Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:12])([CH3:11])[CH3:10])[NH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]1[C:33](O)=[O:34])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:33]([CH:22]2[C:23]3[C:28](=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3)[CH2:29][CH2:30][N:21]2[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:34])[CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (700 mg, 3.48 mmol), 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1176 mg, 3.83 mmol), DMAP (467 mg, 3.83 mmol) and DIEA (3.04 mL, 17.39 mmol) in ethyl acetate (6.0 mL) was added T3P (6.14 mL, 10.43 mmol) at room temperature, and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with diethyl ether/hexane to give tert-butyl 1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (994.1 mg, 2.026 mmol, 58.3%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.Br[CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH2:20][Cl:21])=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1nc(NC2CCCCC2)c2[nH]cnc2n1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCn1cnc2c(NC3CCCCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-6-cyclohexylamino-purine (4 mmol), 1-bromo-2-chloroethane (8 mmol) and potassium carbonate (8 mmol, water free) in DMF (20 ml) are heated up to 45° C. and the mixture is stirred at this temperature for 5 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether and pentane is added. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 150-152° C., Rf=0.17 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:30][Mg]Br.Cl>O1CCCC1.CCOCC>[CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]([OH:21])[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(C=O)OCc1ccccc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(OCc1ccccc1)C(C)O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10 g of 3-(hexadecyloxy)-2-(phenylmethoxy)-propanal in 120 ml of dry tetrahydrofuran, under argon, at 5° C., was added dropwise 16.4 ml of 3M methyl magnesium bromide in ether at a rate to maintain the temperature below 8° C. The mixture was stirred at 5° C. for 15 minutes, then at room temperature for 3 hours, recooled to 5° C. and 50 ml of 1N hydrochloric acid was added dropwise at a rate to maintain the temperature below 10° C. The organic phase was separated and the aqueous phase extracted with ether. The ether extract was combined with the organic phase, washed with saturated aqueous sodium bicarbonate, then saturated brine, dried and taken to dryness. The residue was dissolved in petroleum ether, washed with saline, dried and taken to dryness. The residue was purified by HPLC using ether:hexane (1:5), giving 6.16 g of the desired compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:22][C@H:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[O:25])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:26][C:24](=[O:25])[C@H:23]([NH:22][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:27][CH3:28]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3cccnc3)cc2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3cccnc3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(4-(pyridin-3-yl)phenylamino)pyrazin-2-ylamino)butanamide (90 mg, 0.241 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. To the residue, CH3CN (6 mL) and H2O (8 mL) were added to induce precipitation. The precipitate was collected by filtration, and dried on vacuum to give the titled compound (40 mg). The filtrate was purified by HPLC to give additional titled compound (11 mg). MS 392.3 (M+H); UV 202.3, 235.8, 274.4, 336.1 nm; t 0.404 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:12][CH2:13][CH2:14][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11]
Reactant: BrCCBr
Reactant: FC(F)(F)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccccc1SCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)thiophenol (2.96 ml, 22 mmol; CAS Reg. No. 13333-97-6) in DMF (65 ml) were added 1,2-dibromoethane (9.67 ml, 112 mmol) and potassium carbonate (3.41 g, 25 mmol). The reaction mixture was stirred for 2 h 30 min at ambient temperature. AcOEt (30 ml) and water (30 ml) were added and the layers were separated. The aqueous layer was extracted three times with AcOEt (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give the title compound as yellow oil (6.0 g, 22 mmol; quant.) which was sufficiently pure to be used in the next step.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C.ClCCl>[OH:18][CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Temperature: 95 °C
Yield: 79.6 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), 1-bromo-3-propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95° C. for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:27])[NH:25][OH:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:35]>>[ClH:35].[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:27])[NH:25][OH:26])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:28]([N:29]([CH3:31])[CH3:30])=[O:32]
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Product: CN(C)C(=O)C(N)Cc1ccc(-c2ccc(CCC(=O)NO)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
The hydroxamate 48 (0.9 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×30 mL), decanted, and dried to yield the desired compound 49 as a white amorphous solid (0.68 g, 88%). 1H NMR (DMSO-d6): 10.45 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 4.58 (m, 1H), 3.09 (dd, J=14.0 and 8.4 Hz, 1H), 3.01 (dd, J=14.0 and 7.2 Hz, 1H), 2.84 (t, J=6.8 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 3H), 2.29 (t, J=7.2 Hz, 2H). LCMS (m/e): Obsd. [MH]+ 356, Calcd. 355.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[F:17][CH:18]1[CH:23]([OH:24])[CH2:22][CH2:21][NH:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[F:17][CH:18]1[CH:23]([OH:24])[CH2:22][CH2:21][N:20]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:16])[CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2c1
Reactant: OC1CCNCC1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(O)C(F)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.18 g of (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 0.1 g of 3-fluoropiperidin-4-ol, 0.14 mL of acetic acid was added, the mixture was stirred at room temperature for 1 hour, thereto was added 0.18 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 30 minutes. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.22 g of a brown oily substance, 1-(2-(3-fluoro-4-hydroxypiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])(=[O:22])=[O:21])=[CH:15][CH:14]=1>>[CH2:6]([N:8]([CH2:9][CH3:10])[C:3](=[O:4])[CH2:2][N:19]([C:16]1[CH:17]=[N:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[S:20]([C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[CH3:7]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2C)cn1
Product: CCN(CC)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with diethylamine and N-(6-methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:12]1[CH2:13][CH2:14][CH2:15][O:10][CH2:11]1
Reactant: Oc1cc(F)cc(F)c1
Reactant: OC1CCCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(OC2CCCOC2)c1
Yield: 75.8 %

