Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13](C(OC(C)(C)C)=O)[C:12]2=[CH:21][S:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[C:33]5[C:37]=4[NH:36][C:35](=[O:38])[N:34]5C(OC(C)(C)C)=O)=[CH:26][CH:25]=3)=[C:11]2[NH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:8]=[C:9]1[NH:13][C:12]2=[CH:21][S:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[C:33]5[C:37]=4[NH:36][C:35](=[O:38])[NH:34]5)=[CH:26][CH:25]=3)=[C:11]2[NH:10]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2c(-c3ccc(-c4scc5c4[nH]c(=O)n5C(=O)OC(C)(C)C)cc3)scc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1[nH]c2csc(-c3ccc(-c4scc5[nH]c(=O)[nH]c45)cc3)c2[nH]1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid in an amount of 40 equivalents relative to the obtained tert-butyl 4-[4-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was added and a reaction was carried out at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[4-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[4-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was 90%.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:32])[CH3:31])[N:25]=[C:24]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:32])[CH3:31])[N:25]=[C:24]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
12 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.52 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxyethyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 3 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was neutralized by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of ethyl acetate and hexane, followed by ethyl acetate alone, as the eluent, to afford 0.14 g of the title compound as an amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH:17]=[CH:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3n(n2)CCc2ccccc2-3)cc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3c4ccccc4ccn3n2)cc1
Yield: 56 %

Procedure:
Following substantially the same procedures of Example 58, and starting from 2-phenyl-5,6-dihydro-s-triazolo[5,1-a]isoquinoline, the title compound is prepared. Yield 56%, m.p. 157°-8° C. (from ethyl acetate).
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].Cl>ClCCl.O1CCOCC1>[CH2:25]([N:27]1[C:4](=[O:17])[CH:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[NH:6][C:28]1=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1C(=O)NC(Cc2c[nH]c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.3 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.510 mg, 0.002 mol.) in dichloromethane (10 mL) was added triethyl amine (0.350 mL, 0.0025 mol.) followed by ethylisocyanate (0.198 mL, 0.0025 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was diluted with dioxane (10 mL) and then conc. HCl (5 mL) was added. The mixture was heated at reflux for 3-4 hr. The reaction mixture was extracted in ethyl acetate, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-04 (480 mg, 93%): mp 167-170° C. (lit. 163-164° C.), 1H NMR (400 MHz, CDCl3): 0.99 (t, J=6.8 Hz, 3H), 2.95-3.01 (dd, J=8.4 and 14.8 Hz, 1H), 3.34-3.46 (m, 3H), 4.19-4.22 (dd, J=3.6 and 8.8 Hz, 1H), 5.70 (s, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.06-7.10 (dd, J=8.0 and 6.8 Hz, 1H), 7.16 (dd, J=7.2 and 6.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8.18 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:5][CH:4]([CH3:19])[CH2:3][CH2:2][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8]
Reactant: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)CCOc1cccc(CNC(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture solution of quinoline-6-carboxylic acid 3-hydroxybenzylamide described in Preparation Example E+-4 (13 mg, 0.048 mmol) and N,N-dimethylformamide (0.5 mL) were added potassium carbonate (13 mg, 0.096 mmol) and 1-iodine-3-methylbutane (0.013 mL, 0.096 mmol), and the solution was stirred overnight at room temperature. Water and dichloromethane was added to the reaction solution for extraction, which was then washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), and the title compound (12 mg, 0.033 mmol, 69%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CS(O[CH:30]([O:32][CH2:33][CH3:34])[CH3:31])(=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:31][CH2:30][O:32][CH2:33][CH3:34])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOCCn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Yield: 91.5 %

