Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8](F)=[C:7]([F:14])[C:6]=1[F:15])[CH3:2].N([O-])=[O:18].[Na+].Cl>CS(C)=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([OH:18])=[C:7]([F:14])[C:6]=1[F:15])[CH3:2]
Reactant: CCOC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)c(F)c(O)c(F)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
25 parts by mass of pentafluorobenzoic acid ethyl ester and 21.6 parts by mass of NaNO2 were mixed in 200 parts by mass of DMSO, and the mixture was heated. After the mixture was stirred at 50° C. for 2 hours, it was cooled to room temperature, and 520 parts by mass of ice water was added thereto. Concentrated hydrochloric acid was added to the mixture to adjust pH to 2, and the mixture was then heated to 100° C. followed by stirring for 30 minutes. The mixture was cooled to room temperature followed by extraction with ether. Organic layers were washed with water and dried with anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was washed with hexane to obtain 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid ethyl ester. 200 parts by mass of the obtained 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid ethyl ester was dissolved in 500 parts by mass of DMF, and an equivalent amount of NaH was gradually added thereto followed by stirring for 1 hour. 20 parts by mass of tetrabutylammonium iodide was added thereto, 180 parts by mass of 2-chloroethyl vinyl ether was then added thereto, and the thus obtained mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the reaction solution was added to 4,600 parts by mass of ice water followed by extraction with ethyl acetate. Organic layers were washed with water and dried with anhydrous magnesium sulfate. The solvent was removed, and the residue was subjected to silica gel column chromatography to obtain the objective polymeric compound. The NMR of the thus obtained polymeric compound is shown in FIG. 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[ClH:12]>O>[Cl:12][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10]
Reactant: Cl
Reactant: COc1cccc(C(C)O)c1
Solvent: O
Product: COc1cccc(C(C)Cl)c1

Procedure:
Into a solution of 152.1 g (1 mol) of 1-(3'-methoxyphenyl)-ethan-1-ol in 750 ml petroleum ether, one introduces hydrogen chloride during ice cooling until water separation is completed. The organic phase is then washed with ice-cold water, dried and the petroleum ether is removed in vacuo. The thermo-labile residue is used without any further purification.
Reaction SMILES: [CH3:1][NH2:2].[ClH:3].[Cl:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:7]=1>[Pd].CO>[ClH:4].[ClH:3].[CH3:1][NH:2][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1
Reactant: ClCC1=NCC(c2ccccc2)c2ccccc21
Reactant: CN
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21

Procedure:
To a stirred solution of methanol (1 liter) and monomethylamine (300 ml) maintained under nitrogen and cooled in an ice bath was added portionwise 1-chloromethyl-3,4-dihydro-4-phenylisoquinoline hydrochloride (83.0 g, 0.28 m) and the mixture heated to reflux (ca 50°-55°) for 2 hours . After cooling, the solution was poured into a pressure bottle and hydrogenated on a Parr apparatus over 5% Pd/C catalyst (5.0 g) at 40 psi for 16 hours. The catalyst was removed by filtration and the solvent evaporated to a gummy residue. This was dissolved in a mixture of methanol (200 ml) and isopropanol (200 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 64.0 g of the major isomer cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride, m.p. 276°-277°. A second crop of solid was obtained from the crystallization (26.1 g) which consisted (TLC) mostly of the minor isomer. Two recrystallizations of this crop provide the pure minor isomer trans-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride, m.p. 269°-270°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:30]2[CH:31]=[C:32]([C:36]3[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:38](=[O:39])[CH2:37][C:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:31]=1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 52.2 %

Procedure:
Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G34) (245 mg, 0.75 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (300 mg, 1.1 mmol) according to the general procedure K. Obtained as a yellow-brown foam (211 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[CH2:18])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)CCC(=O)OC)nc1
Yield: 15 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in toluene (10 mL) was added palladium; triphenylphosphane (0.101 g, 0.0871 mmol) and tributyl(vinyl)stannane (0.33 g, 0.30 mL, 1.04 mmol). The reaction mixture was refluxed overnight. Then, 0.05 eq of palladium triphenylphosphane and 0.6 eq of tritutylvinylstannane were added. Volatiles were removed under vacuum and residue taken up in acetonitrile. The acetonitrile phase was washed twice with hexane and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[(5-vinyl-2-pyridyl)amino]butanoate (compound A40) (0.20 g, 15%). 1H NMR (400 MHz, CDCl3) 8.26 (s, 1H), 8.19 (sb, 1H), 8.15 (m, 2H), 7.76 (m, 1H), 6.65 (m, 1H), 5.34 (d, 1H), 5.30 (d, 1H), 3.72 (s, 3H), 2.75 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[I-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 80 °C
Yield: 51.2 %

