Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=C[CH:20]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1
Reactant: O=C1Nc2ccc(C3(C(=O)O)CC3)cc2C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 983.2 %

Procedure:
6.5 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)cyclopropanecarboxylic acid are dissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h and subsequently evaporated in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate and stirred at 60° C. for a further 12 h. The mixture is neutralised using sodium hydrogencarbonate, and the organic phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo, giving 6.7 g (92%) of ethyl 1-(2,3-dioxoindolin-5-yl)cyclopropanecarboxylate; LC-MS retention time: 1.30 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:6][C:5]([S:19](Cl)(=O)=O)=[C:4]([O:23][CH3:24])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:6][C:5]([SH:19])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a suspension of 4-chloro-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-methoxy-benzenesulfonyl chloride (0.83 g) in tetrahydrofuran (10 mL) were added triphenylphosphine (1.98 g) and water (1.5 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.62 g).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:16])=[N:3][CH:4]=[N:5][C:6]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)ncnc1O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)ncnc1Cl
Yield: 81.8 %

Procedure:
A suspension of methyl (4-hydroxy-6-methyl-5-pyrimidinyl)-acetate (116 g, 0.64 mol) in toluene (200 ml) and phosphorous oxychloride (94 ml, 1.0 mol) is refluxed for three hours. The solvent is removed under reduced pressure and the resulting oil is poured onto crushed ice with stirring. The pH is adjusted to 9 by adding potassium carbonate. Extraction with ether, drying and destillation under high vacuum gives methyl(4-chloro-6-methyl-5-pyrimidinyl)-acetate as a yellowish oil (105 g, 82 %). b.p./l torr 88°-91° C.
Reaction SMILES: [C:1]1(=O)[N:6]([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3=[N:19][C:20]4[C:25]([N:26]=[C:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:5](=O)[CH2:4][CH2:3][CH2:2]1.[Li].O>O1CCCC1>[N:6]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3=[N:19][C:20]4[C:25]([N:26]=[C:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCC(=O)N1CCCn1c2ccccc2c2nc3ccccc3nc21
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2nc3c(nc2c1)c1ccccc1n3CCCN1CCCCC1
Reaction time: 1 h

Procedure:
6-(3-glutarimidopropyl)-6H-indolo(2,3-b)quinoxaline (3.72 g) is heated under reflux with lithium aluminumhydride (0.80 g) in tetrahydrofuran (40 ml) for 6 hours, and then water (2 ml) is dropped thereto carefully. After stirring for 1 hour solid material is separated away and the residue is concentrated. The residue is dissolved in dry ether and the base is precipitated as hydrochloride by addition of hydrogen chloride. Yield: 2.60 g (68%), mp. 262°-266° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.35 g, 0.73 mmol) and 1H-indol-5-ylboronic acid (0.14 mg, 0.88 mmol) in CH3CN (10 mL) was added 1 M Na2CO3 (10 mL) followed by bis(triphenylphosphine)palladium(II)dichloride (0.050 g, 0.071 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 466.2/468.2 (M+1)+, calc. 465.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][N:16]([CH2:27]C)[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].OCCN(C)C(=O)OCC1C=CC=CC=1>>[C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][N:16]([CH3:27])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CN(CCO)C(=O)OCc1ccccc1
Product: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 67 %

