Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[F:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:28]2[C:33]([NH2:34])=[CH:32][N:31]=[C:30]3[CH:35]=[CH:36][S:37][C:29]=23)[CH2:23][CH2:22]1>O1CCCC1.C(O)C>[F:19][CH2:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([N:27]2[C:28]3=[C:29]4[S:37][CH:36]=[CH:35][C:30]4=[N:31][CH:32]=[C:33]3[N:34]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:25][CH2:26]1
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CF)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CF)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.184 g, 2.07 mmol) and triethyloxonium tetrafluoroborate (0.371 g, 1.95 mmol) in tetrahydrofuran (2.8 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (1.2 mL) and added to a suspension of N7-[trans-4-(fluoromethyl)cyclohexyl]thieno[3,2-b]pyridine-6,7-diamine (0.18 g, 0.64 mmol) in ethanol (4.3 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.10 g, 50%). LCMS calculated for C17H21FN3OS (M+H)+: m/z=334.1. Found: 334.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][C:10](C)([CH3:14])[C:11](O)=O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[NH4+].[OH-]>S(=O)(=O)(O)O.O.[N+]([O-])([O-])=O.[Ag+]>[C:10]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][N:5]=1)([CH3:14])([CH3:11])[CH3:9]
Reactant: CC(C)(C)C(=O)O
Reactant: N#Cc1cccnc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To a mixture of 3-cyanopyridine (10 g, 96 mmol), trimethylacetic acid (9.8 g, 96 mmol) and silver nitrate (1.63 g, 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70° C. was added dropwise a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml). After complete addition the mixture was stirred at 70° C. for 2 hours. The mixture was cooled and basified by the addition of 33% aqueous NH4OH, and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (Na2SO4) and evaporated to give the title compound (15.6 g, 100%).
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][NH2:22]>[Pd].CO>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][NH:22][CH:2]1[CH2:5][CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: COC(=O)CC1CC(=O)C1
Reactant: COc1ccc(CN)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CC(NCc2ccc(OC)cc2OC)C1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To methyl 2-(3-oxocyclobutyl)acetate (426 mg) and (2,4-dimethoxyphenyl)methanamine (501 mg) in a flask was added MeOH (20 mL) and Pd/C (10%, 100 mg). The reaction mixture was stirred under hydrogen atmosphere for overnight. Catalyst was removed by filtration through the Celite pad. Removal of the solvent afforded the crude product (850 mg) which was used directly to the next step without further purification.
Reaction SMILES: [CH3:1][PH:2](=[O:11])[C:3]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH3:4].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][P:2](=[O:11])([CH3:12])[C:3]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(C)(OCC)[PH](C)=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C)(OCC)P(C)(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methyl(1,1-diethoxyethyl)phosphine oxide, prepared as described in EP 0 501 702 (89.3 g, 0.5 mol) in THF (900 ml) at -78° C. under an atmosphere of argon is added a solution of potassium bis(trimethylsilyl)amide (688 ml, 0.521 mol) in toluene over 15 minutes. After stirring for 1 hour at -78° C., methyl iodide (34 ml, 0.55 mol) is added over 5 minutes and stirring at -78° C. continued for 1 hour. The reaction is then quenched by the addition of a 1% solution of NaH2PO4 (450 ml) and slow warming to room temperature. Concentration gives an aqueous suspension to which dichloromethane (600 ml) is added. The organic phase is separated and washed with 1% NaH2PO4 (500 ml), followed by water (500 ml). Drying over MgSO4, concentration and purification by flash vacuum silica column chromatography (chloroform-ethanol 40:1) gives a clear oil which is distilled to give dimethyl (1,1-diethoxyethyl)phosphine oxide. b.p. 100° C. at 0.05 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:10]([OH:13])(=[O:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:3]1[CH2:4][CH:11]([C:10]([OH:13])=[O:12])[CH2:6][CH2:7][C:2]2=1
Reactant: CC(=O)O
Reactant: NNc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)C1CCc2c([nH]c3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-fluorophenyhydrazine (0.90 g, 7.14 mmol) was dissolved in glacial acetic acid (25 mL) under a nitrogen atmosphere and added dropwise to a refluxing solution of 3-cyclohexanonecarboxylic acid ethyl ester (1.73 g, 10 mmol) dissolved in glacial acetic acid (15 mL). After the addition was complete, the solution was heated under reflux for 1 hr, cooled to room temperature and allowed to stir overnight. The orange solution was evaporated under reduced pressure to give a yellow-brown solid. The solid was suspended in 10% sulfuric acid and heated under reflux for 5 hrs, cooled to room temperature and allowed to stir overnight. The brown solid was collected by filtration and recrystallized from acetic acid and water to give the compound I (1.21 g), mp: >200° C. MS [M−H]− m/z 232.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Cl[CH2:36][C:37](=[O:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:36][C:37](=[O:39])[CH3:38])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCOc1c(OCC(C)=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (183 mg, 0.37 mmol), chloroacetone (0.033 mL, 0.41 mmol) and potassium carbonate (162 mg, 1.17 mmol) in DMF (3 mL) was stirred at room temperature overnight. Ethyl ether and water were added and the aqueous layer was re-extracted with ether (2 x). The organic extracts were combined, dried, and evaporated to a syrup, which was purified by preparative TLC (hexane-ethyl acetate; 1:2, v/v) to give the title compound Rf 0.33; NMR (CDCl3) δ 1.06 (t, CH2CH2CH3), 2.33 (s, CH2COCH3), 3.66 (q, SO2CH2CH2), 3.97 (b, SO2CH2CH2) 4.20 (t, CH2CH2CH3), 4.68 (s, CH2COCH3), 5.12-5.28 (m, H-2 & H-5), 6.62 (s, 2 H, C5ArH), 7.17 & 7.56 (2 d, 2 H, C2ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][S:19]C(=O)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][SH:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)SCCC1CCCCN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCCC1CCS
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-acetylsulfanylethyl)-piperidine-1-carboxylic acid benzyl ester (174 mg in 5.0 mL methanol) was added 2.16 mL of a 0.5N solution of sodium hydroxide and the mixture stirred at room temperature for 30 minutes. At this time the reaction was diluted with ethyl acetate and quenched by the addition of 0.1N hydrochloric acid. The organic portion was washed sequentially with 0.1N hydrochloric acid, water and brine then dried over magnesium sulfate. Concentration in vacuo gave the crude title compound.
