lithium hydroxide monohydrate (3-6 equivalents) in 50% aq THF is stirred at selected temperatures between rt and 60° C. until the reaction is substantially complete as monitored by LCMS or TLC. The reaction mixture is neutralized with aq hydrochloric acid and partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid (I-3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S:10]C.[Na]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CSC
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,6-dibromopyridine. (1.0 eq.) in DMSO (0.3M) was added sodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rt then poured in water. The resulting precipitate was filtered off and the filtrate was extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a colorless oil.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC([O-])(C)C.[K+].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[CH:2][O:19][C:15]=1[CH:16]([CH3:18])[CH3:17])=[O:5])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1C(C)C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanoacetate (4.52 g) was added drop-wise to a stirred suspension of KOtBu in THF (35 ml) at 0° C. under nitrogen. After complete addition, the dark brown solution was stirred for 30 minutes and then a solution of isobutyryl chloride (2.1 ml) in THF (15 ml) added drop-wise, keeping the temperature below ˜10° C. The reaction was stirred for 1 hour then evaporated to dryness. The residue was treated with acetic acid (1.14 ml) and water (25 ml), and then extracted with ether (3×30 ml). The combined ether extracts were washed with saturated brine, dried over sodium sulfate, filtered and evaporated to give a brown oil that was purified by column chromatography, eluting with 1% MeOH in dichloromethane. This gave the title compound (1.91 g) as a colourless oil.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+:48].C(O)(=O)C>CCOC(C)=O.O>[Na+:48].[C:33]1([S:30]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([O-:39])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ccccn3)cc2)S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C([O-])COc1cccc(CN(Cc2ccc(-c3ccccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared following the method described in Example 3, Step C from (3-{[benzenesulfonyl-(4-pyridin-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester of Step B. The TFA salt was diluted with EtOAc and water and the aqueous solution was basified to about pH 11 with NaOH (1N). The aqueous solution was acidified with glacial acetic acid to about pH 5 and was washed with EtOAc (3×). The organic solution was dried (MgSO4), filtered, and concentrated, azeotroping with toluene, to provide the free acid (128 mg). The acid was dissolved in a mixture of acetone (4 mL), MeOH (4 mL) and water (0.5 mL), and NaHCO3 (22 mg, 0.258 mmol) was added. The reaction was stirred for 24 h and was concentrated in vacuo, azeotroping with EtOH (3×) and CHCl3 (1×) to provide the title sodium salt (137 mg). 1H NMR (400 MHz, CD3OD) δ 8.56 (dd, 1H), 7.89-7.76 (m, 6H), 7.65-7.56 (m, 3H), 7.33 (m, 1H), 7.21 (d, 2H), 7.05 (t, 1H), 6.74 (d, 1H), 6.63 (m, 2H), 4.40 (s, 2H), 4.31 (s, 2H), 4.21 (s, 2H); MS 487 (M−1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:19]=[C:20]([S:24]([CH2:27][CH2:28][S:29][C:30]2[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O1CCOCC1.CCCCCC>[CH:7]1([CH2:12][C:13]([NH:36][C:35]2[C:30]([S:29][CH2:28][CH2:27][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:37])([F:38])[F:16])[CH:19]=3)(=[O:26])=[O:25])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CC1CCCC1)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
254 μl (3.0 mmol) oxalylchloride were added to a solution of 192 mg (1.5 mmol) 2-cyclopentyl acetic acid in DCM (10 ml) and the mixture was stirred for 3 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with dioxane (6 ml). This solution was added at 0° C. to a solution of 362 mg (1.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in dioxane (5 ml). Then the reaction solution was mixed with 420 mg (5.0 mmol) NaHCO3 and stirred for 16 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water. Then it was extracted with EE and the organic phase was washed with a saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 3:1) of the residue yielded 231 mg (0.5 mmol, 54%) 2-cyclopentyl-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 473.1 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7]([O:11][C:12]([NH:14][CH:15](P(OC)(OC)=O)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12]([NH:14]/[C:15](=[CH:1]\[C:2]([CH3:5])([CH3:4])[CH3:3])/[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CC(C)(C)C=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Pivalaldehyde (303.2 g, 3.41 mol, 10 equivalents) and methyl {[tert-butoxycarbonyl]amino}-(dimethoxyphosphoryl)acetate (101.5 g, 0.341 mol, 1.0 equivalent) are dissolved in tetrahydrofuran (800 ml) and cooled to −70° C. At −70° C., N,N,N,N-tetramethylguanidine (78.7 g, 0.683 mmol, 6.95 ml, 2.0 equivalents) is slowly added dropwise and the mixture is then stirred at −70° C. for 4 h, subsequently, the mixture is stirred at RT for 4 days. The reaction mixture is concentrated, then extracted with ethyl acetate (2×500 ml) against water, and the combined organic phases are washed with a saturated sodium chloride solution (100 ml) and dried over sodium sulfate. After concentration, the crude product is chromatographed (1.5 kg of silica gel, eluent: cyclohexane/ethyl acetate 5:1). 67 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(O)c(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3.0 g (16.6 mmol) of methyl 5-ethyl-2-hydroxybenzoate in 100 mL of CH2Cl2 at 0° C. was added 5.8 mL (41.5 mmol, 2.5 eq.) of Et3N. To this stirred solution was added dropwise 3.6 mL (21.6 mmol, 1.3 eq.) of Tf2O. Following complete addition 0.2 g (cat.) of 4-dimethylamino pyridine was added and the reaction mixture was allowed to warm to room temperature. After 4 h stirring at this temperature the reaction was judged complete, and quenched by the addition of a saturated aqueous solution of NaHCO3 (100 mL). The resulting layers were separated and the aqueous layer extracted twice with CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the desired methyl 5-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate. 1H NMR (400 MHz, CDCl3): δ=7.94 (d, J=2.3 Hz, 1H), 7.47 (dd, J=2.3, 8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.00 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>>[O:13]1[CH:14]=[C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[N:11]=[CH:12]1
Reactant: COC(=O)c1csc(-c2cocn2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc(-c2cocn2)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.2 %