Procedure:
A solution of 3,5-difluorophenol (1.15 g, 8.81 mmol), tetrahydro-2H-pyran-3-ol (0.900 g, 8.81 mmol), triphenylphosphine (2.31 g, 8.81 mmol) and DIAD (1.74 mL, 8.81 mmol) in THF (10 mL) was stirred overnight. The solution was then concentrated under reduced pressure and the residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-30%). The purification afforded 1.43 g (75.8%) of the sub-title compound as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:7][CH2:6]CC1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[CH3:19]O>>[CH3:12][CH2:13][CH2:8][CH2:9][CH2:10][CH3:11].[CH:7]([O:3][CH:8]([CH3:13])[CH3:18])([CH3:6])[CH3:19]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)OC(C)C
Product: CCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
19.3 g (511 mmol) of NaBH4 were added to a solution of 78.5 g (341mmol) of the isomer mixture 3/3a in 700 ml of a solvent mixture of tetrahydrofuran/analytical grade methanol (2:1) at room temperature. After the mixture had been stirred at room temperature for 2 hours, 120-130 mL of half-concentrated HC1 were added, and the mixture was extracted with ether. The combined organic phases were dried with Na2SO4. The residue which remained after the solvent had been stripped off was taken up in 500 ml of methylene chloride, and the mixture was heated under reflux with 6.5 g (34mmol) of p-toluenesulfonic acid for 15 minutes. The residue which remained after the solvent had been stripped off was chromatographed on 1.5 kg of silica gel 60.56 g of the isomer mixture 4/4a were able to be isolated in the form of a colorless oil with a mobile phase mixture of hexane/diisopropyl ether 20:1. The overall yield was 86%.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[S:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]=[C:10]1[C:18](=[O:20])[CH3:19]>CN(C=O)C.CCOC(C)=O.O>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:19]/[C:18]([C:10]1[S:9][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]=1)=[O:20]
Reactant: CC(=O)c1cc2cnccc2s1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/C(=O)c1cc2cnccc2s1
Temperature: 70 °C

Procedure:
N,N-dimethylformamide-dimethylacetal (DMF-DMA) (9.5 ml) was added to a solution of 1-(thieno[3,2-c]pyridin-2-yl)ethanone (3.17 g) in 20 mL DMF. The reaction was heated to 70° C. overnight. The reaction was then cooled to room temperature. The DMF was removed on a rotary evaporator to obtain a dark brown orange solid. The residue was diluted with EtOAc and water. A large amount of yellow solid was evident. This was collected by filtration (3.54 g). This solid was dried in a 50° C. vacuum oven.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.N1C=C[CH:13]=[CH:12][C:11]=1[C:16]1C=CC=CN=1.C([Li])CCC.CC(CC)C(Cl)=O.Cl>O1CCCC1>[CH3:16][CH:11]([CH2:12][CH3:13])[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCC(C)C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)CC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of monoethyl malonate (49.5 mL, 0.42 mol) and a few milligrams of 2,2′-bipyridyl in tetrahydrofuran at −70° C. was added 2.5 M n-butyl lithium in hexanes (0.34 L, 0.84 mol) dropwise over approximately 1.5 hours. Then 2-methylbutyryl chloride (26 mL, 0.21 mol) was added dropwise. The mixture was allowed to warm to ambient temperature and was then poured into 1 N hydrochloric acid. The mixture was extracted three times with ether and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting oil was purified by vacuum distillation (boiling range 75-85° C.) to afford ethyl 4-methyl-3-oxohexanoate (36.4 g, 100%). 1H-NMR (400 MHz, DMSO-d6) δ 4.06 (q, J=7 Hz, 2H), 3.60 (s, 2H), 2.57-2.49 (m, 1H), 1.64-1.53 (m, 1H), 1.36-1.26 (m, 1H), 1.15 (t, J=7 Hz, 3H), 0.97 (d, J=7 Hz, 3H), 0.78 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Br:32]N1C(=O)CCC1=O.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC>C(Cl)(Cl)Cl>[Br:32][CH:23]1[C:9]2[C:10](=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=3)[N:8]=2)[N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:22]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3)cc1
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3Br)cc1

