Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:13]2[N:26]([C:29](=[O:43])[CH:30]([NH:35]C(OC(C)(C)C)=O)[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:13]2[N:26]([C:29](=[O:43])[CH:30]([NH2:35])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
A solution of carbamate 81 (542 g, 0.90 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 20 min, the reaction mixture was warmed to ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and filtered. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to afford 82 (401 mg, 89%) as a light yellow-colored foam was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.31-7.26 (m, 5H), 7.00-6.95 (m, 1H), 6.65-6.60 (m, 1H), 6.49-6.47 (m, 1H), 5.14-5.08 (m, 2H), 4.41 (m, 2H), 3.95-3.92 (m, 1H), 3.83-3.72 (m, 2H), 3.40-3.29 (m, 2H), 2.79 (app q, J=5.4 Hz, 1H), 2.34-2.19 (m, 1H), 1.66 (m, 2H), 0.94 (s, 9H) ppm. Mass spectrum, m/z [502.6] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC2C=CC=CC=2)[CH:7]=1.COC(=O)C(OC)CC1C=CC=C(O)C=1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: CCOC(Cc1cccc(OCc2ccccc2)c1)C(=O)OC
Agent: COC(=O)C(Cc1cccc(O)c1)OC
Product: CCOC(Cc1cccc(O)c1)C(=O)OC

Procedure:
The title compound was prepared from 3-(3-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (Example 378, Step 3) via the same procedure used for the preparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) to afford the title compound as a yellow oil. MS (ES) for C12H16O4 [M+H]+: 225.1.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]COC)[CH:27]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[OH:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:31]=[CH:30][CH:29]=1
Reactant: COCOc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cccc(CCc2ccccc2OCCC2CCNCC2)c1
Yield: 95 %

Procedure:
8 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 890 mg of 1-t-butoxycarbonyl-4-(2-{2-[2-(3-methoxymethoxyphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in step (a) above] in 8 ml of dioxane, and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo, to give 651 mg (yield 95%) of the title compound as colorless needles, melting at 156°-158° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:27]([S:35][CH2:36][C@H:37]([CH3:41])[C:38](Cl)=[O:39])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:10]([C:38](=[O:39])[C@H:37]([CH3:41])[CH2:36][S:35][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Yield: 76.6 %

Procedure:
27.6 g of tert.-butyl (4S)-1-benzyl-2-oxo-imidazolidine-4-carboxylate, 11.2 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 22.4 g of (2S)-3-benzoylthio-2-methylpropionic acid and 25 ml of thionyl chloride) and 200 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate(20:1)) and triturated with n-hexane. 34.1 g of tert.-butyl (4S)-1-benzyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 70.7%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)C1CC1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) cyclopropylcarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 387(M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5](=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:14][N:4]([CH2:3][CH:2]=[O:1])[C:5](=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCC(=O)N(C)CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)N(C)CC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a mixture of 11.9 g of ethyl 4-[(2-hydroxyethyl)(methyl)amino]-4-oxobutanoate and 120 mL of methylene chloride was added slowly 26.0 g of Dess-Martin Periodinane under ice cooling, and the mixture was allowed to warm to room temperature over 3 hours. An aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction mixture, followed by stirring for 30 minutes at room temperature. An aqueous layer was extracted with methylene chloride, the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), thereby obtaining 4.48 g of ethyl 4-[methyl(2-oxoethyl)amino]-4-oxobutanoate.
Reaction SMILES: C[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=S.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:18](=S)=[S:19]>>[CH3:18][S:19][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: Cc1ccccc1C=CC(O)=S
Reactant: S=C=S
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1cccc2c1CCC2=O
Reaction time: 3 h

Procedure:
To a solution of 50 g of o-methylthiocinnamic acid in 500 ml of carbon disulfide was gradually added with stirring 34 g of aluminum chloride, and the resulting mixture was then boiled with stirring for 3 hours. The reaction liquid after reaction was poured into a cooled 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate solution was washed with an aqueous potassium carbonate solution, followed by water-washing and then drying over anhydrous sodium sulfate, to remove the solvent therefrom. The residue was purified by column chromatography to obtain 18 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1.C(N(CC)CC)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 85 °C

Procedure:
To a solution of 0.20 g (0.57 mmol) of 4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-7-[(trifluoromethanesulfonyl)oxy]-2(1H)-quinolinone (Compound 18) in 1.45 g (2.0 mL, 14 mmol) of triethylamine were added 0.70 g (1.0 mL, 7.1 mmol) of (trimethylsilyl)acetylene and 94 mg (0.13 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 85° C. for 16 h. The reaction mixture was cooled, methylene chloride was added and the mixture adsorbed onto silica gel. The mixture was purified by flash chromatography (25% ethyl acetate in hexanes) to give the title compound as a foam. PNMR (300 MHz, CDCl3) d 0.19 (9 H, s), 1.40 (6 H, s), 2.44 (3 H, s), 2.66 (2 H, s), 6.53 (1 H, d, J=1.4 Hz), 7.09 (2 H, d, J=8.4 Hz), 7.15 (1 H, dd, J=7.9, 1.4 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.33 (2 H, d, J=8.4 Hz).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:12])([F:11])[C:7](OC)=[O:8]>>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:12])([F:11])[F:5])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: COC(=O)C(F)(F)F
Product: C#CCNC(=O)C(F)(F)F
Yield: 91.4 %

Procedure:
Propargylamine (24.79 g, 0.450 mole; Aldrich, 99%) was added dropwise over 1 hour to methyl trifluoroacetate (69.19 g, 0.540 mole, 1.2 eq, Aldrich) at 0°. After stirring an additional hour at 0°, distillation through a 15 cm Vigreaux column afforded 62.12 g (91%) of trifluoroacetamide 18 as a colorless liquid (bp 68.5°-69.5° at 11 torr). This material was homogeneous by NMR and GC and was used interchangeably with spectroscopically-identical material prepared by acylating propargylamine with trifluoroacetic acid anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([OH:11])=[O:10]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccccc1Cl
Yield: 97.6 %

Procedure:
Step AR (1): 2-(2-Chlorophenyl)acetic acid (5.0 g, 29.3 mmol) was deprotonated with NaHMDS (2.0 M in THF, 29.3 mL, 58.6 mmol) and reacted with 1-chloro-4-iodobutane (5.38 mL, 44.0 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(2-chlorophenyl)hexanoic acid (7.47 g, 88% yield). LC-MS (M−H)− 259.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:34]2[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]2)=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(O)CC2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (94 mg, 0.223 mmol) obtained in Example 12 in methylene chloride (3 ml), 4-hydroxypiperidine (27 mg, 0.268 mmol), 1-hydroxybenzotriazole (30 mg, 0.223 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.268 mmol) and 4-methylmorpholine (29 μl, 0.268 mmol) were added, and the resulting mixture was stirred for 18 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with an aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (76 mg, 0.151 mmol, 68%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:20]1[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([CH2:31][OH:32])=[CH:21]1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:20]1[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH:31]=[O:32])=[CH:21]1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A mixture of [1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]methanol (2.39 g), activated manganese dioxide (4.80 g), and tetrahydrofuran (50 ml) was stirred at room temperature for one hour. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The colorless crystals obtained were collected by filtration to yield 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2.24 g, yield: 94%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 140–141° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24].C(=O)(O)[O-].[Na+:30].O>O1CCCC1>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([O-:25])=[O:24].[Na+:30]
Reactant: O=C(O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid (34.9 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added sodium bicarbonate (8.4 mg, 0.10 mmol) and water (2 mL). The reaction mixture was stirred at room temperature for 1 hour then freeze dried, to give sodium 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])C.CC([O-])(C)C.[K+]>C1COCC1>[CH2:27]([O:26][C:24]([C:23]1[N:22]=[CH:21][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[S:10][C:6]=2[C:4]=1[OH:5])=[O:25])[CH3:28]
Reactant: CCOC(=O)CN(Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2nc(-c3ccc(C(F)(F)F)cc3)sc2c1O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A mixture of 4-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (302 mg, 0.58 mol) in THF (5 mL) was added drop wise a solution of 1 M KOtBu in THF (702 μL, 0.70 mmol) at −78° C. The mixture was stirred at −78° C. for 15 min, warmed to room temperature and stirred at that temperature for 1.5 h before it was quenched with brine, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow foam (469 mg). It was dissolved in dichloromethane (10 mL) and TFA (2.5 mL) was added. The mixture was stirred at room temperature for 1 h before it was concentrated in vacuo. It was redissolved in dichloromethane, triethylamine (923 μL) was added. The mixture was stirred under air overnight before it was partitioned between dichloromethane and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (257 mg): MS: (+) m/z 330.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(I)ccc1I
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(I)ccc1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 108 %

