Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:15])[C:7]=1[CH2:8][CH2:9][C:10]([O:12]CC)=O.[Li]CCCC>C1COCC1>[Br:15][C:6]1[C:7]2[CH2:8][CH2:9][C:10](=[O:12])[C:2]=2[CH:3]=[N:4][CH:5]=1
Reactant: CCOC(=O)CCc1c(Br)cncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCc2c(Br)cncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 3-(3,5-dibromopyridin-4-yl)propanoate (30 g, 89 mmol) in THF (50 mL) was added slowly n-BuLi (71.2 mL, 178 mmol, 2.5 M in hexane) at −78° C. The resulting mixture was stirred for another 30 min at −78° C. before it was quenched with water, and extracted with EtOAc (500 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=5:1) to give title compound (7 g, 37%) as a white solid. MS: 211.8 (M+H+, 1 Br).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1.[ClH:39].CCOCC>O1CCOCC1>[ClH:39].[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn(-c4ccc(OC(F)F)cc4)nn3)c(F)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cn(-c2ccc(OC(F)F)cc2)nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylate (62 mg, 0.116 mmol) was dissolved in dioxane (0.6 ml) and a solution of HCl in dioxane (4M, 0.35 ml, 1.39 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (53 mg, 97%) as a white solid. MS (ISP): 434.4 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[N:18][N:17]=[N:16]2)=[CH:11][C:10]=1[F:21])C1C=CC=CC=1>C(O)C.[Pd]>[F:21][C:10]1[CH:11]=[C:12]([N:15]2[C:19]([CH3:20])=[N:18][N:17]=[N:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1nnnn1-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(O)c(F)c1
Yield: 114.6 %

Procedure:
A suspension of 1-(4-benzyloxy-3-fluoro-phenyl)-5-methyl-1H-tetrazole (4.6 g) in ethanol (300 ml) was hydrogenated at room temperature and pressure over a pre-reduced suspension of palladium-on-carbon (10% paste, 1.4 g) until uptake ceased. The catalyst was filtered off and the filtrate evaporated to give the title compound as a cream solid (3.6 g). T.l.c. (Dichloromethane/methanol (995:5)), Rf 0.45.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=O)[C:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10]([C:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH3:13])[CH3:12])=[N:9][C:3]=2[CH:4]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Br)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(NC(=O)OCc1ccccc1)c1nc2cc(Br)ccc2[nH]1
Yield: 23.2 %

Procedure:
A solution of benzyl {2-[(2-amino-5-bromophenyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (Preparation 28, 80 g, 0.2 mol) and p-TsOH (34 g, 0.2 mol) in anhydrous MeOH (1 L) was heated to reflux for 48 hours. The reaction was cooled, concentrated in vacuo and partitioned between DCM (1 L) and water (500 mL). The organic layer was collected, washed with water (200 mL), brine (200 mL), dried over Na2SO4 and concentrated to low volume to enable the precipitation of a yellow solid. The solid was collected and dried to afford the title compound (18 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:20][C:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:35][CH2:36]O)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.[OH-].[Na+]>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:23]3[C:21](=[O:22])[N:20]([C:5]4[CH:6]=[CH:7][C:8]([O:9][Si:10]([CH:11]([CH3:12])[CH3:13])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:36]=[CH:35][C:24]=3[N:25]=2)=[CH:33][CH:32]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
Treat a solution 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (3-methoxy-4-triisopropylsilanyloxy-phenyl)-amide (1.0 g, 1.79 mmol) in CH2Cl2 (30 mL) with Dess-Martin periodinane (1.13 g, 2.67 mmol). Stir at room temperature for 18 h, dilute with 1N NaOH, and extract with CH2Cl2 (2×). Dry, filter, and concentrate the organic solution and purify the crude material by flash chromatography, using a gradient of 0-10% MeOH in CH2Cl2 to give the title compound (0.47 g, 48%). MS (ES+) 541.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.4 Hz), 7.41 (d, 1H, J=7.5 Hz), 6.93 (m, 3H), 6.81 (dd, 1H, J=8.4, 2.6 Hz), 3.80 (s, 3H), 1.25 (m, 3H), 1.09 (d, 18H, J=7.5 Hz).
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1.C(O)(C)C>[Pd].C(O)C>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Yield: 75.2 %

Procedure:
Hydrochloric acid (2.6 g) and 10% palladium on carbon (1.1 g, 50% wet) were added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (10 g) in aqueous ethanol (Ethanol:Water::96 mL:26 mL) at ambient temperature. The reaction mass was flushed with nitrogen twice and hydrogenated at about 35° C. to 40° C. under a hydrogen pressure of about 0.5-1 kg/cm2 for about 1 hour. The reaction mass was filtered and washed with 10% aqueous ethanol (10 mL). Ethanol was distilled out completely under reduced pressure at about 30° C. to 35° C. The residue was dissolved in water (6.25 mL) and stirred to obtain clear solution. Iso-propanol (56 mL) was added slowly over a period of about 1 hour. The reaction mass was cooled to about 10° C. to 15° C., maintained for about 1 hour, filtered, washed with 10% aqueous iso-propanol (10 mL) followed by washing with iso-propanol (10 mL) and dried to obtain valganciclovir hydrochloride (5.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[C:5]([CH3:12])=[CH:4][N+:3]=1[O-:13].[ClH:14].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[Cl:14][C:6]1[C:5]([CH3:12])=[CH:4][N+:3]([O-:13])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cl
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2,3,5-trimethyl-4-nitropyridine 1-oxide (850 g, 4.67 mol) was charged with water (400 g) and 36% concentrated hydrochloric acid (1.69 kg), and the resultant solution was heated to 70° C. The solution was then charged with N,N-dimethylformamide (115 mL) and heated to 100° C. Once the reaction had finished, the solution was cooled to 20° C. and then charged into a mixture of potassium carbonate (1.40 kg) and water (7 L). The resultant mixture was extracted with chloroform (1.0 L×3), dried over sodium sulfate and then concentrated. The resultant crude product was stirred for 2 hours in a mixed solution of diisopropyl ether (500 mL) and n-hexane (1.0 L), and the resultant solution was then filtered with suction. The resultant wet substance was dried overnight under vacuum to obtain 666.4 q of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].Cl>O1CCCC1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(O)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (0.70 g, 0.0036 mol) with 1.0 M of L-Selectride® in tetrahydrofuran (18 mL) was microwave irradiated at 120° C. for 2 hours. The completion of the reaction was achieved after LCMS indicated that the starting material was consumed. Then reaction mixture was acidified (pH=2) with concentrated HCl solution. The mixture was concentrated and the residue was diluted with water and stirred at rt to precipitate the white solid product, which was filtered and dried under vacuum to give the desired product. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[CH:15])[CH:5]=[CH:4][C:3]1=2.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C.Cl>CN(C)C=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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:24]3[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(S(C)(=O)=O)cc3)ccc21
Yield: 117.2 %

Procedure:
3.2 g (0.015 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetylene, 3 g (0.0128 mol) of 4-methylsulfonylbromobenzene, 12.7 g (0.126 mol) of triethylamine, 12.3 mg (0.047 mmol) of triphenylphosphine, 1.9 mg (0.0027 mmol) of bis(triphenylphosphine)palladium(II) chloride and 6.5 mg (0.034 mmol) of copper(I) iodide in 4 ml of dry dimethylformamide were refluxed under nitrogen. After the reaction was complete, the cooled mixture was poured into water, and the mixture was adjusted to pH 5 with dilute hydrochloric acid and extracted with ether. The organic phase was washed with water, dried over sodium sulfate and evaporated to give 5.5 g of a residue which was recrystallized from methanol to provide 3.5 g of the title compound. Melting point: 153°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]I)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2C=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A suspension of 1-tert-butoxy-4-(4-iodobutyl)benzene (10.0 g), 2-formyl-1H-imidazole (3.47 g) and potassium carbonate (4.16 g) in DMF (100 ml) was stirred at 70° C. for 17 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazole-2-carbaldehyde as a pale brown oil. Sodium borohydride (1.25 g) was added to a solution of the compound in methanol (200 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water, concentrated and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; hexane:ethyl acetate=1:3 to ethyl acetate) to give the titled compound (8.29 g) as a colorless amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I-:24].[K+].N([O-])=O.[Na+].C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:24])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1ccc(I)cc1Cl
Yield: 73.4 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)aniline (450 mg, 2.30 mmol) and toluene 4-sulfonic acid (1.19 g, 6.92 mmol) in CH3CN (10 mL) was added a solution of potassium iodide (955 mg, 5.76 mmol) and sodium nitrite (318 mg, 4.61 mmol) in water (1.8 mL) over 15 min at 10° C., then after 20 min the reaction mixture was poured onto water, neutralized with sat. aq. NaHCO3 solution, treated with 2 M aq. sodium thiosulfate solution (6 mL), and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (517 mg) as a light brown oil, which was directly used in the next step.
Reaction SMILES: C([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14](=[O:19])[CH2:15][CH2:16][C:17]=2[CH:18]=1)(C)(C)C.[O:21]1CCOCC1.[OH-].[Na+].Cl>CO>[NH2:13][C:12]1[N:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:20])=[CH:18][C:17]=1[CH2:16][CH2:15][C:14]([OH:19])=[O:21]
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(/C=C/C(=O)O)cc1CCC(=O)O
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid tert-butyl ester (0.86 g, 3.0 mmol) was stirred in methanol (10 mL), dioxane (10 mL) and aq. NaOH (15 mL of a 1 N solution, 15 mmol) for 4 days. The clear solution was neutralized with aq. HCl (15 mL of a 1 N solution, 15 mmol) and stirred for 20 min. The white precipitate was collected by filtration to give (E)-3-[6-amino-5-(2-carboxy-ethyl)pyridin-3-yl]acrylic acid (0.57 g, 78%): MS (ESI) m/e 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1)=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=3.[O-2].[Ba+2].[CH2:20](Br)[C:21]#[CH:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:16])[N:13]([CH2:22][C:21]#[CH:20])[C:14]=2[CH:15]=1)=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=3
Reactant: C#CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccc(Cl)cc12
Agent: [Ba+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c2cc(Cl)ccc2c2ccc(Cl)cc21

Procedure:
A mixture of 5 g (19 mmol) of 3,8-dichloro-6(5H)phenanthridinone, 3,2 g (21 mmol) of barium oxide and 1.9 ml (21 mmol) of propargyl bromide in 40 ml of dimethylformamide was heated on the steam bath for 1 hour. After cooling, the product was precipitated by addition of water, filtered off and washed with water. It was dissolved in methylene chloride and the solution was dried and evaporated. The residue was chromatographed over 150 g of silica gel using 10% (v/v) of hexane in methylene chloride. The fractions containing the product were combined and evaporated. The solid residue was recrystallized from ethanol to give colorless crystals of 3,8-dichloro-5-(2-propynyl)-6(5H)-phenanthridinone with m.p. 248°-250°.
Reaction SMILES: CC(O)C.O.NN.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)=[C:13]([CH:26]=1)[CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)=[C:13]([CH:26]=1)[CH2:14][NH2:15]
Reactant: Cc1cc(COc2ccc(Cl)cc2CN2C(=O)c3ccccc3C2=O)on1
Agent: NN
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(Cl)cc2CN)on1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a flask containing anhydrous 2-propanol (40 mL), hydrazine hydrate (4 mL, and anhydrous THF (60 mL), at room temperature, was added 2-{5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzyl]isoindole-1,3-dione (5 g, 13 mmol). The reaction was stirred at 50° C. for 3 h. The solids were filtered and washed with THF. The filtrate was concentrated, dissolved in ether (100 ml) and washed with 1N NaOH (1×) and brine, dried (MgSO4), filtered and concentrated to afford the title product as a solid.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Yield: 80.7 %

