Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.O>[C:24]([NH:28][C:29](=[O:30])[N:20]([CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[N:9]([CH:8]1[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]1=[O:2])[C:10]2=[O:22])[CH3:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CNCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and t-butyl-isocyanate (0.26 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added water (40 mL) and 1N HCl (40 mL). The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.59 g, 76%): mp 188-190° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.14 (96%); 1H NMR (DMSO-d6): δ 1.28 (s, 9H), 2.08 (m, 1H), 2.64-2.50 (m, 2H), 2.85 (s, 3H), 2.87-2.95 (m, 1H), 4.87 (s, 2H), 5.14-5.18 (dd, J=5.3, 12.6 Hz, 1H), 5.71 (s, 1H), 7.50-7.52 (m, 1H), 7.79-7.88 (m, 2H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 29.13, 30.90, 34.81, 47.02, 48.82, 50.07, 121.70, 127.45, 131.73, 132.49, 134.78, 139.63, 157.40, 166.95, 167.61, 169.80, 172.73. Anal Calcd for C20H24N4O5: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.87; H, 6.01; N, 13.83.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:21]=1)[CH3:18]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:28][CH2:29][N:30]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:31][CH2:32]2)[CH:21]=1)[CH3:18]
Reactant: CCOc1cc(C)nc(N2CCNCC2)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C)nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (11 μl, 0.12 mmol) was added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(4-ethoxy-6-methyl-2-pyridyl)piperazine hydrochloride (22 mg, 0.086 mmol) and TEA (42 μl, 0.3 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters X-Bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 12 mg of a solid (0.035 mmol, yield 41%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (19 μl, 2 eq) followed by addition of DIEA (65 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (400 μl) at 60° C. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (178) (10.5 mg, yield: 35.4%, purity>95%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([CH3:10])[N:6]=[C:5]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[N:4]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1Br.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.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:19]1([CH3:18])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[N:6][C:7]=1[CH3:10]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: CCCN(CCC)c1nc(C)c(N)c(OC)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)c1nc(C)c(Nc2c(C)cc(C)cc2C)c(OC)n1
Temperature: 115 °C
Yield: 57.9 %

Procedure:
4-Methoxy-6-methyl-N2,N2-dipropylpyrimidin-2,5-diamine (0.022 g, 0.092 mmol) was charged with 2,4,-6-trimethylbromobenzene (16.7 μL, 0.11 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.012 g, 0.018 mmol), sodium t-butoxide (0.012 g, 0.13 mmol) and tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3) (0.017 g, 0.018 mmol). The reagents were diluted in 1 mL of toluene and heated at 115° C. for 1.5 h. The solution was cooled and flash chromatographed (5% ethyl acetate/hexanes) to give 0.019 g (58%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH:24](=[O:28])[CH:25]([CH3:27])[CH3:26].[Cl-].[NH4+]>C1COCC1>[OH:28][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4′-(methylsulfonyl)biphenyl-3-carbonitrile obtained in Reference Example 102 (2.00 g, 7.77 mmol) in THF (40 mL) was added dropwise n-butyllithium (1.6M hexane solution, 5.34 mL, 8.55 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 hr. Isobutyraldehyde (1.06 mL, 11.7 mmol) was added to this solution at −78° C., and the mixture was further stirred at −78° C. for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed with saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (25%-50% ethyl acetate/hexane) to give the title compound as a pale-yellow oil (1.66 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([CH2:10]Cl)=[CH:4][CH:3]=1.[C:12]1([C:18]([NH2:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:31]([C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccc(Cl)nc1CCl
Product: Clc1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2 (b) from 6-chloro-2,3-bis-chloromethyl-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>ClCCl>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH:24]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CNCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.68 mmol) of 2,4-dichlorobenzylamine was dissolved in 20 ml of dichloromethane and treated with 2.94 g (22.7 mmol) of diisopropylethylamine and 1.43 g (6.25 mmol) of 3-bromomethyl-benzoic acid methyl ester. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH:23]([CH3:27])[C:24](Cl)=[O:25].[OH-].[K+]>ClCCl.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][O:12][CH:23]([CH3:27])[C:24]2=[O:25])=[CH:13][CH:14]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: COc1ccc(CNCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCCOC(C)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 3-(4-methoxy-benzylamino)-propan-1-ol (2.00 g, 10.2 mmol) in dichloromethane (30 ml) was added triethylamine (1.09 g, 10.8 mmol) and 2-chloropropionyl chloride (1.37 g, 10.8 mmol) at 0° C. The mixture was stirred at 0° C. for one hour and partitioned between 0.5N hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (50 ml) and potassium hydroxide (1.15 g, 20.5 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 4 hours and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=3/1) to afford 4-(4-methoxybenzyl)-2-methyl-[1,4]oxazepan-3-one as colorless oil (2.00 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (2.0 g, 0.009 mol) in DMF (10 mL) was added K2CO3 (3.8 g, 0.02 mol) at RT. The reaction mixture was stirred for 10 minutes and then 2-(chloromethyl)quinoline (1.2 g, 0.19 mol) was added. The reaction mixture was refluxed for 16 h, quenched with ice water and filtered. The residue that was obtained was extracted with DCM (2×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 45%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:6](OCC)=[O:7])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH:6]=[O:7])([CH3:16])[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C=O)CCC(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 36.6 %