Reaction SMILES: [C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]3)=[C:35]([F:47])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH:8]([O:10][C:11](=[O:25])[C@@H:12]([NH:17]C(OC(C)(C)C)=O)[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH3:9])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:61]>C(OCC)C>[ClH:61].[C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][S:42](=[O:45])(=[O:46])[CH2:43][CH2:44]3)=[C:35]([F:47])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH:8]([O:10][C:11](=[O:25])[C@@H:12]([NH2:17])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
2(S)-tert-butoxycarbonylamino-3(S)-methyl-pentanoic acid 1-(acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-ethyl ester (12j) (1.00 g, 1.46 mmol), anisole (0.24 g, 2.188 mmol) and THF (30 mL) are cooled in an ice bath. Hydrochloric acid (4 N in dioxane, 10.94 mL) is added dropwise. The solution is stirred in an ice bath for 30 min and then at RT for 4 h. The reaction mixture is re-cooled to 0° C. and ethyl ether is added. The resulting solids are collected by filtration and washed with a cold ethyl ether/ethyl acetate mixture to afford the title compound. Isolated yield: 64%. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (br s, 3H), 7.43-7.39 (m, 1H), 7.36 (t, 1H), 7.22 (d, 1H), 6.85-6.79 (m, 1H), 4.77-4.71 (m, 1H), 4.13-4.00 (m, 2H), 3.96 (dd, 1H),3.88-3.84 (m, 1H), 3.80-3.74 (m, 1H), 3.51-3.28 (m, partially obscured by water, 2H), 3.18-3.12 (m, 1H), 3.04 (d, 2H), 2.40 (d, 3H), 2.08 (q, 2H), 1.97-1.93 (m, 2H), 1.90-1.84 (br m, 1H), 1.50 (dd, 3H), 1.44-1.36 (m, 1H), 1.26-1.14 (m, 1H), 0.88 (dd, 3H), 0.84-0.79 (m, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:12][C:11]([Si:8]([CH3:10])([CH3:9])[O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 14 g of (S)-3-hydroxy-2-pyrrolidinone, 45 g of tert-butyldimethylsilyl chloride, 50 ml of triethylamine and 500 ml of dichloromethane was stirred overnight. The solution was washed four times with water, once with brine, dried and concentrated in vacuo. The residue was dissolved in 500 ml of methanol, refluxed overnight and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 21.5 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone; [α]D260 =-52° (dichloromethane); mp 48°-49° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH:10]=[CH:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(C=C[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl5-[5-(5-phenylpentanoyl)furan-2-yl]pent-1-enylphosphonate (127.8 mg, 0.23 mmol) obtained in Example (29c) in ethanol (2.3 ml) was added chlorotris(triphenylphosphine)rhodium(I) (22.0 mg, 0.024 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 8 hours. After cooling, to the reaction mixture was furthermore added chlorotris(triphenylphosphine)rhodium(I) (21.5 mg, 0.023 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 8 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using ethyl acetate as the eluent to afford the crude product (142.1 mg). Furthermore, the crude product obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (109.5 mg, yield: 85%).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][N:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:26]/[N:27]3[CH2:31][C:30](=[O:32])[NH:29][C:28]3=[O:33])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Reactant: NN1CC(=O)NC1=O
Solvent: CO
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 23.7 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (20 mg, 0.059 mmol) and 1-aminoimidazolidine-2,4-dione (13.6 mg, 0.12 mmol) was stirred in MeOH at room temperature over a weekend. Light yellow solid was filtered to give the title compound (6 mg, 0.014 mmol). The filtrate was purified on HPLC (acidic with 0.05% TFA) to give the title compound as TFA salt (8 mg, 0.0145 mmol). The combined yield was 48%. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1H), 9.02 (d, 1H), 8.55 (d, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.18 (d, 1H), 8.0 (s, 1H), 7.98 (s, 1H), 7.65 (d, 1H), 4.54 (s, 2H), 2.24 (s, 3H). LCMS (method B): [MH]+=437.1, tR=2.06 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[N:19]2CC2C=CC(OC)=CC=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]>FC(F)(F)C(O)=O.O>[CH2:1]([O:3][C:4](=[O:42])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[NH:19]2)=[CH:13][CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2Cc2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2)cc1
