Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:23])=[CH:17]2.ClCCN1CCOCC1>CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:18]([CH3:23])=[CH:17]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2cc(Cl)ccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (100 mg, 0.60 mmol) in 0.3 mL DMSO was added pulverized KOH (102 mg, 1.81 mmol), then after 10 min, a solution of 5-chloro-2-methylindole (134 mg, 0.72 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. Additional 2-chloroethylmorpholine (22 mg, 0.12 mmol) and KOH (17 mg, 0.3 mmol) added and stirred overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2 to give a final yield of 154 mg (0.55 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.47 (s, 3H), 2.48-2.57 (m, 4H), 2.63 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.4 Hz, 4H), 4.16 (t, J=7.2 Hz, 2H), 6.20 (s, 1H), 7.11 (dd, J=8.6 Hz, 1.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.88, 41.23, 54.13, 57.86, 66.95, 99.88, 109.78, 119.15, 120.64, 124.97, 129.18, 134.99, 138.03. MS m/z 279.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43](O)=[O:44])[C:38]2=[O:46])=[CH:33][CH:32]=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>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:29][C:43]([C:39]2[C:38](=[O:46])[N:37]([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=3)[CH:42]=[CH:41][CH:40]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
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: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine 30 mg, 0.075 mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in DMF (1.0 mL) at room temperature were added HATU (57 mg, 0.15 mmol, Perseptive Biosystem), and DIEA (0.05 mL, 0.3 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and was then quenched by the addition of 2 mL of methanol. The reaction mixture was purified by preparative HPLC. The desired fractions were combined, concentrated in vacuo, and neutralized to pH 8 with aq. K2HPO4. The title compound (30 mg, 64%) was obtained as a white solid which was collected by filtration and dried under vaccum. 1H NMR (DMSO-d6) δ 12.09 (br s, 1H), 8.58 (dd, 1H, J=7.15, 2.20 Hz, 1H), 8.12 (dd, 1H, J=6.60, 1.65 Hz), 7.98 (s, 1H), 7.95 (d, 2H, J=3.85 Hz), 7.62-7.59 (m, 2H), 7.45-7.40 (m, 4H), 6.72 (t, 1H, J=9.90 Hz), 4.13 (t, 2H, J=5.5 Hz), 2.71 (d, 2H, J=5.5 Hz), 2.60-2.25 (m, 8H), 2.35 (s, 3H), 2.16 (s, 3H); MS(ESI30) m/z 616.40 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:20])([F:19])[CH:16]([OH:18])[CH3:17].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH:16]([CH3:17])[C:15]([F:20])([F:19])[F:14]
Reactant: CC(O)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1nc(C(=O)O)ccc1Br)C(F)(F)F
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stirred for 15 min. Then 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto icewater/1N HCl (200 mL) and extracted with EtOAc (2×400 mL). The organic layers were washed with icewater/brine (200 mL), combined and dried over Na2SO4 and concentrated in vacuo to give the title compound (6.9 g, quant.) as orange solid. MS (EI): m/e=312.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=3)=[O:19])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:44].[OH-].[Na+]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[O:19])=[CH:16][CH:17]=2)=[CH:7][C:6]=1[CH3:44]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COCOc1c(C)cc(-c2ccc(C(=O)NCCOc3ccc(CC(Oc4ccccc4)C(=O)O)cc3)cc2)cc1C
Yield: 75.8 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using ethyl 3-[4-[2-(4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (720 mg), which is the product of Reference example 24(a) and aqueous sodium hydroxide (1N, 2.40 ml) and the reaction mixture was treated to afford the title compound (520 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15]>O>[F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(O)c1F
Temperature: 140 °C
Yield: 73.9 %