Procedure:
5-Oxazol-4-yl-thiophene-3-carboxylic acid methyl ester (0.049 g, 0.23 mmol) was suspended in IMS (1 mL), sodium hydroxide (1 M, 0.35 mL) was added and the mixture stirred for 60 hours at room temperature. The mixture was quenched with HCl (1 N, 0.35 mL) and then concentrated, azeotroping twice with methanol to afford 5-oxazol-4-yl-thiophene-3-carboxylic acid as a white solid (0.045 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[CH3:15])[N:3]=1.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1N.[H-].[Na+]>O1CCCC1.[NH4+].[Cl-]>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[CH3:15])[N:3]=1
Reactant: Nc1c(F)cccc1F
Reactant: Cc1cc(F)ccc1-c1cccc(Br)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1cccc(-c2c(F)cccc2F)n1
Yield: 42.3 %

Procedure:
In a 50 ml round-bottomed flask, 550 mg (2.07 mmol) of 2-bromo-6-(4-fluoro-2-methylphenyl)pyridine produced in step B was dissolved in 30 ml of anhydrous tetrahydrofuran forming a clear, colorless solution. 2,6-difluoroaniline (2.14 ml, 2.14 mmol) was added followed by 112 mg (2.79 mmol) of a 60% NaH suspension in mineral oil. Gas evolution was observed along with a mild exotherm. The solution was heated to reflux overnight and then cooled. The reaction mixture was poured in 10% NH4Cl and extracted with CH2Cl2. The organic extract was dried (MgSO4) and evaporated in vacuo to afford a brown oil that was a mixture of the product and starting material. The material was chromatographed on a short column of silica gel using 50% CH2Cl2/hexane to afford 262 mg (40%) of 2-(2,6-difluorophenyl)-6-(4-fluoro-2-methylphenyl)pyridine as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][C:14]=3[O:27][C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1(B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([CH:35]1[CH2:37][CH2:36]1)=[CH:15][C:14]=3[O:27][C:28]([F:29])([F:30])[F:31])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)cc3C2C1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cc(C4CC4)cc3C2C1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-trifluormethylsulfonyloxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (100 mg, 0.19 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101 mg, 0.6 mmol), and potassium carbonate (138 mg, 1.0 mmol) in DME (2 mL) under Ar was added bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (5 mg, 0.006 mmol) and water (0.2 mL). The reaction was heated to reflux for 3 h and then cooled to room temperature. The reaction was quenched with 1M NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield 70 mg of the desired product as a white solid. MS (ESI) 413 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[C:14]([CH2:19][C:20](OCC)=[O:21])(=O)[CH2:15][CH2:16][CH3:17].Cl>O>[OH:21][C:20]1[CH:19]=[C:14]([CH2:15][CH2:16][CH3:17])[N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reaction time: 8 h
Yield: 11 %