Yield: 60.5 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (2.51 g, 4.36 mmol) in trifluoroacetic acid (70 mL) was stirred at room temperature under N2 for 1 h. The reaction was diluted with water, and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 98:2 CH2Cl2:MeOH to afford 1.20 g (60%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C26H35N2O5 (M+1) 455. Found m/z 455 (100%). 1H NMR.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].FC(F)(F)S(O[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([C:32]1[N:36]3[CH:37]=[CH:38][C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:40][C:35]3=[N:34][CH:33]=1)[CH:28]=[CH:27]2)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:15][C@H:3]1[C@@H:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[C:29]([C:32]2[N:36]4[CH:37]=[CH:38][C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:40][C:35]4=[N:34][CH:33]=2)[CH:28]=[CH:27]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OS(=O)(=O)C(F)(F)F)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCCOc1ccn2c(-c3ccc4cccc(N[C@H]5CCN(C(=O)OC(C)(C)C)C[C@H]5F)c4n3)cnc2c1
Yield: 109.4 %

Procedure:
(cis)-tert-Butyl 4-amino-3-fluoropiperidine-1-carboxylate (0.040 g, 0.18 mmol) was combined with 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yl trifluoromethanesulfonate (Steps 1A-1D; 0.065 g, 0.140 mmol), micronized Cs2CO3 (0.064 g, 0.197 mmol), BINAP-racemic (0.0087 g, 0.014 mmol) and Pd2dba3 (0.0064 g, 0.0070 mmol). The mixture was treated with toluene (0.75 mL), degassed with argon and heated to reflux for 16 hours. The reaction was cooled, diluted with CHCl3 and purified by silica gel chromatography, eluting with a gradient from 1-20% (6% NH4OH in MeOH)/ethyl acetate to provide the desired product (82 mg). MS ESI (+) m/z 536.1 (M+1) detected.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.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>[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)c1cccc(Br)n1
Reactant: CN1CCNc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCNc2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Temperature: 100 °C
Yield: 38.3 %

Procedure:
Tert-butyl 6-bromopicolinate (25A) (157 mg, 0.61 mmol) in 1,4-dioxane (1.0 mL) was added dropwise to 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoxaline (25F) (167 mg, 0.61 mmol), K2CO3 (207 mg, 1.52 mmol), tetrabutylammonium bromide (19.5 mg, 0.061 mmol), and dichlorobis(triphenylphosphine)palladium(II) (17.9 mg, 0.024 mmol) in 1,4-dioxane (2.0 mL) and water (1.0 mL) at rt. The mixture was microwave (150W) heated to 100° C. for 50 minutes, cooled to 20° C., diluted with water and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-70:30, to provide 76 mg (38%) of the desired product tert-butyl 6-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25G): 1H NMR (300 MHz, MeOD) δ 7.84-7.78 (3H, m), 7.35 (1H, d), 7.30 (1H, d), 6.62 (1H, d), 3.41 (2H, t), 3.31 (2H, t), 2.92 (3H, bs), 1.64 (9H, s).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][C:43]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52])=[N:44]2)=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][C:43]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52])=[N:44]3)=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCOc1ccc2ccc(CCl)cc2n1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc2n1

Procedure:
Analogously to Method D, 0.300 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.181 g of 7-chloromethyl-2-(3-methoxy-propoxy)quinoline are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=6.33.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([F:23])[CH:14]=[C:15]([CH:20]4[CH2:22][CH2:21]4)[CH:16]=3)[C:11]2=[O:24])[C:3]=1[CH:4]=[O:5].CC(O)C.[BH4-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([F:23])[CH:14]=[C:15]([CH:20]4[CH2:22][CH2:21]4)[CH:16]=3)[C:11]2=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1c(Cl)cccc1-n1ccc2cc(C3CC3)cc(F)c2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=c1c2c(F)cc(C3CC3)cc2ccn1-c1cccc(Cl)c1CO
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-chloro-6-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)benzaldehyde (64.6 g, 0.19 mol) was dissolved in DCM (650 ml), then, IPA (325 ml) was added to the solution. At 4° C., NaBH4 (7.15 g, 0.19 mol) was added to the reaction mixture portion wise, then the resulting solution was stirred for 1 hr. The reaction was quenched by water (170 mL), then the mixture was filtered through Celite pad. DCM layer was collected by phase separation, and DCM was distilled out and IPA was added in the same time. The desired product was crystallized out from IPA, collected by filtration, and washed with cold IPA. The filter cake was dried under vacuum at 70° C. to afford 56.3 g of the title compound (86.6% isolated yield) as a white solid. MS (ESI) 343, 345 (M+H)+.