Procedure:
A solution of 2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (500 mg, 2.05 mmol) in anhydrous dichloromethane (4 mL) was stirred at −78° C. under a blanket of nitrogen and treated dropwise via syringe with a 1.0 M solution of diisobutylaluminum hydride in toluene (4.1 mL, 4.1 mmol) over a period of 15 min. The reaction was stirred for 4 h at −78° C. and quenched sequentially with a saturated aqueous ammonium chloride solution (3 mL) and a 4% aqueous hydrochloric acid solution (3 mL). The resulting gelatinous suspension was allowed to warm to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (Teledyne Isco RediSep column; 0-20% ethyl acetate in hexanes) to afford the desired product, 2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (150 mg, 0.75 mmol, 36%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (d, 6H, J=6.9 Hz), 1.07-1.15 (m, 2H), 1.23-1.26 (m, 3H), 1.28 (s, 3H), 1.52 (septet, 1H, J=6.6 Hz), 1.83-1.92 (m, 2H), 4.21 (q, 2H, J=6.9 Hz), 9.69 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H-].[Na+].Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1.O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1)[CH3:2]
Reactant: Cc1cc(Cl)nc(-n2ccnc2)n1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of (benzhydrylidene-amino)-acetic acid ethyl ester (2.67 g, 10.0 mmol) in DMSO (50 mL) was added NaH (600 mg of a 60% dispersion on mineral oil, 15.0 mmol) slowly at r.t. under nitrogen and the mixture was stirred for 5 min. Then a solution of 4-chloro-2-imidazol-1-yl-6-methyl-pyrimidine (1.95 g, 10.0 mmol) in DMSO (15 mL) was added and the reaction mixture stirred at r.t overnight. Water was added and the solution was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave residue which was purified by column chromatography to give 1.30 g (31%) of (benzhydrylidene-amino)-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester. [M+H]+ 426.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[OH:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC

Procedure:
13.2 g of α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol are dissolved in 200 ml of methylene chloride and, after treatment with 130 g of manganese dioxide, the mixture is stirred at the reflux temperature for 2 hours. After filtration, the solvent is distilled. There is obtained 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketone in the form of yellowish crystals of m.p. 212°-213°.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([OH:17])=[O:16].[C:18]([O-])([O-])=O.[Na+].[Na+]>CO>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (1.50 mL) was added cautiously to a solution of 2-bromo-4-fluorophenylacetic acid (1.00 g, 4.29 mmol) in MeOH (25 mL) and the resulting mixture stirred overnight at room temperature. Saturated aqueous Na2CO3 solution was added until the pH of the mixture was 14, then the aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried over MgSO4 then the volatiles were removed in vacuo to yield the title compound A48 as a clear oil (1.00 g, 94%); 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J=8.2, 2.6 Hz, 1H), 7.29 (dd, J=8.5, 6.0 Hz, 1H), 7.03 (td, J=8.3, 2.6 Hz, 1H), 3.79 (s, 2H), 3.74 (s, 3H). LCMS-A: rt 5.911 min.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[C:33]([CH3:42])=[N:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=4)[C:20](=[O:43])[C:19]=3[C:18]=2[O:44][CH3:45])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[C:33]([CH3:42])=[N:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=4)[C:20](=[O:43])[C:19]=3[C:18]=2[O:44][CH3:45])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1ccc(C(F)(F)F)nc1C)c1ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1ccc(C(F)(F)F)nc1C)c1ccccc21
Yield: 40.7 %

Procedure:
A solution of 2-(4-{[(3-methoxy-1-methyl-5-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl)carbonyl]amino}piperidin-1-yl)-2-oxoethyl acetate (50 mg) and potassium carbonate (55 mg, 0.40 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (19 mg, 5%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=2)=[CH:23][CH:22]=1.CN(C)CC(O)=O>CS(C)=O.[Cu]I>[CH3:32][N:30]1[CH:31]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]3)=[CH:26][CH:25]=2)[N:28]=[CH:29]1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: Cn1cnc(-c2ccc(Br)cc2)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1cnc(-c2ccc(-n3nc(C(F)(F)F)c4c3CCCC4)cc2)c1
Temperature: 180 °C
Reaction time: 0.02 h
Yield: 16.7 %

Procedure:
A mixture of copper (I) iodide (10 mol %, 5 mg, 0.02 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (50 mg, 0.26 mmol), potassium carbonate (73 mg, 0.52 mmol) in DMSO (2 ml) was stirred for 1 min, then 4-(4-bromophenyl)-1-methyl-1H-imidazole (62 mg, 0.26 mmol) (WO91/09855) and N,N-dimethylglycine (20 mol %, 5.4 mg) were then successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 180° C. for 40 mins. The reaction mixture was partitioned between ethyl acetate and water, dried with sodium sulphate and solvent was removed by rotary evaporation and the sample purified by MDAP. The solvent was removed by rotary evaporation to give the title compound as a solid (15 mg, 16%).
Reaction SMILES: [F-].[Cs+].[OH:3][C:4]([CH:7]1[CH:10]([C:11]#[C:12][Si](C)(C)C)[NH:9][C:8]1=[O:17])([CH3:6])[CH3:5].O1CCCC1.CO>O.C(OCC)(=O)C>[OH:3][C:4]([C@H:7]1[C@H:10]([C:11]#[CH:12])[NH:9][C:8]1=[O:17])([CH3:5])[CH3:6]
Reactant: CC(C)(O)C1C(=O)NC1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#C[C@@H]1NC(=O)[C@H]1C(C)(C)O
Yield: 41.2 %

Procedure:
A solution of cesium fluoride (0.05 g) in water (3 ml) is added to a mixture of 3-(1-hydroxy-1-methylethyl)-4-trimethylsilylethynyl-2-azetidinone (0.143 g) (cis-trans mixture), tetrahydrofuran (10 ml) and methanol (3 ml). The mixture is refluxed for 0.5 hour and then poured into a mixture of ethyl acetate (100 ml and water (50 ml). The organic layer is separated, washed with aqueous sodium chloride and dried over magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 30-40% ethyl acetate/60-70% hexane). The first fraction gives 0.04 g of trans-3-(1-hydroxy-1-methylethyl)-4-ethynyl-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C:10]([CH2:39][CH:40]=O)([CH2:26][CH2:27][O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C:10]([CH2:26][CH2:27][OH:28])([CH2:39][CH2:40][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1N(CC2CC2)[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)CC1(CCO)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 94 mg (0.15 mmol) of crude 245R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde (Example 69, Step B, mixture of diastereomers), 66 μL (0.76 mmol) of morpholine, 97 mg (0.46 mmol) of sodium triacetoxyborohydride and 30 μL (0.53 mmol) of acetic acid was suspended in a mixture of 1,2-dichloroethane (6 mL) and DMF (2 mL). After being stirred at room temperature for 20 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase preparatory HPLC (SunFire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 50% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of C-3 epimers) along with the corresponding TIPS ether (mixture of C-3 epimers) and the corresponding trifluoroacetate (mixture of C-3 epimers) as a colorless oil.