Procedure:
A similar procedure to that described for INTERMEDIATE 48 utilizing benzyl 2-hydroxyethyl(methyl)carbamate (INTERMEDIATE 51, 0.46 g, 2.20 mmol) as starting material was followed, with subsequent purification by column chromatography (ISCO, 12 g silica gel column, eluting with 0→100% EtOAc/hexanes) to give the title product (590 mg, yield: 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:39][CH:38]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:40]4[CH:39]=[CH:38][N:37]=[CH:42][CH:41]=4)[CH2:45][CH2:46]3)=[O:23])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(Cc4ccncc4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-(pyridin-4-ylmethyl)piperazine (53 mg, 0.30 mmol) in DCE (4.5 mL).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)(=O)C.C[O-].[Na+].Cl>CO.O1CCOCC1>[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: CC(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
To a solution of (3S)-3-acetoxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (5.51 g, 17.8 mmol) (obtained as described in Reference Example 53(1)) in methanol (200 ml) was added a catalytic amount of sodium methoxide, and the mixture was stirred at room temperature for 4.5 hours. After checking the completion of the reaction, a solution of 4N hydrogen chloride in 1,4-dioxane (4.3 ml) was added thereto to neutralize the reaction mixture. The resulting reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over-anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3S)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.00 g, yield 84%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:17]([N-]C(C)C)([CH3:19])[CH3:18].[Li+].ICCC.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH:12]([CH2:18][CH2:17][CH3:19])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCC(=O)c1ccc(OC)c(OC)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCCI
Solvent: CCOC(C)=O
Product: CCCC(CCC)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3′,4′-Dimethoxyvalerophenone. 3′,4′-Dimethoxyvalerophenone (9.91 grams, 55 mmol) was added over 20 minutes to a cooled (0° C.) stirred solution of lithium diisopropylamide (28.9 milliliters, 2M, 57.8 mmol). After an additional 5 minutes the solution was cooled to −78° C. and 1-iodopropane (10.73 milliliters, 110 mmol) was rapidly added. The solution was allowed to slowly warm to room temperature and stirring was continued for 3 days. Reaction progress was monitored by TLC (30%, ethyl acetate/hexane, UV) and an equilibrium had been reached after three days between starting material (Rf=0.15), monoalkylated product (Rf=0.32) and dialkylated product (Rf=0.42). The reaction was treated with water (60 milliliters), ethyl acetate (100 milliliters) and a saturated solution of sodium bicarbonate (100 milliliters). The organic layer was separated and washed successively with 5% hydrochloric acid (100 milliliters) and saturated aqueous sodium bicarbonate (100 milliliters). The organic layer was dried over magnesium sulfate and concentrated to afford 15.17 grams of crude product as an orange oily liquid. The crude product was purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to afford 3.68 (25%) of the dialkylated product (3′,4′-dimethoxy-2-propylvalerophenone) as a yellow solid and 1.01 grams (8%) of the monoalkylated product (3′,4′-dimethoxyvalerophenone) as a yellow oily liquid: 1H NMR (CDCl3) δ 7.65-7.50 (m, 2H), 6.95-6.85 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H ), 2.99-288 (m, 2H), 1.52-1.34 (m, 2H), 1.04-0.91 (m, 3H); 13C NMR (CDCl3), δ 199.1, 152.9, 148.8, 130.2, 122.5, 110.0, 109.8, 55.9, 55.8, 37.7, 26.7, 22.4, 13.8.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:12]1[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Reactant: NCCCCCO
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Reaction of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone with 5-aminopentanol at 170°-180° gave 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which was isolated as the dihydrochloride salt m.p. 215°-217°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10][C:11]([NH2:13])=S.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.C(O)(=O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10][C:11]#[N:13]
Reactant: NC(=S)Nc1c(Br)cc(F)cc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CNc1c(Br)cc(F)cc1Br
Temperature: 100 °C
Yield: 62.9 %

Procedure:
A solution of (2,6-dibromo-4-fluoro-phenyl)-thiourea (0.300 g, 0.920 mmol) and 1M aq. KOH (7.23 mL) was heated to 100° C. Lead (II) acetate trihydrate (0.400 g, 1.05 mmol) in water (2 mL) was then added. The mixture was heated at 100° C. for another 10 minutes while a precipitate was observed. The mixture was cooled to 0° C. and filtered to provide a clear colorless solution. The filtrate was acidified to pH 5 with acetic acid. The precipitate was collected by filtration to yield titled compound (0.170 g, 63%). 1H NMR (400 MHz, DMSO-d6): 7.80-7.78 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[C:14](=O)(OCC)[O:15]CC.Cl>C1(C)C=CC=CC=1>[OH:13][C:11]1[C:5]2[C:4](=[CH:9][C:8]([CH3:10])=[CH:7][CH:6]=2)[O:3][C:14](=[O:15])[CH:12]=1
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(O)cc(=O)oc2c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a mechanically stirred suspension of sodium hydride (60% in oil, 30 g, 749 mmol) in toluene (400 mL), heated at 80° C., a solution of the commercially available 2′-hydroxy-4′-methylacetophenone (50 g, 0.333 mmol) in 150 mL of toluene was added dropwise over 1 h. After complete addition, the mixture was stirred 15 min and a solution of diethyl carbonate (81 mL, 666 mmol) in toluene (500 mL) was added dropwise over 1 h. The reaction mixture was then stirred overnight at reflux. After cooling, the reaction mixture was poured into 800 mL of 2N HCl. The precipitate formed was collected by filtration, co-evaporated twice with toluene and dried under high vacuum at 55° C. 1H NMR (400 MHz, acetone-d6): 11.1 (bs, 1H), 7.76 (d, 1H), 7.18 (d, 1H), 7.14 (s, 1H), 5.60 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:12]#[N:13])[CH2:5][C:6]1([CH3:11])[O:10][CH2:9][CH2:8][O:7]1.[C:15]([NH2:23])(=[NH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:13][C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[C:3]([OH:2])[C:4]=1[CH2:5][C:6]1([CH3:11])[O:7][CH2:8][CH2:9][O:10]1
Reactant: COC(=O)C(C#N)CC1(C)OCCO1
Reactant: N=C(N)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: CC1(Cc2c(N)nc(-c3ccccc3)nc2O)OCCO1