Procedure:
A mixture of 15.0 g (0.09 mole) trichloroacetamidine, 12.6 g (0.09 mole) potassium carbonate, 14.6 g (0.09 mole) ethyl butyrylacetate and 300 ml water was stirred overnight. The aqueous solution was decanted from the oil that formed and acidified with hydrochloric acid. The precipitate that formed was filtered, washed, and dried to give 2.6 g (11% yield). An analytical sample that was recrystallized from ligroin had mp 107°-110° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]3[C:13]4([CH2:20][S:21][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.Cl.O>[CH3:19][N:16]1[CH2:15][CH2:14][C:13]2([C:10]3[C:9](=[CH:8][C:7]4[CH2:6][CH2:5][NH:4][C:12]=4[CH:11]=3)[S:21][CH2:20]2)[CH2:18][CH2:17]1
Reactant: CC(=O)N1CCc2cc3c(cc21)C1(CCN(C)CC1)CS3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1CCC2(CC1)CSc1cc3c(cc12)NCC3
Reaction time: 3 h

Procedure:
5-Acetyl-1'-methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] (D52) (0.047 g, 0.156 mmol) was dissolved in a mixture of ethanol (2 ml) and 5M HCl (4 ml) and was heated to reflux with stirring under argon. After 3 h, the reaction mixture was allowed to cool, was diluted with water (10 ml) and was basified using solid potassium carbonate. The resulting suspension (pH 9 ) was then extracted with dichloromethane (3×10 ml) and the combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound as an off white solid, which was dried in vacuo (0.029 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[NH:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=1.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>C(Cl)Cl.C1COCC1>[CH2:41]([O:40][C:38]([C:36]1[NH:37][C:33]([NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)=[O:39])[CH3:42]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1ccc(N)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.428 mmol), ethyl 5-amino-1H-pyrrole-2-carboxylate (180 mg, 1.17 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 200 mg, 0.526 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (4 mL) and THF (4 mL) was stirred at 25° C. for 16 hours. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (20%-95% of acetonitrile/water) to afford chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-1H-pyrrole-2-carboxylic acid ethyl ester (42 mg, 16.3%) as an off-white powder. HRMS (ES) m/z Calcd for C30H30Cl2F2N4O3+H [(M+H)+]: 603 736. found: 603.1736.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:25]>>[Br:25][C:14]1[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:10]=2)[N:15]=1
Reactant: O=C(c1ccccc1)c1ccc2[nH]c(=O)c(C(F)(F)F)nc2c1
Reactant: BrP(Br)Br
Product: O=C(c1ccccc1)c1ccc2nc(Br)c(C(F)(F)F)nc2c1
Temperature: 0 °C

Procedure:
A mixture of 6-benzoyl-3-trifluoromethylquinoxalin-2(1H)-one (1.0 g, 3.13 mmol) [J. Org. Chem. 57(21). 5630,1992] and 10 ml of phosphorous tribromide was refluxed for 5 hours. The mixture was cooled and poured into ice water and the precipitate was isolated, washed with water and dried. Yield 0.87 g (73%) of the title compound as beige crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:2]([OH:1])[CH:3]=3)=[CH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reaction time: 8 h

Procedure:
To 3.0 g (2.5 mmol) of above resin-bound [4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid were added 1.30 g (7.5 mmol) of 2-amino-5-bromopyridine, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide