Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:26][N:25]([CH2:27][CH3:28])[CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+]>C(O)CCC>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:26][N:25]([CH2:27][CH3:28])[CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH3:32])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCO
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
The title compound from example 119 (120 mg, 0.28 mmol) and cesium carbonate (274 mg, 0.84 mmol) were dissolved in n-butanol (4 ml), and heated at 90° C. under nitrogen with molecular sieves for 96 h. The mixture was then partitioned between water (10 ml) and dichloromethane (10 ml). The organic layer was separated, and the aqueous layer extracted further with dichloromethane (3×15 ml). The combined organic layers were dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (95:5:0.5-90:10:1 ethyl acetate:methanol:0.88 NH3 as eluents), to yield the title compound as a colourless glass (77 mg, 0.18 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22]>>[CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2CC)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.041 mol of 7-ethyl-3-methyl-xanthine and 0.049 mol of diethyl 3-bromopropanephosphonate analogously to Example 32.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[NH:8][C:7]=1[CH3:29])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[NH:8][C:7]([CH3:29])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=3[CH3:11])[NH:13][C:14]=2[CH:20]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
The 5-(5-benzoylbenzimidazole-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid ethyl ester (200 mg) obtained in Example 53 (2) was dissolved in ethanol (5 ml) and tetrahydrofuran (5 ml). To this solution was added a 4 N sodium hydroxide aqueous solution (10 ml), and the mixture was heated under reflux for 12 hours. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazol-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid (139 mg, 75%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29]I>ClCCl.C([O-])(=O)C.[Ag+]>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[I:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)cc1)CCC2
Reactant: II
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
To a solution of 4-(4-benzyloxyphenoxy)-5-methyl-7-nitroindane (3.21 g) in dichloromethane (15 mL) was added silver acetate (1.86 g). After adding iodine (2.60 g), the mixture was stirred under an argon atmosphere in the dark at room temperature for 2 days. The insoluble material was removed by filtration. The filtrate was washed with an aqueous solution of sodium sulfite (1.7 g/40 mL), a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.18 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44]O)=[N:41][CH:42]=1)[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:44][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:35][CH3:36])=[CH:42][N:41]=3)=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1ccc(CCO)nc1
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCCc3ccc(CC)cn3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (50 mg, 0.111 mmol), 2-(5-ethylpyridin-2-yl)ethanol (16.8 mg, 0.111 mmol) and triphenylphosphine (44 mg, 0.167 mmol) were dried for 3 hrs in vacuo, purged with argon, added tetrahydrofuran (1 mL) and diethyl azodicarboxylic acid (2.2 mol/L toluene solution, 76 μL, 0.167 mmol), and stirred at room temperature for 2 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 4′-{[4-butyl-1-{5-[2-(5-ethylpyridin-2-yl)ethoxy]pyrimidin-2-yl}-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl]biphenyl-2-carbonitrile (49 mg, 76%).
Reaction SMILES: [OH:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.O1CCC[CH2:24]1.[H-].[Na+].CI>CN(C)P(=O)(N(C)C)N(C)C>[CH3:24][O:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: C1CCOC1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC(O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: COC(CCC(C)=CCOc1ccc2c(c1)OCC2)C(C)(C)C
Temperature: 40 °C
Reaction time: 12 h

Procedure:
0.4 g. of 6-[(6-hydroxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 10 ml. of absolute tetrahydrofuran and, while stirring, warmed to 40° C. for 2 hours with 0.5 g. of a 55% by weight sodium hydride suspension in oil. Then 2 ml. of hexamethylphosphoric acid triamide and 1 ml. of methyl iodide are added and the mixture is stirred for 12 hours at room temperature. For the working up, the mixture is poured onto ice-water and extracted twice with diethyl ether. The ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (19:1 parts by volume) there is obtained 6-[(6-methoxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran; nD25 = 1.5170.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cycloheptyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([CH:18]=1)[CH:8]=[N:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17].[CH3:23][O:24]C1C(OC)=CC(C=O)=C(OCOC)C=1>>[CH3:23][O:24][C:4]1[C:3]([O:2][CH3:1])=[CH:18][C:7]([CH:8]=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[C:6]([O:19][CH2:20][O:21][CH3:22])[CH:5]=1
Reactant: COCOc1cc(OC)c(OC)cc1C=O
Reactant: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Product: COCOc1cc(OC)c(OC)cc1C=Nc1c(C)cccc1O

Procedure:
2-[(4,5-dimethoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F5) was prepared in a similar manner for the preparation of 2-[(5-Methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) by using 4,5-dimethoxy-2-methoxymethoxybenzaldehyde (F2) (2.26 g, 10 mmol) instead of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) in 86% (2.80 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 3H), 5.24 (s, 3H), 7.17 (d, 1H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:19][CH3:20])=[O:7])[CH3:2]
Reactant: CCOc1ncccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the compound prepared in Example 284 (1.3 g) and cesium carbonate (2.53 g) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hours and then treated with ethyl iodide (0.62 mL) at room temperature, and stirring continued for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous solution of sodium bicarbonate. The combined organic extracts were washed with brine, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (0.904 g) having the following physical data.
Reaction SMILES: CCCCCCC.[CH3:8][CH:9]([OH:11])[CH3:10].[CH3:12][CH2:13][N:14](CC)[CH2:15][CH3:16]>CC(O)C.C1COCC1>[CH3:8][CH:9]([OH:11])[CH3:10].[NH:14]([CH2:15][CH3:16])[CH2:13][CH3:12]
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CCNCC

Procedure:
The racemate was resolved by chiral support chromatography. Portions of the racemate (0.2 g dissolved in 10 mL of 3:1 iPrOH/THF) were injected onto a preparative Chiralcel OD™ column equilibrated at 30° C. with 800:200:1 heptane/iPrOH/Et3N. Assignment of absolute configurations to the separated enantiomers was made by comparison of the CD spectra to those of the 10-chloro strictures. Analytical HPLC analysis (tR=17.2 min on a Chiralcel™ OD-H at a 0.5 mL min−1 flow rate of 800:200:1 hepane/iPrOH/Et2NH) gave an ee of 97%: UV λmax nm (ε, L.mol−1.cm−1) 284 (4740); CD λmax nm (θ, deg.cm2.dmol−1) 298 (3700), 273 (4400).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[N+:30]([O-])=O)=O)(=[O:3])[CH3:2]>[Zn].C(O)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17]1[NH:30][C:21]2[C:20]([CH:19]=1)=[CH:25][C:24]([O:26][CH3:27])=[C:23]([O:28][CH3:29])[CH:22]=2)(=[O:3])[CH3:2]
Reactant: COc1cc(CCNC(C)=O)c(C(=O)Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3[nH]2)cc1OC
Yield: 44.8 %