Procedure:
N-phenylglycine ethyl ester (781 mg, 4.3 mmol), 4-chlorobenzyl chloride (690 mg, 4.3 mmol) and sodium iodide (64 mg) were dissolved in toluene (7 mL) under argon. The reaction was heated in a graphite bath at 80° C. for 24 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with 1M HCl followed by brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification of the resultant oil by flash chromatography (10:1 hexanes/EtOAc) afforded the title compound as a green oil (669 mg, 51%). MS (ES+) m/z 304 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:18])=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[C:4]([I:18])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
To a solution of methyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (1.5 g, 40.1 mmol) in THF (110 mL) was added a 1.0 M solution of sodium hydroxide in water (50 mL). The reaction mixture was allowed to stir at rt overnight and was then allowed to settle. The two layers were separated and the aqueous solution was washed with EtOAc and acidified with 1 N HCl. A precipitate formed and was filtered to give 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.2 g, 82%). LCMS: (FA) ES+ 365.0, ES− 363.1. 1H NMR (400 MHz, d6-DMSO) δ: 3.71-3.78 (m, 4H) and 3.51-3.58 (m, 4H).
Reaction SMILES: CC(C1C=C2C[CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])(C)[CH2:16][CH2:15][CH2:14][C:13]3(C)C2CC1)C.C(OCC1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OC(C)C)(=O)CCCCCCCCCCCCC>>[CH:19](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Agent: CCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O=C(OCc1ccccc1)c1ccccc1
Product: CCCCCCCC=O

Procedure:
The foregoing formula may require a solubilizing agent, e.g., the methyl ester of dihydroabietic acid (commercial name: HERCOLYN D®, benzyl benzoate, isopropyl myristate and/or C12 -C14 isoparaffin hydrocarbons.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: OCC1CCNCC1
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)N2CCC(CO)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid (5.0 g.) is added to a solution of 4-piperidyl carbinol (6.9 g.) in 40 ml. of methylene chloride. The solution is refluxed for 2 hours, cooled to room temperature and stirred overnight. The solution is evaporated to dryness, the gummy residue dissolved in 1N sodium hydroxide, and the alkaline solution extracted twice with ether. The aqueous solution is acidified with concentrated hydrochloric acid, and the precipitate recovered by filtration. Recrystallization from ethyl acetate yields crystals, m.p. 184°-187° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:18][CH3:19])[C:13]([O:16][CH3:17])=[C:14]([Cl:15])[C:8]=2[CH:7]=1)=[O:5])C.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:15][C:14]1[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)c(OC)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc2sc(C(=O)O)cc2c(Cl)c1OC
Yield: 100.2 %

Procedure:
4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (29.5 g) was suspended in a mixture of methanol (450 ml), water (75 ml) and potassium carbonate (20.4 g) under an atmosphere of nitrogen. The reaction mixture was heated at reflux for 1 hour then cooled and poured into water (2.5 liter) containing hydrochloric acid (5M, 60 ml). The resultant white solid was filtered and dried at 65° C. under vacuum to give 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (26.8 g). A portion crystallised from dichloromethane:methanol had, m.p. 267°-270° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:34])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O)c1ccccn1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (150 mg, 0.432 mmol), picolinic acid (64 mg, 0.518 mmol) and HOBT (73 mg, 0.540 mmol) in DMF (4 mL) was added N-methylmorpholine (62 μL, 0.562 mmol) followed by EDCI HCl (108 mg, 0.562 mmol). After 2 days, the DMF was removed under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated to give a brown oil. Purification by chromatography (3-5% MeOH/CH2Cl2) afforded the title compound as a tan foam (160 mg, 0.354 mmol, 82%). The structure was confirmed by NMR and mass spectrometry. MS m/z 453 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1NC1CCCC1

