Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:24]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[C:49]([N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(CC)CC)C>CC#N>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:9]3[CH:8]=[C:7]([CH:2]([N:59]4[CH2:58][CH2:57][N:56]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:61][CH2:60]4)[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][C:10]=3[NH:13][C:14]3[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=3)[N:24]=2)=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N4CCN(C(=O)OC(C)(C)C)CC4)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A solution of 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.059 g, 1.548 mmol) in CH3CN (10.00 mL) was treated with 1-N-Boc-piperazine (Aldrich, 0.577 g, 3.10 mmol) and triethylamine (1.079 mL, 7.74 mmol) and the mixture was heated at 100° C. for 3 h. The reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH (w/NH3 in DCM) to give tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperazine-1-carboxylate (1.24 g, 1.487 mmol, 96% yield) as a brown foam. m/z (ESI, +ve ion) 834 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH3:21])[CH:14]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:13]2[CH:14]=[C:15]([NH:19][CH2:20][CH3:21])[N:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCNc1cc(Cl)ncn1
Product: CCNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 143A but using 3-dimethylaminomethyl-phenylamine (334 mg, 2.20 mmol, 1 eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine (Example 143B) and stirring the reaction mixture for 3 h at 160° C. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) followed by trituration of the resulting solid in diethyl ether, affords 335 mg of the title compound as a beige solid: ESI-MS: 272.1 [MH]+; tR=1.18 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>COCCOC.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:1]3[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:27][CH:26]=2)=[O:24])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc[nH]c1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Under argon gas, diethyl 1H-pyrrole-2,3-dicarboxylate (4.79 g) was dissolved in DME (100 ml) and the solution was cooled to 0° C. Then, sodium hydride (990 mg) was added and the mixture was stirred at room temperature for 0.5 hour, after which it was cooled to 0° C. again. To this reaction mixtrue was added 4-(4-chlorobenzoyl)benzyl bromide (8.53 g) and the mixture was stirred at room temperature for 14 hours. This reaction mixture was diluted with water and extracted with ethyl acetate (500 ml) and the organic layer was washed with NaHCO3 /H2O (300 ml) twice and saturated aqueous NaCl solution (100 ml) once, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (stationary phase 250 g; hexane: ethyl acetate=6:1→1:1) to provide 9.56 g (yield 96%) of the title compound. 1H-NMR (CDCl3) δ: 1.26(3H,t,J=7.1Hz), 1.35(3H,t,J=7.0Hz), 4.26(2H,q,J=7.1Hz), 4.30(2H,q,J=7.1 Hz),5.49(2H,s), 6.57(1H,d,J=3.OHz), 6.88(1H,d,J=3.2Hz), 7.19(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.72(4H,d,J=8.8Hz).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH:27][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Yield: 94 %

Procedure:
Following a procedure similar to that described in Example (1a), 1.0 g of 3-nitrophenyl phenyl ketone, 1.12 g of (R)-1-(3-fluorophenyl)ethylamine, 3.27 ml of triethylamine, 0.56 ml of titanium tetrachloride, 1.13 g of sodium cyanoborohydride and 0.37 ml of acetic acid were reacted, to obtain 1.45 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][N:20]=[C:21]=[O:22]>O1CCCC1>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:21]([NH:20][CH3:19])=[O:22])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: CN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.5 g, 1.77 mmol) was dissolved in tetrahydrofuran (THF) (5 ml). To this was added NaH (60%, 0.14 g, 3.54 mmol) as a suspension in THF (2 ml) and the reaction mixture was stirred for 5 minutes. After this time methyl isocyanate (0.2 g, 3.55 mmol) was added in one portion and the reaction mixture was stirred at room temperature for a further 48 hours. After this time, the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.47 g, 78% yield) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(c2ccccc2C=C2CCN(c3ccc(F)c(F)c3)C2=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2ccccc2CC2CCN(c3ccc(F)c(F)c3)C2=O)CC1
Yield: 88.3 %

Procedure:
A mixture of 1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one (125 mg, 0.326 mmol), ammonium formate (411 mg, 6.53 mmol) and 10% palladium on carbon (40 mg) in 30 mL of anhydrous methanol was refluxed under nitrogen for 18 hours. After cooling, the catalyst was removed In vacuo and the residue was treated with saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was removed, combined with a second extraction of the aqueous layer with additional methylene chloride, washed with saturated aqueous sodium chloride (NaCl) and dried. The solvent was again removed In vacuo to give the crude product as a white solid (111 mg). This solid was dissolved in hot ethyl acetate and crystallized by the addition of a few drops of hexanes. The title product, 29 mg, has m.p. 130-131° C. From the filtrate a second crop of product was also obtained as above, 50 mg, mp. 130-131° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2].[CH:23](I)=[CH2:24]>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[C:21][CH:23]=[CH2:24])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2]
Reactant: C#CCn1c(-c2ccccc2)nc(C(F)(F)F)c(CC)c1=O
Reactant: C=CI
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C=CC#CCn1c(-c2ccccc2)nc(C(F)(F)F)c(CC)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.4 %