Procedure:
In a reaction vessel, 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) prepared in the Example 10, toluene (10 mL) and potassium hydroxide (0.8 g) were introduced, and temperature of the mixture was controlled to 50° C. or more. To the mixture, ethoxyethanol methane sulfonate (1.3 g) was added, and then, it was stirred at the same temperature until the reaction was completed. After the reaction was completed, distilled water (10 mL) was added to separate layers, and then an organic layer was condensed to obtain 4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 91%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
NaBH4 (1.18 g, 31.1 mmol) was added carefully in portions (exothermic) to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)-piperazine (3.54 g, 8.9 mmol), nickel(II)chloride hexahydrate (1.06 g, 4.4 mmol), MeOH (100 mL) and THF (50 mL) at 0° C. The ice bath was removed and the reaction mixture was warmed to rt. TLC analysis indicated the complete consumption of the starting material. The reaction mixture was concentrated onto silica gel and flash chromatography afforded the title compound of step B (2.93 g, 90%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.46 (m, 2H), 6.27 (dd, J=8.5, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.44-3.38 (m, 2H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.61-2.54 (m, 4H), 2.35-2.26 (m, 1H), 1.80-1.77 (m, 2H), 1.56-1.46 (m, 2H).
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[CH:17]=[C:18]3[N:23]([C:15]=2[CH2:14][CH2:13][NH:12]1)[CH2:22][CH2:21][CH2:20][CH2:19]3.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[N:23]4[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:17][C:16]=3[C:11]2=[O:24])[N:9]=[CH:8][CH:7]=1
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: O=C1NCCc2c1cc1n2CCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 80 °C
Yield: 50 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 2-bromo-4-chloronicotin-aldehyde 103a (1.4 g, 6.4 mmol), 3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one 112d (0.6 g, 3.2 mmol), Pd2(dba)3 (293 mg, 0.32 mmol), XantPhos (370 mg, 0.64 mmol), and potassium acetate (627 mg, 6.4 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. overnight. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with CH2Cl2/CH3OH (20:1, UV) to afford 147a (528 mg, 50%) as a yellow solid. MS: [M+H]+ 330. 1H NMR (500 MHz, CDCl3) δ 10.09 (s, 1H), 8.37 (d, J=5.5, 1H), 7.16 (d, J=5.5, 1H), 6.25 (s, 1H), 4.29-4.32 (m, 2H), 3.83-3.86 (m, 2H), 2.96-2.99 (m, 2H), 2.77-2.78 (m, 2H), 2.00-2.07 (m, 2H), 1.83-1.85 (m, 2H)
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].O.C(OCC)(=[O:43])C>C(O)C>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:20]3[C:21]([CH3:37])=[C:22]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH3:36])=[O:43])=[CH:33][CH:34]=4)[C:23]([CH3:26])=[C:24]([CH3:25])[C:19]=3[O:18][C:17]2([CH3:39])[CH3:38])=[CH:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: CSc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccc(S(C)=O)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 79 %

Procedure:
Sodium periodate (0.766 g, 3.58 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-5-(4-methylthiobenzyloxy)-2,3-dihydrobenzofuran (1.50 g, 3.26 mmol) in a mixture of ethanol (80 mL) and water (8 mol), and the mixture was heated under reflux for 2 hours. To the reaction mixture were added ethyl acetate and water to separate it into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.23 g, yield 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[CH:19]=1>[OH-].[Na+].C1COCC1.C(O)C.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
In 1N sodium hydroxide (13.0 ml) and THF:ethanol (1:1, 50 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (2.77 g), and the mixture was stirred at room temperature for 15 hours. To the mixture was added IN hydrochloric acid (12.5 ml), and the mixture was concentrated. To the residue was added water (200 ml), and the mixture was adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (300 ml×3), and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (2.52 g, 100%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]2[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][C:6]=2[C:10]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1csc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)sc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
A solution of bromine (3.20 g) in chloroform (10 ml) was added dropwise to a stirred solution of 5-bromo-3-methylbenzo[b]thiophene (4.54 g) in chloroform (40 ml) and the solution was stirred at room temperature for 1.5 hours. It was then washed with dilute sodium hydroxide solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from petrol (b.p. 80°-100°) to give 2,5-dibromo-3-methylbenzo[b]thiophene (5.45 g), m.p. 118°-122°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23].C(=[NH:39])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:39][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(Br)ccc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a stirred solution of 6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.65 g, 4.1 mmol), benzophenone imine (0.90 g, 4.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.46 g, 0.51 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.96 g, 1.6 mmol) in toluene (50.0 mL) was added sodium tert-butoxide (0.55 g, 5.8 mmol). The solution was heated at reflux for 2 h, cooled to ambient temperature, diluted with ethyl acetate (75 mL), filtered through celite and concentrated in vacuo to dryness. The residue was dissolved in tetrahydrofuran (150 mL) and 3 M hydrochloric acid (15 mL). The solution was diluted in ethyl acetate (250 mL), and adjusted to basic with 5 M NaOH. The aqueous phase was further extracted with ethyl acetate (2×100 mL). The combined organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 6-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.84 g, 61%) as a colorless solid: mp 71-74° C.; 1H NMR (300 MHz, CDCl3, mixture of diastereomers) δ7.29-7.22 (m, 1H), 7.14-6.95 (m, 3H), 6.46 (d, J=8.1 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 6.10 (dd, J=8.1, 2.0 Hz, 1H), 4.75 (ABq, 2H), 4.31-4.19 (m, 1H), 3.99-3.61 (m, 6H), 2.08-1.80 (m, 3H), 1.77-1.61 (m, 1H); 13C NMR (75 MHz, CDCl3, mixture of diastereomers) δ178.3 (2), 162.1, 148.4, 142.9 (2), 132.7 (2), 128.6 (2), 123.7, 123.6 (2), 123.2 (2), 118.8 (2), 109.4 (2), 108.4, 97.2, 80.3 (2), 68.2 (2), 57.6 (2), 44.5 (2), 29.1 (2), 25.6 (2); MS (ES+) m/z 337.0 (M+1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:3]2[CH2:4][C:5]3[C:10]([C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:20])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccccc3C2)cc1
Yield: 57 %