Procedure:
2-(3,4-dimethyl-benzoyl)-3-phenylamino-acrylic acid methyl ester 2a(7.00 g, 22.6 mmol) (prepared as described by Silin, O. V.; et al. Heterocycles, 2004, 63, 1883-90) was heated at 260° C. in 150 mL of diphenyl ether for 6 h, then cooled down and 100 mL of hexane was added to the reaction solution. The mixture was filtered and the solid was washed with hexane to give 5.06 g of 3-(3,4-Dimethyl-benzoyl)-1H-quinolin-4-one 3a as off-white crystals: LC-MSD, m/z for C18H15NO2 [M+H]+=278.4; HPLC retention time: 1.7 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[C:13]3[CH2:14][CH:15]([CH:17]([F:19])[F:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1>CCOC(C)=O.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([OH:22])[C:13]3[CH2:14][CH:15]([CH:17]([F:19])[F:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(C(F)F)C3)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
10% Pd on Carbon (20 mg) was added to a solution of 4-benzyloxy-2-difluoromethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (222) (186 mg, 0.466 mmol) in EtOAc (5 mL). The mixture was stirred at room temperature with a H2 balloon overnight, then filtered through Celite, washed with EtOAc, and concentrated to give yellow solid (143 mg, 99% yield). 1H NMR (400 MHz, CDCl3) δ 9.44 (br. s., 1 H) 7.27 (br. s., 1 H) 7.07 (br. s., 1 H) 6.90 (br. s., 1 H) 6.79 (br. s., 1 H) 5.67-6.04 (m, 1 H) 4.94 (br. s., 1 H) 3.73 (br. s., 3 H) 3.14-3.37 (m, 2 H); LCMS for C14H13F2N3O3 m/z 310.00 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10]>O1CCCC1>[CH:1]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Add cyclopropylmagnesium bromide (4.8 g, 33.0 mmol) to a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (7.5 g, 27.5 mmol) in tetrahydrofuran (120 mL) at 0° C. Remove the cooling bath and stir at ambient temperature overnight. Add an additional cyclopropylmagnesium bromide (20 mL) and stir an additional 4 hours. Pour into a solution of saturated sodium bicarbonate and extract once with diethyl ether and once with EtOAc. Combine organic extracts, dry over sodium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify via flash column chromatography using a gradient of 0-40% ethyl acetate in hexane to give the title compound (6.4 g, 91.7%). MS (m/z): 198 (M+1-tBu).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH2:4][O:3]1.ClC(N(C)C)=C(C)C.[CH3:20][NH:21][O:22][CH3:23].N1C=CC=CC=1>C(Cl)Cl.O.C(=O)(O)[O-].[Na+]>[CH3:23][O:22][N:21]([CH3:20])[C:8](=[O:10])[C@@H:7]([C@H:5]1[CH2:4][O:3][C:2](=[O:1])[NH:6]1)[CH3:11]
Reactant: CNOC
Reactant: C[C@@H](C(=O)O)[C@H]1COC(=O)N1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)[C@H](C)[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 195.4 %

Procedure:
To a mixture of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.1 g, 6.91 mmol) in DCM (20 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.385 g, 10.37 mmol) at 0° C. The ice bath was removed and the mixture was stirred for 30 min at ambient temperature. A mixture of N,O-dimethylhydroxylamine (1.011 g, 10.37 mmol) and pyridine (1.677 mL, 20.74 mmol) in DCM (20 mL) was added and stirring was continued for ˜1 hr. The mixture was diluted with water (˜2 mL) and saturated sodium bicarbonate solution (˜2 mL) and stirred for ˜15 min. The mixture was diluted with dichloromethane (˜30 mL). The separated aqueous layer was extracted with DCM (1×), the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure providing crude (R)—N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (2.73 g) as an orange oil which was directly used without further purification. MS m/z 203.1 (M+H)+; Rt-0.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.Cl[Si:17]([CH3:28])([CH3:27])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][Si:17]([CH3:27])([CH3:28])[CH:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]2[CH3:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(Br)cc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 11.2 g (55.9 mmol) of 4-bromo-2,6-dimethylaniline in 170 ml of THF, 22.4 ml of 2.5 M (55.9 mmol) nBuLi in hexanes were added at −80° C. This mixture was warmed for ca. 1 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 12.0 g (55.9 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 80 ml of THF. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 170-175° C./0.6 mm Hg. The product crystallizes slowly at ambient temperature. Yield 8.45 g (40%).