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.89 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (200 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (140 mg) following general procedure E. The above ethylamide (0.42 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopentyl-3-ethyl-9-fluoro-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (13 mg). LCMS: m/z 358 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.O>C1COCC1>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([O:12][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCl
Reactant: COC(=O)c1cc(Br)c(OC)c(Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1c(C(=O)OC)cc(Br)c(OC)c1Cl
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of methyl 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoate (5.00 g) in THF (120 mL) was added sodium hydride (1.01 g) under ice-cooling, and the mixture was stirred for 1 hr under nitrogen atmosphere. To this reaction mixture was added dropwise chloromethyl methyl ether (1.63 g), and the mixture was stirred at 20° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.08 g).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15](=[O:24])[CH:16](Cl)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCOCC1>[Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15](=[O:24])[CH:16]([N:37]4[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(C(=O)N2CCc3c(cnc4[nH]nc(Br)c34)C2)c2ccccc2)CC1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a solution of 1-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-chloro-2-phenylethanone (0.38 g, 0.94 mmol) in 1,4-dioxane (15 mL) was added Hunig's Base (0.50 mL, 2.82 mmol) and tert-butyl piperazine-1-carboxylate (0.349 g, 1.88 mmol). The reaction mixture was heated at 100° C. for 16 hours. The solvent was removed under reduced pressure and the crude product was purified using (SiO2, gradient from 80% EtOAc in hexanes to 100% EtOAc in hexane) to give the desired product, tert-butyl 4-(2-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethyl)piperazine-1-carboxylate as a white solid (0.188 g, 41%). M.p.=159-161° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.95 (s, 1H), 8.41 (s, 1H), 7.46-7.2 (m, 5H), 5.07-4.65 (m, 3H), 4.0-3.7 (m, 2H), 3.3-3.1 (m, 5H), 2.95-2.85 (m, 1H), 2.53-2.3 (m, 4H), 1.35 (s, 9H); LCMS [M+H]: 555.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>C(Cl)Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:10])[C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CCCCC1=NCC(=O)N1
Solvent: ClCCl
Product: CCCCC1=NC(=CN(C)C)C(=O)N1
Yield: 77.1 %

Procedure:
A solution of 5.00 g (35.67 mmol) of 2-butyl-2-imidazolin-5-one and 7.02 g (39.24 mmol) of N,N-dimethylformamide diisopropyl acetal in 25 ml of methylene chloride was stirred at room temperature for 2.5 hours. Then, the solvent was removed on a Rotavapor, and the residue was treated with 40 ml of methylene chloride. The solution thus obtained was washed twice, each time with 10 ml of water, and dried (MgSO4) and concentrated on the Rotavapor. The residue was then dried in a high vacuum. 5.37 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one was obtained; the product had a content of greater than 90 percent, according to H-NMR: This corresponds to a yield of about 71 percent, based on the 2-butyl-2-imidazolin-5-one.
Reaction SMILES: [CH:1]([Li])([CH2:3]C)[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:17]([CH:27]([CH3:29])[CH3:28])[C:16](=[O:30])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(Br)C=C>C1COCC1>[CH2:3]([C@@H:15]1[CH2:14][C@H:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[C@:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)([CH3:19])[N:17]([CH:27]([CH3:28])[CH3:29])[C:16]1=[O:30])[CH:1]=[CH2:2]
Reactant: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Reactant: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@](C)(c2ccc(Cl)cc2)N(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
sec-Butyllithium (0.8N in cyclohexane, 0.274 mL, 0.219 mmol) was added over a period of one minute to a degassed (Argon bubbled through solution for 10 minutes at RT) solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one (Example 418, Step H, 75 mg, 0.199 mmol) in THF (6 mL) cooled by an acetone-dry ice bath. The cold bath was removed and the reaction equilibrated to room temperature over fifteen minutes. The reaction was stirred at room temperature for 30 minutes. Allyl bromide (1M in THF, 0.219 mL, 0.219 mmol) was added over one minute at room temperature. After two hours the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was diluted with ethyl acetate and separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were then dried with anhydrous magnesium sulfate and concentrated to afford a faintly orange glass. The diastereomeric products were isolated by chromatography on silica gel (12 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 20 to 80% ethyl acetate gradient in hexane to afford 25 mg of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting first on silica gel TLC plate (Rf=0.52 in 3:1 hexane:ethyl acetate eluent) and 25 mg of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting second on silica gel TLC plate (Rf=0.28 in 3:1 hexane:ethyl acetate eluent).
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>>[CH3:1][C:2]([O:10][Si:11]([CH3:12])([CH3:13])[CH3:14])(/[CH:3]=[CH:4]\[Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#CC(C)(CCCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCCCC(C)(/C=C\[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Yield: 66 %

Procedure:
The compound 7 was prepared according to the procedure for the synthesis of 3. The 3-methyl-3-trimethylsilyloxy 1-octyne (48 retool) was treated with tributyl tinhydride to yield 7 (66 %).