Procedure:
A solution of acetal (2) (1 g, 5.02 mmol), benzamidine (786 mg, 5.02 mmol), and DBU (1.5 mL, 10.04 mmol) in dry DMF (15 mL) was heated to 85° C. for 15 h. The mixture was diluted with CHCl3 (30 mL) and washed with 0.5 N NaOH (10 mL) and H2O (20 mL). The organic fraction was dried, filtered and concentrated to a brown oil. Flash chromatography (SiO2; 1/9 EtOAc/CH2Cl2, Rf 0.35) was attempted, but material crystallized on the column. The silica gel was washed with MeOH. Fractions containing the product (3) were concentrated and used without further purification (783 mg, 54.3%):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]1([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH2:11][CH2:10]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(C2CC2)c1
Yield: 38.3 %

Procedure:
Stir the mixture of 3-bromoaniline (400 mg, 2.35 mmol), cyclopropylboronic acid (240 mg, 2.79 mmol), tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol), cesium carbonate (1.5 g, 4.60 mmol) in dioxane (5 mL) and water (0.3 mL) under nitrogen atmosphere for 17 hrs at 100° C. Cool the reaction to room temperature, filter and concentrate the filtrate under reduced pressure. Purify by flash chromatography (silica gel, EtOAc:PE=3:7) to afford the title compound (120 mg, 38.8%). MS: (M+1): 134.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:31])[C:16]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][N:22]([CH3:24])[C:20]1[CH:21]=[C:16]([N:15]([CH3:14])[CH3:31])[N:17]=[C:18]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[N:19]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CN(C)c1cc(N(C)C)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(N(C)C)cc(N(C)C)n3)CC2)cc1
Yield: 109.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.7 g), 1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (0.9 g) and potassium carbonate (0.7 g) in dimethylformamide (10 ml) was stirred at 80° C. for 6 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (1.6 g). The obtained brown solid was crystallized from ethyl acetate/ethanol (2:1, 30 ml) to give the title compound (0.9 g) as pale-yellow crystals.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([C:67](Cl)=O)=[CH:63][CH:62]=2)=[CH:57][CH:56]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:60]=[CH:59][C:58]([C:61]6[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=6)=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:31])([F:30])[F:32])[CH:23]=1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 20: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (104 mg, 0.169 mmol) and DIEA (47.0 μL, 0.254 mmol) in dioxane (4 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (39.0 mg, 0.169 mmol) in dioxane (1 mL). After stirring at room temperature for 30 min, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature then diluted with NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 54 mg (40%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-34. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=1.70 min (Method 10).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([O:22]CC=C)=[O:21])=[CH:18][CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(OCC(=NO)c2ccc(NCCC(C)=O)c(C(C)(C)C)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(=O)CCNc1ccc(C(COc2ccc(C(=O)O)cc2)=NO)cc1C(C)(C)C
Reaction time: 0.08 h

Procedure:
360 mg (0.8 mmol) of allyl 4-{2-[4-(acetylethylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}benzoate are dissolved in 10 ml of THF. 48 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium are added and the medium is stirred for 5 min. 73 μl (0.8 mmol) of morpholine are then added and the reaction medium is stirred for 15 hours. After treatment with 1N hydrochloric acid solution and extraction with ethyl acetate, the residue is purified by chromatography (eluent: 5/5 heptane/ethyl acetate). A white powder is obtained (m.p.=192° C., m=200 mg, yield=60%); (1H NMR (DMSO): 1.05-1.07 (t, 3H); 1.29 (s, 9H); 1.64 (s, 3H); 2.73 (m, 1H); 4.13 (m, 1H); 5.33 (s, 2H); 6.46 (1H); 6.6 (1H); 7.07-7.09 (d, J=8.1 Hz, 1H); 7.51-7.53 (d, J=8 Hz, 1H); 7.54-7.64 (m, 2H); 7.86 (s, 1H); 12.1 (s, 1H)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCCF)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCCCF)nc1Cl
Yield: 35.3 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(3-fluoropropoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (127f) (0.16 g, 0.8 mmol), 2 N lithium hydroxide (6 mL, 12 mmol) and methanol (5 mL), to obtain 0.13 g of the title compound as a light brown solid (88%).