Procedure:
To a deoxygenated solution of 1.01 g (3.28 mmol) of 5-ethyl-2-phenyl-3-propargyl-6-trifluoromethyl-4(3H)-pyrimidinone and 0.61 g (3.96 mmol) of vinyl iodide in 25 mL of triethylamine was added a mixture of 60 mg of copper (I) iodide and 60 mg of bis(triphenylphosphine) palladium (II) chloride. The mixture was stirred at room temperature for 22 h and rotovapped to remove the bulk of the triethylamine. The residue was taken up in 150 mL of ethyl acetate, washed with 75 mL of 5% aqueous hydrochloric acid, 75 mL of saturated aqueous sodium bicarbonate and 75 mL of brine, and dried. Removal of the solvent left 1.51 g of a brown tar. Flash chromatography on a column of 30 g of silica gel eluting with 20, 40, 60 and 60% ether in hexanes afforded 0.31 g of crude 5-ethyl-3-(pent-2-yn-4-en-1-yl)-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone. A second chromatography yielded 0.25 g (23%) of pure 5-ethyl-3-(pent-2-yn-4-en-1-yl)-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 111) as a solid, mp 104°-106° C. 1H-NMR (CDCl3) d 1.25(3H,t), 2.8(2H, q), 4.75(2H,s), 5.5-5.9(3H,m), 7.55(3H,m) 7.7(2H,m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>>[C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][C:10]=1[Cl:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1cccc(N)c1
Product: CC(C)(C)c1cc(N)ccc1Cl

Procedure:
Prepared from 3.48 g of 3-tert-butyl-phenylamine and 3.12 g NCS. Yield: 1.5 g. LC-MSD, m/z for C18H14ClN [M+H]+=184.1, 186.1;
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=2)([CH3:10])[CH3:9])=CC=1Cl.[CH3:20]C(=C)C>C1(C)C=CC=CC=1>[OH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[Cl:18])[C:8]([CH3:9])([CH3:10])[CH2:5][C:6]2([CH3:7])[CH3:20]
Reactant: C=C(C)C
Reactant: CC(C)(c1ccc(O)c(Cl)c1)c1ccc(O)c(Cl)c1
Solvent: Cc1ccccc1
Product: CC1(C)CC(C)(C)c2cc(Cl)c(O)cc21
Temperature: 230 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
99 g (0.33 mol) of 2,2-bis-(4-hydroxy-3-chlorphenyl)-propane, 20 g of an acid-activated fuller's earth and 60 g (1.07 mol) of isobutylene are introduced into an autoclave. After stirring for 6 hours at 230° C., 200 ml of toluene are added, the catalyst is filtered off and the solvent evaporated. The residue (127.1 g) is distilled in vacuo in a packed column. 12.2 g (0.055 mol) of 5-hydroxy-6-chlor-1,1,3,3-tetramethyl indane (VII) melting at 51° C. are obtained from the fraction boiling at 75°-83° C./0.2 Torr by recrystallisation from 25 ml of petroleum ether. ##STR25##
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4])=[O:24])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)COC(C#N)C(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Yield: 100 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile in 25 ml of anhydrous DMA was stirred with 6.68 g of ethyl bromoacetate in the presence of 2.76 g of anhydrous potassium carbonate. The mixture was heated at 50° C. for 16 hours, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness, to obtain 3.55 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile (oil) (Yield 100%), which was used as such for the reaction described in the previous example.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH:25]([C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[O:39][CH3:40])C(OCC)=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:38][O:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([O:39][CH3:40])[C:31]=1[CH:25]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:5]
Reactant: CCOC(=O)C(c1c(OC)cccc1OC)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(OC)c1C1C(=O)NCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A cooled (0° C.) solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)-N-(4-(trifluoromethoxy)-benzyl)acetamido)-2-(2,6-dimethoxyphenyl)acetate (900 mg; 1.57 mmol) in anh. DCM (18 ml) was treated dropwise with 4 M HCl in dioxane (6.00 ml; 24.00 mmol), and the resulting mixture was further stirred at rt, under nitrogen, for 2.5 h. The reaction mixture was concentrated to dryness under reduced pressure, the resulting residue was treated with aq. sat. NaHCO3 (7.5 ml) and AcOEt (7.5 ml), and stirring at rt was then continued for 17 h. The separated aq. layer was extracted with AcOEt (20 ml), and the mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-piperazine-2,5-dione as a slightly orange solid. LC-MS (conditions D): tR=0.94 min.; [M+H]+: 424.88 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Compound 1b (400 mg) was dissolved in a water-ethanol (1:1) mixture (10 mL), and iron powder (1.0 g) and ammonium chloride (1.0 g) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was filtered through Celite to thereby remove iron powder, and water (100 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated brine (100 mL) and dried over sodium sulfate, followed by concentration under reduced pressure, to thereby yield compound 1c (335 mg, yield: 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17](O)(=O)[CH:18]([CH3:20])[OH:19].C>Cl>[CH3:17][CH:18]([C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:19]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: CC(O)C(=O)O
Agent: Cl
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Temperature: 140 °C