Procedure:
2700 g of 3,5,6-trifluoro-4-hydroxyphthalic acid and 6 liters of water were placed in an autoclave, and the mixture was heated at 140° C. for 3 hours in an atmosphere of nitrogen. At the end of this time, the reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure, to precipitate crystals, which were collected by filtration, washed with chloroform and dried to give 1623 g of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F] as a colorless powder, melting at 144°-146° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][C:4]([O:6][CH3:7])=[O:5].N1CCCCC1.[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOCC>CO>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C:2]([S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:8])[CH3:1]
Reactant: COC(=O)C=C(C)C
Reactant: COC(=O)CCS
Solvent: CCOCC
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)CCSC(C)(C)CC(=O)OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a well-stirred mixture of methyl 3-methylbut-2-enoate (50.0 g, 438 mmol), 40% Triton B in MeOH (5 mL) and piperidine (4 mL) were added dropwise at 0° C., then methyl 3-mercaptopropanoate (50 g, 396 mmol) was added. After stirring for 24 h at 60° C., Et2O (500 mL) was added, and the organic phase washed thoroughly with 10% H2SO4 (150 mL), sat. NaHCO3 (150 mL), and brine (200 mL) successively, dried over Na2SO4 and evaporated under vacuum to give the title compound as a colorless oil (90.1 g, 97.23%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[C:30]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:45])=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[C:30]([NH:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]([N:46]5[CH2:47][CH2:48][O:49][CH2:50][CH2:51]5)=[O:45])=[CH:42][CH:43]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cc3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cc5)c5nccn5c4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyridin-6-yl}-benzyl ester (200 mg, 0.29 mmol) was dissolved in methanol (10 ml). To this solution was added K2CO3 (80 mg, 0.58 mmol) and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was poured into water (10 ml), extracted by DCM (100 ml). The organic extracts were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate 1:3) to afford the desired product as a yellow solid (30 mg, yield 16%). 1H NMR (300 MHz, CDCl3): δ 8.37 (d, J=2.7 Hz, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.45 (dd, J=7.7, 5.7 Hz, 3H), 7.36 (dd, J=6.6, 2.7 Hz, 1H), 7.32 (s, 3H), 7.19 (d, J=1.4 Hz, 1H), 4.38 (s, 2H), 3.57 (s, 8H), 1.35 (s, 9H). LC-MS: 647[M+1]+, tR=1.407 min. HPLC: 97.75% at 214 nm, 98.27% at 254 nm, tR=3.633 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][NH:12][C:9]=3[C:10]=2[CH:11]=1.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C1COCC1>[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][N:12]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]=3[C:10]=2[CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 642.9 %

Procedure:
At 0° C., NaH (60 percent, 1.3 g, 33 mmol) was added to a THF solution (40 mL) containing 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (8.3 g, 24.0 mmol). Then SEM-Cl (5.6 mL, 2.8 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% ETOAc in hexane) to give 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (9 g, 18 mmol) as brown solid in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].CC(C)([O-])C.[K+].C(O[C:21](=O)[CH:22]([CH3:38])[CH2:23][C:24]1[N:28]([CH:29]2[CH2:31][CH2:30]2)[C:27]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][N:25]=1)C>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:21]([CH:22]([CH3:38])[CH2:23][C:24]3[N:28]([CH:29]4[CH2:31][CH2:30]4)[C:27]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[N:26][N:25]=3)[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCO
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 100 °C
Yield: 59 %

Procedure:
After 3-chloro-N-hydroxy-benzamidine (0.7 g, 4.1 mmol) was mixed with potassium-tert-butoxide (0.373 g, 3.33 mmol) in n-propanol at 80° C. for 10 min, 3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid ethyl ester (1.0 g, 3.33 mmol) was added to the reaction mixture and heated at 100° C. for 3 h. The reaction mixture was concentrated, quenched with sat. ammonium chloride and extracted with DCM. The organic layer was dried with MgSO4, purified by column chromatography and triturated with Et2O to give racemic 4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (0.8g, 59%). The title product (10 mg) was obtained by separation on Chiracel OJ with EtOH:hex. (1:4). 1H-NMR: 8.78(d, 2H), 8.05 (s, 1H), 7.96 (d, 1H), 7.74 (d, 2H), 7.50 (d, 1H), 7.43 (t, 1H), 4.15 (m, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.67 (d, 3H), 1.25 (m, 2H) and 0.78 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
1-Benzyl-5-oxo-2-pyrrolidinecarboxylic acid (9.69 g, 44.2 mmol) in methanol (75 mL) was treated with sulfuric acid (0.5 mL) and refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate phase was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]([NH:10][C:11](=[O:22])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[N:9][C:5]=2[CH:4]=1)=O.CC([O-])=O.[Na+].Cl.[NH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=O.[BH3-]C#N.[Na+]>CC(O)=O.C([O-])(O)=O.[Na+].CCOC(C)=O.CO>[O:43]=[C:41]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:1][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]([NH:10][C:11](=[O:22])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: O=Cc1ccc2c(c1)nc(NC(=O)c1cccc(C(F)(F)F)c1)n2-c1ccccc1
Reactant: CCOC(=O)CCCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1nc2cc(CN3CCCC3=O)ccc2n1-c1ccccc1)c1cccc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 57 %