Procedure:
To a 80% acetic acid solution of 4.60 g of 2-(2-acetamidoethyl)-2'-nitro-4,4', 5,5'-tetramethoxydeoxybenzoin was slowly added 4.7 g of zinc at 85° C. The reaction mixture was filtered, washed with ethanol, and the solvent was evaporated. To the residue was added an ammonium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate) to yield 1.84 g of the title compound.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([C@@H:33]([CH3:42])[CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.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]>[NH2:14][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([C@@H:33]([CH3:42])[CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1
Reactant: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
Benzophenone imine (0.40 mL, 2.4 mmol) was added to (5-bromopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (891 mg, 2.0 mmol) (see Preparation 27), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (68 mg, 0.16 mmol) and freshly ground potassium phosphate tribasic (1.06 g, 5.0 mmol) in 1,2-dimethoxyethane (4 mL). The mixture was stirred at 50° C. for 17 hours. The reaction mixture diluted with DCM (10 mL), filtered through Arbocel™ and the pad was washed with DCM (5 mL). The filtrate was evaporated in vacuo and the crude material was dissolved in THF (10 mL). Aqueous citric acid (5 mL, 2M) was added and the mixture was stirred at room temperature for 16 hours. Water (40 mL) was added then sodium hydroxide was added to basify the mixture. The mixture was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 80:20) to afford the title compound as a white solid in 70% yield, 506 mg.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:17]=1[O:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])=[CH:21][CH:20]=1>>[Cl:36][C:34]1[CH:33]=[CH:32][C:17]([O:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:35]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C(=O)NCCOC)cc3)ccnc2n1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 126e (116 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (101.7 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.35 Hz, 3H) 1.70-1.90 (m, 2H) 2.90-3.01 (m, 2H) 3.24 (s, 3H) 3.32-3.47 (m, 4H) 6.73 (d, J=6.99 Hz, 1H) 6.98 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1H) 7.61 (dd, J=8.82, 2.57 Hz, 1H) 7.71-7.81 (m, 4H) 8.42 (t, J=4.78 Hz, 1H) 8.53 (d, J=6.99 Hz, 1H) 8.85 (d, J=8.82 Hz, 1H) 10.92 (s, 1H) 14.57 (s, 1H); MS (ESI+) m/z 491 (M+H−TFA)+.
Reaction SMILES: [OH:1][C@H:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:4][CH2:5][CH3:6].O.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH2:7][C@@H:3]([CH2:4][CH2:5][CH3:6])[C@@H:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:1]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H](N)[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
The pure tert-butyl (1R,2S)-1-hydroxy-1-phenylpentan-2-ylcarbamate was dissolved in ethyl acetate (1.2 ml). Water (50 μl) and hydrochloric acid in ethyl acetate (1.0 ml, 1.5 M) were added. The solution was stirred at 50° C. for 90 min. A precipitation was formed. The volume was reduced to ⅔ by heavy stirring and a stream of argon gas. The stirring was continued for 1 h at r.t. The suspension was filtered and the solid was dried at 50° C. under reduced pressure for 2 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=3)[C:11](=[O:20])[C:10]=2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br.[OH-].[Na+]>CC(O)=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:20])[C:10]=2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(c1cccnc1)C2=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Temperature: 120 °C
Yield: 99.4 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-methoxy-2-(pyridin-3-yl)-1H-inden-1-one (210 mg, 0.60 mmol) obtained in Step 4 in AcOH (6 mL) was added HBr (3 mL). The mixture was heated to reflux at 120° C. for 16 h. The reaction mixture was cooled to room temperature and neutralized with 3N—NaOH. The resulting solution was extracted with EtOAc (10 mL). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by recrystallization with CH2Cl2/hexanes to afford the desired product (200 mg, 99%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([C:21]([O:23][CH2:24]C)=[O:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]>OS(O)(=O)=O.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([C:21]([O:23][CH3:24])=[O:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c(-c2ccc(CC)cc2)cc1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccc(-c2cc(C)c(C(=O)OC)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure E, ethyl 5-(4-ethylphenyl)-3-methyl-6-phenylpyridine-2-carboxylate (Compound 26, 29 mg, 0.08 mmol) and conc. H2SO4 (3 drops) in MeOH (5 ml) were reacted to produce the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[CH3:16])=O.[C:19]([C:24]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:16])=[C:5]2[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Reactant: COc1ccc2[nH]c(C)c(C(=O)C(F)(F)F)c2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Temperature: 120 °C
Yield: 98.4 %

Procedure:
A suspension of the indole from Step 1 (18.3 g, 71.4 mmol) and carbethoxy-methylenetriphenylphosphorane (49.7 g, 142.8 mmol) in 100 mL of toluene was pressurized to 900 psi nitrogen in a stainless steel, high pressure Parr reactor and was heated to 120° C. for 39 h. The reaction mixture was cooled, concentrated and purified by flash chromatography (30% ethyl acetate/hexanes) to give 23 g of the title compound as a mixture of E- and Z- isomers.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:28])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[Br:27])[CH2:14][CH2:13]1)=[O:11])(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:28])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[Br:27])[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Saturated HCl in 1,4-dioxane (1.0 ml) was added to a stirred solution of {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (375 mg, 0.82 mmol) in 1,4-dioxane (1.0 mL) at room temperature and the resulting mixture was stirred for 15 minutes. The mixture was then concentrated and the product obtained was washed with diethyl ether to afford 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone hydrochloride in 87.8% yield. LC-MS purity: 83.28%
Reaction SMILES: C1(=O)CCC=C1.C(OCC1C=CC=CC=1)C1C=CC=CC=1.[CH:22]([C:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=1)([CH3:24])[CH3:23]>>[CH:22]([CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)C1=CC(=O)CC1
Agent: O=C1C=CCC1
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CC(C)C1CCC(=O)C1
Yield: 88 %

Procedure:
Cyclopentenones designed to test the tolerance of the catalyst to functional groups and steric hindrance were subjected to the reduction conditions. A cyclopentenone that contained an isolated olefin was successfully reduced in high ee (entry 5). Substrates with either a benzyl ether (entry 6) or an ester (entry 7) were also reduced with high enantioselectivity. Examination of the tolerance of the catalyst to steric hindrance on the substrate revealed that longer reaction times were necessary as the steric bulk of the substituent on the β-carbon increased. For instance, the reduction of 3-isopropylcyclopentenone (entry 8) proceeded to 90% completion after 3 days to afford 3-isopropylcyclopentanone in 88% yield and 94% ee.13,14 To date, attempted reductions of cyclopentenones with vinyl or alkynyl groups conjugated to the enone to gave mixtures of products resulting from competing 1,4- and 1,6-reductions.