Procedure:
A RBF equipped with a reflux condenser was charged with 4-bromophenol (15.5 g, 89.4 mmol), 2,5-diiodobenzoic acid (25.700 g, 68.7 mmol), EtOAc (0.337 ml, 3.44 mmol), and toluene (100 mL). Cs2CO3 (44.8 g, 137 mmol) was carefully added portion-wise. After stirring at RT for 1 min, the mixture was heated to 50° C. for 40 min and then heated to 100° C. for 20 hrs. The reaction mixture was allowed to cool to RT. The mixture was filtered through Celite and the solids were washed with EtOAc. The filtrate was diluted with water (200 mL), acidified with 2N HCl (300 mL), and extracted with EtOAc (4×500 mL). The organic extract was washed with brine and dried over sodium sulfate. The organic fraction was concentrated under reduced pressure to afford crude 2-(4-bromophenoxy)-5-iodobenzoic acid (31.1 g) as a tan oil that solidified upon standing.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:22])=[C:4]([CH2:8][CH2:9][C@H:10]([OH:21])[C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[Si:14]([O:13][C@@H:11]([CH3:12])[C@@H:10]([OH:21])[CH2:9][CH2:8][C:4]1[C:3]2[O:22][C:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc(N)c1O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc2nc(-c3ccc(Cl)cc3)oc12
Yield: 76.3 %

Procedure:
A mixture of (3S,4S)-1-(3-amino-2-hydroxyphenyl)-4-(tert-butyldimethylsilyloxy)pentan-3-ol (P0016; 445 mg) and 4-chlorobenzaldehyde (192 mg) in toluene (15 ml) was refluxed for 2 hours. And then to the resulting mixture of the Schiffs base was added manganese triacetate (733 mg) and the reaction mixture was refluxed for 1 hour. The precipitated manganese diacetate was then separated by filtration and the solvent was removed under reduced pressure. The crude product was purified by silica gel (26 g) column chromatography eluting with hexane/ethyl acetate (20:1) to give (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-7-benzoxazolyl]pentan-3-ol (P0012; 465 mg).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41](=O)[C:42]1[O:46][CH:45]=[CH:44][CH:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:46]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH2:41][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=Cc1ccco1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccco3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol) in DCE (0.5 mL) was added furfural (5.71 μL, 0.069 mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg, 0.110 mmol) was added. After stirring the mixture for 16 h at rt an additional 5 μL of furfural was added along with an additional 0.025 g of sodium triacetoxborohydride. After stirring the mixture overnight at rt, it was purified by passing through a plug of silica gel and washing with 0-25% EtOAc in hexanes. The fractions containing the product were combined and concentrated under reduced pressure to give the title compound (31 mg, 0.050 mmol, 90% yield) as a light-yellow film. The product was used in the next step with no additional purification. LCMS: m/e 625.6 (M+H)+, 3.08 min (method 2).