Procedure:
and (e) To a suspension of 409 mg N-(5-Formyl-1-phenyl-1H-benzoimidazol-2-yl)-3-trifluoromethylbenzamide (1.00 mmol, 1.00 equiv) prepared above in Example 7 in 40 mL of 1:9 HOAc:MeOH, 0.205 g NaOAc (2.50 mmol, 2.50 equiv), and 0.84 g ethyl 4-aminobutyrate hydrochloride (5.00 mmol, 5.00 equiv) was added 0.138 g NaCNBH3 (2.00 mmol, 2.00 equiv). The pink suspension was allowed to stir 20 h, after which time the resulting brown solution was diluted with 50 mL sat. NaHCO3 and 50 mL EtOAc. The aqueous layer was extracted (2×EtOAc) and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 1-2% MeOH/CH2Cl2 with 1% aq. NH4OH) gave 300 mg of the product as a colorless solid (0.57 mmol). A solution of 105 mg of this product (0.20 mmol, 1.00 equiv) in 20 mL toluene and 2 mL HOAc was heated to reflux temperature for 1 h. The solution was concentrated under reduced pressure and purified by flash chromatography (SiO2, 2-5% MeOH/CH2Cl2 with 1% aq. NH4OH) to give 80 mg of the product as a colorless solid (0.17 mmol). 1H NMR (CDCl3, 400 MHz) δ 13.03 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.65-7.75 (m, 5H), 8.26 (t, J=7.1 Hz, 1H), 7.53 (s, 1H), 7.16 (m, 2H), 4.47 (s, 2H), 3.26 (t, J=7.0 Hz, 2H), 2.31 (t, J=8.0 Hz, 2H), 1.94 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C([O-])([O-])=O.[K+].[K+]>CCO.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>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(I)cc2)cc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Oc2ccc(-c3ccsc3)cc2)cc1
Yield: 88.1 %

Procedure:
A mixture of the product of step 2 (0.5 g, 1.4 mmol), 3-thiophenboronic acid (0.2 g, 1.4 mmol), K2CO3 (1.1 g, 8.1 mmol) and (Ph3P)4Pd (0.08 g, 0.07 mmol) in EtOH (10 mL) was heated to reflux for 24 h. After the solids were filtered off, the filtrate was concentrated to dryness. The residue was purified by a column chromatography on silica gel to yield the title compound (0.4 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1c(NCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
2-Methyl-3-nitroaniline (3.40 g, 22.3 mmoles) and benzaldehyde (3.9 mL, 38 mmoles) in dichloroethane (78 mL) were treated with glacial acetic acid (5.1 mL, 89 mmoles). The yellow reaction mixture was stirred for 4 hours at room temperature, treated with sodium triacetoxyborohydride (9.5 g, 44.6 mmoles) and allowed to stir overnight at room temperature. The mixture was poured into saturated aqueous NaHCO3 (400 mL), extracted with diethyl ether (400 mL) and the phases separated. The organic phase was washed with brine (200 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1→4:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (4.72 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:6]1.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:6][N:7]([C:9]2[N:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:10]=2[C:11]([NH:28][C:29]2([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:31][CH2:30]2)=[O:13])[CH2:8]1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2F)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)cc4F)C3)CC2)cc1
Yield: 76.5 %

Procedure:
The title compound (D178) (106 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(2,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D127) (95 mg, 0.253 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (57.79 mg, 0.253 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH:22]([CH3:45])[CH:23]([C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[N:27](S(C2C=CC=CC=2)(=O)=O)[CH:26]=1)O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.O1CCCC1>[CH2:15]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:22]([CH3:45])[CH2:23][C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[NH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise to a dioxane/tetrahydrofuran (90 ml/10 ml) solution of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol (1.9 g, 3.3 mmol) under N2 at 0° C. After the addition is complete, the reaction is allowed to warm to room temperature, then is refluxed for 1 hour. The reaction is quenched with H2O and 15% aqueous NaOH, filtered, and the filtrate is diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.2 g of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(S)-methyl-ethyl]-amine (86%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[CH:36][C:37]2[O:41][CH:40]=[CH:39][C:38]=2[CH:42]=1)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:32]3[N:31]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:33]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: N=C(NO)c1ccc2occc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4occc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (147.7 mg, 0.72 mmol), HOBt (143 mg, 0.94 mmol) and EDC (180 mg, 0.94 mmol) in DMF (2.0 mL) was stirred for 0.5 h at room temperature under an atmosphere of N2. A solution of N-hydroxybenzofuran-5-carboximidamide INT-68 (218 mg, 0.79 mmol) in DMF (2.0 mL) was added to the mixture. After 1 h at room temperature, the mixture was stirred at 85° C. overnight. The reaction mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried over Na2SO4, and concentrated. The resulting crude material was chromatographed (EA/hexanes) to provide 110 mg (44%) of 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 69 as a white solid. LCMS-ESI (m/z) calculated for C20H15N3O3: 345.4; found 346.1 [M+H]+, tR=2.77 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=4.5, 1.9 Hz, 2H), 8.35 (dd, J=8.9, 2.2 Hz, 1H), 8.12 (dd, J=8.6, 1.7 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.80 (s, 1H), 1.48 (d, J=6.1 Hz, 6H).