Procedure:
A slurry of 13.25 g (50 mmol) of 1-oxo-2-(4-methoxybenzoyl)indane in a mixture of 300 mL of ether and 300 mL of benzene was prepared. To the slurry was added 35.66 g (197 mmol) of phenylmagnesium bromide. The resulting mixture was heated to reflux for sixteen hours and poured into a mixture of ice and sulfuric acid. The mixture was allowed to separate and the organic layer was removed. The organic extract was washed with a bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to a red oil. A small amount of ether was added to the oil and a crystalline precipitate formed. The crystals were removed by filtration. The filtrate was concentrated to dryness and the product crystallized from methanol to yield 9.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:34])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:34])[C:23]2[S:24][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccccc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccccc3)s2)c(Cl)c1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-phenylthien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-phenylthien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 12 equivalents of trifluoroacetic acid. After stirring for 12 hours at room temperature, the reaction mixture is washed with water and then the dichloromethane is removed by evaporation under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH2:8][N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][N:5]([CH2:24][C@@H:25]2[C@H:28]([NH:29][C:30](=[O:66])/[C:31](=[N:45]\[O:46][C:47]3([C:50]([O:52]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:51])[CH2:49][CH2:48]3)/[C:32]3[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=3)[C:27](=[O:67])[N:26]2[S:68]([OH:71])(=[O:70])=[O:69])[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:31](=[N:45]/[O:46][C:47]2([C:50]([OH:52])=[O:51])[CH2:49][CH2:48]2)/[C:30]([NH:29][C@@H:28]2[C:27](=[O:67])[N:26]([S:68]([OH:71])(=[O:69])=[O:70])[C@@H:25]2[CH2:24][N:5]2[N:6]=[C:7]([CH2:8][NH2:9])[C:3]([CH2:2][NH2:1])=[N:4]2)=[O:66])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Yield: 19 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((4-(aminomethyl)-5-((bis(tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (109 mg, 0.11 DCM (1.1 mL), and TFA (0.49 mL, 6.36 mmol) for 2 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (12 mg, 19%). LCMS: Rt=0.46 min, m/z=559.2 (M+1), Method 2m_acidic; 1H NMR (400 MHz, D2O): δ 7.16 (s, 1H), 5.61 (d, J=5.6 Hz, 1H), 5.07-4.88 (m, 3H), 4.34 (s, 4H), 1.39-1.13 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:32])([F:33])[F:31])=[O:21])=[CH:18][CH:19]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C(F)(F)F)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4C(F)(F)F)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.90,(1H, d), 7.80-7.51,(9H, m), 7.41,(1H, b), 4.89-4.71,(2H, m), 3.01-2.96,(3H, m), 2.56,(3H, s), 2.33-2.24,(3H, m). LCMS; retention time 3.62 min, MH+ 466.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[B].[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][CH:33]=[CH:32][C:31]=1Br)(=[O:27])[CH3:26]>CO>[C:25]([O:28][CH2:29][C:30]1[C:31]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:32][CH:33]=[CH:34][C:35]=1[N:36]1[CH2:48][CH2:47][N:39]2[C:40]3[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=3[CH:46]=[C:38]2[C:37]1=[O:49])(=[O:27])[CH3:26]
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [B]
Solvent: CO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 44.8 %

Procedure:
Following Example 306b, 307a (422 mg, 1.26 mmol) was converted to the boron intermediate 307b, which was coupled under Suzuki conditions with 109a (420 mg, 1.0 mmol). The crude product was purified via column chromatography: ISCO 24 g silica, 50-100% ethyl acetate/hexanes then 0-10% MeOH, to give 307c (285 mg, 36% yield).