Procedure:
3-Amino-4-(2-methylpropylamino)quinoline (29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol) were mixed and heated at 140° C. for 6 hr. The mixture was then dissolved in dilute hydrochloric acid and treated with charcoal. The solids were filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as an oil. The oil was extracted into ethyl acetate. The ethyl acetate solution was treated with decolorizing carbon and the solids were filtered from the mixture. The filtrate was evaporated to dryness to yield a greenish oil which was pure enough for further reactions. A small sample was triturated with hexane to obtain a solid which was recrystallized from ethyl acetate for analysis. m.p. 152°-166° C. Analysis: Calculated: C, 71.4; H, 7.11; N, 15.6. Found: C, 71.1; H, 7.33; N, 15.4.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:8]3[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:13][C:14]=2[F:30])=[CH:23][CH:22]=1)=[N+:32]=[N-:33]
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
A solution of 52 (9.27 g, 21.26 mmol) in anhydrous N,N-dimethylformamide (DMF, 50 mL) was treated with sodium azide (NaN3, 5.53 g, 85.04 mmol, 4.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 70–80° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with H2O (150 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0–5° C. for 1 h. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×50 mL), and dried in vacuo. The crude desired N-[3-(4′-azidomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 53 (7.16 g, 88% yield) was obtained as off-white solids. The material was found to be essentially pure by TLC and HPLC and was directly used in the subsequent reaction without further purification. LCMS (ESI) m/e 384 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:9])[CH3:8].Cl[C:11]1[C:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:19]([CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>CN(C=O)C.O>[CH2:7]([S:9][C:11]1[C:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:19]([CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:8]
Reactant: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2ccccc2c(C)c1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2.1 g (15.4 mmol) of K2CO3 and 760 μl (10.3 mmol) of ethanethiol were added in succession to a solution of 2.1 g (5.1 mmol) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione in DMF (36 ml). The mixture was then heated for 16 h at 60° C. A further 2.1 g (15.4 mmol) of K2CO3 and 760 μl (10.3 mmol) of ethanethiol were then added, and the mixture was again heated for 16 h at 50° C. After cooling to RT, the mixture was diluted with water and extracted twice with EA. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. There were obtained as residue 1.7 g (4.0 mmol, 78%) of 2-(2-(ethylthio)-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][O:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:19][O:20][CH2:21]3)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(C2COC2)CC1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCN(C2COC2)CC1
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 5-nitro-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (9.8 g, 1.0 eq, 34.0 mmol) and Pd—C (10% loading, 3,6 g) in EtOH (300 mL) was stirred in a 500 mL round bottom flask. The reaction flask was evacuated under house vacuum and subsequently filled with hydrogen while stirring. This procedure was repeated three times and the reaction mixture was hydrogenated for 3 hours under an H2 balloon. The mixture was filtered through celite and the filter cake was washed with EtOH (2×50 mL). The filtrate was concentrated under vacuum to leave a white solid, which upon high vacuum drying gave 5-amino-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile in 93% yield.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:15])([CH3:5])[CH3:4]>C(O)(=O)C.[Fe]>[CH:3]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([Br:1])[C:7]=1[OH:15])([CH3:5])[CH3:4]
Reactant: BrBr
Reactant: CC(C)c1ccc(O)c(C(C)C)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 85.3 %

Procedure:
1 g of iron powder and then, dropwise, 101 g (32.2 ml, 0.63 mol) of bromine are added in the course of 90 minutes to a solution of 102.3 g (0.57 mol) of 2,4-diisopropylphenol in 900 ml of glacial acetic acid at 95° C. The mixture is stirred for a further hour at 100° C. and cooled, the reaction mixture is partitioned between toluene and water and the toluene phase is washed with NaHCO3 solution. It is dried, filtered and concentrated, and the residue is distilled in a high vacuum. 125 g of the title compound is obtained as a pale yellow oil, b.p. 85° C./0.15 torr.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([CH:15]([CH2:20][CH2:21]O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]([O:18][CH3:19])=[O:17])[C:6]1=[O:40])(=[O:3])[CH3:2].N1C=CC=CC=1.C1C[O:50]CC1>>[C:1]([O:4][C@@H:5]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([CH:15]([CH:20]([OH:50])[CH3:21])[C:16]([O:18][CH3:19])=[O:17])[C:6]1=[O:40])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: COC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC(C)=O)C1c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(C(C)O)N1C(=O)[C@H](OC(C)=O)[C@@H]1c1ccccc1

Procedure:
The diastereomeric mixture of Example 2 (444 mg, 0.793 mmol) in anhydrous THF (4 mL) was treated with HF/pyridine (4.4M, 1.80 mL, 7.93 mmol) at room temperature for 5 days. Quench and work up as in the above Example 5, followed by chromatography (40% ethyl acetate/hexane) gave title compound as a white solid. (139 mg, 54%).