Procedure:
To a stirred solution of tert-butyl 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1) (530 mg, 1.275 mmol) in chloroform (10 ml) was added N-bromosuccinimide (272 mg, 1.531 mmol) followed by lauroyl peroxide (50.8 mg, 0.128 mmol) and the mixture was heated to reflux for 1 hour. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound which was used directly into the next step
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(-c2ccc(C=O)nc2)c1
Temperature: 77.5 °C
Yield: 64.8 %

Procedure:
To a solution of 5-bromopicolinaldehyde (1.0 g, 5.43 mmol) in toluene (10 mL) and ethanol (8 mL) was added (3-methoxyphenyl)boronic acid (1.2 g, 8.1 mmol), 2M sodium carbonate (3.4 g, 32.6 mmol, 8 mL water), Pd(PPh3)4 (0.228 g, 0.25 mmol) under argon. The resulting mixture was heated at 75-80° C., for 4 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate, which was distilled off to obtain the crude product. The crude product was purified by flash chromatography (100-200 microns; 15% ethyl acetate in hexane) to afford 5-(3-methoxyphenyl)picolinaldehyde (0.75 g, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.14 (s, 1H), 8.33 (d, 1H), 7.98 (d, 1H), 7.45 (t, 1H), 7.38 (d, 2H), 7.03 (d, 1H), 3.84 (s, 3H); LC-MS m/z calculated for [M+H]+ 214.08 found, 214.3.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][NH:40]2)=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:60]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:70][C@H:69]([C:71](O)=[O:72])[CH2:68]1)([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][N:40]2[C:71]([C@H:69]2[CH2:68][C@H:67]([CH2:66][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:74])[CH2:70]2)=[O:72])=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (86 mg, 0.23 mmol) was added to a solution of (R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (70 mg, 0.19 mmol), DIEA (0.064 mL, 0.38 mmol) and trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (42.3 mg, 0.20 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give tert-butyl 2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (92.3 mg, 0.162 mmol, 86%) as a white solid.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([O-:18])=[O:17])[CH:7]=1)(O)=O.[C:19]([O:23][CH3:24])(=[O:22])C=C.[CH3:25]O>C(N(C(C)C)C(C)C)C>[CH3:24][O:23][C:19]([CH2:1][CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([O:18][CH3:25])=[O:17])[CH:7]=1)=[O:22]
Reactant: CO
Reactant: O=C(O)CSc1cc(C(=O)[O-])nc2ccccc12
Reactant: C=CC(=O)OC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cc(C(=O)OC)nc2ccccc12

Procedure:
Methyl 4(lH)-thioquinolone-2-carboxylate (1.0 equivalent) from example 24 is suspended/dissolved in MeOH containing a catalytic amount of ethyldiisopropylamine. To this mixture is added methyl acrylate (3 equivalent) and the whole is refluxed for 3 hours. The bulk of the solvent is removed under vacuum and the residue is recrystallized from ethyl acetate/ hexane to give methyl 4-(2-methoxycarbonyl-ethylthio)-quinoline-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.Cl.[NH2:23][CH2:24][C:25](=[O:38])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1>O.C1COCC1.CCN(CC)CC>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[O:27][CH2:26][C:25](=[O:38])[CH2:24][NH:23][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: COc1ccc(OCC(=O)CN)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(OCC(=O)CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a THF (14 ml) solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.557 g) and Et3N (0.790 ml), ethyl chloroformate (0.295 g) was added over an ice bath, followed by stirring at the same temperature for 30 minutes. The reaction mixture was added at 0° C. to a THF (7 ml) solution of the compound (0.701 g) obtained in Example 19-(3) and the mixture was stirred at room temperature for 17 hours. After adding water and performing extraction with AcOEt, the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.540 g, brown amorphous.)