Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](C#CCF)[CH:10]=2)[N:3]=1.[F:29]C(F)OC1C=CC(C(=O)C(C2C=CC=C(C#CCO)C=2)=O)=CC=1.[CH2:53](O)[CH2:54][C:55]#[CH:56]>>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:24]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:56]#[C:55][CH2:54][CH2:53][F:29])[CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCF)c2)N=C1N
Reactant: C#CCCO
Reactant: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCCF)c2)N=C1N

Procedure:
This material was synthesized in a fashion similar to 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one by coupling 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione with but-3-yn-1-ol in step 1.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[N+](=[CH2:30])=[N-]>ClCCl.CCOCC>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([O:19][CH3:30])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(OC)c2cc(C)ccc2n(Cc2ccccc2)c1=O

Procedure:
A solution of 1-benzyl-3-ethoxycarbonyl-4-hydroxy-6-methyl-2(1H)-quinolinone obtained in Step (3) of Preparation A (12.4 g) in dichloromethane (50 ml) and methanol (10 ml) was treated with excess diazomethane in ether for 10 mins and was then evaporated. The crude methylation product, upon chromatography on silica gel, yielded 1-benzyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (11.5 g). This product (7.13 g) in dry toluene (80 ml) was cooled to -78° C. and a 1M solution of di-isobutyl aluminum hydride (30 ml) was added dropwise in 10 min. After 2.5 hours stirring at -78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and crystallized from ethyl acetate/hexane to give 1-benzyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone as a yellow solid (7.8 g). That the expected product was obtained was confirmed by the spectral data: NMR (CDCl3): δ2.40 (s, 3H, CH3), 4.18 (s, 3H, OCH3), 10.58 (s, 1H, CHO); MS (FAB): m/e 308 (M.+ +1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[CH:17]1([Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1COCC1>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>[CH:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: [Zn+]C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C3CCCCC3)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M cyclohexylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 7 PBS, extracted with DCM. Silica gel chromatography (gradient 0% to 40% EtOAc/Hexanes) gave 2-cyclohexyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001106449). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C17H18N2S 282, observed m/e 283.3 (M+H)+. +H-NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.30 (d, 1H), 8.03 (s, 1H), 7.71 (d, 1H), 2.94 (m, 1H), 2.69 (s, 3H), 1.35-1.91 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-Methyl-2-nitrobenzoic acid 67 (30.0 g, 166 mmol, 1.0 equiv.) was suspended in CH2Cl2 (150 ml) and the suspension was cooled to 0° C. using an ice bath. Oxalyl chloride (2.0 M in CH2Cl2, 166 ml, 332 mmol, 2.0 equiv.) was added to the stirred reaction mixture through a pressure equalizing dropping funnel over 30 min. DMF (10 drops) was added dropwise. The reaction mixture was allowed to warm up to room temperature. After 30 min., the reaction was concentrated to dryness on a rotary evaporator. The solid material was re-dissolved in CH2Cl2 (200 ml) and was concentrated to dryness on a rotary evaporator to give 3-methyl-2-nitro-benzoylchloride 68 (32.9 g, 99%) as an off white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=3)[C:17](O)=O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>>[ClH:25].[N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=3)[CH2:17][Cl:25])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2cccc(N3CCCCC3)c2)[nH]c1=O
Product: Cl
Product: O=c1[nH]c(-c2cccc(N3CCCCC3)c2)ccc1CCl

Procedure:
6-(m-Piperidinylphenyl)-1,2-dihydro-2-oxonicotinic acid, 5.22 g. (0.0165 mole) is added to 100 ml. of thionyl chloride and the mixture is stirred overnight at room temperature. The solid 6-(m-piperidinylphenyl)-1,2-dihydro-2-oxonicotinyl chloride hydrochloride is separated by filtration, washed three times with 100 ml. of hexane and dried over phosphorous pentoxide in vacuo. The product may be used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH2:31](I)[CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:31][CH3:32])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.63 g) in N,N-dimethylformamide (15 ml) were added potassium hydroxide (0.16 g) and ethyl iodide (0.66 ml) and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 ml), and was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.39 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:10]=2)[O:3]1
Reactant: ClCCN1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 4-(2-chloroethyl)morpholine hydrochloride (252 mg, 0.28 mmole, Aldrich, Cat. No. C42203), cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) in a sealed reaction vial was stirred at 90° C. overnight. LC/MS showed it worked well. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[O:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:27]=[C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:28])[N:18]1[CH2:17][C@@H:16]([NH:15][C:12]([C:9]1[O:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:38])([F:37])[F:39]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1coc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1coc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (108 mg, 0.28 mmol)[prepared in Preparation 6] and N,N-diisopropylethylamine (0.24 ml, 1.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (158 mg, 0.34 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (100 mg, 0.14 mmol, 50% yield) as a white solid: LCMS (ES) m/e 523 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18]
Reactant: Fc1cc2c(N3CCNCC3)ccnc2cc1Cl
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)c(F)cc23)CC1

Procedure:
7-Chloro-6-fluoro-4-(piperazin-1-yl)quinoline (0.36 g, 1.35 mmol) and 4-fluorophenyl isocyanate (171 μL, 1.5 mmol) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:13]=[CH:14][CH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1>C1COCC1.N12CCCC1=NCCC2.C1C=CC=CC=1>[CH2:17]([C:16]1[C:2]2[C:1](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4](=[O:11])[C:3]=2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CC1CC=CCC1
Reactant: O=C1CCC(=O)C2CC=CC=C12
Agent: C1CN=C2CCCN2C1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=CCCc1cccc2c1C(=O)C1=C(CCCC1)C2=O
Reaction time: 65 h
Yield: 34 %

Procedure:
A 45 g sample of the tetrahydronaphthoquinone-butadiene dimer adduct of Example 1 was dissolved in 400 ml THF and 20 drops of 1,5-diazabicyclo[4.3.0]non-5-ene were added. The solution was stirred for 65 hours while exposed to air. The THF was then blown off with air and the residue was dissolved in benzene. The benzene solution was filtered to remove insoluble impurities and the solution was then chromatographed on Florisil. The product was eluted with a 4:1 mixture of benzene/ethyl acetate, and the yield of crude product was 15 g (34% yield). An analytical sample, after recrystallization first from ethanol, then from hexane, had a mp of 111° to 113° C.
Reaction SMILES: [OH:1][C:2]1([CH2:21][N:22]([CH3:33])[C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:7][CH2:6][N:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.O1CCCC1.C(Cl)(Cl)Cl.Cl.CO>CO>[OH:1][C:2]1([CH2:21][N:22]([CH3:33])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(C(=O)Cc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
Borane-methylsulfide complex (10M; 0.86 mL) was added to a mixture of the compound (1.36 g) obtained in Step 1, anhydrous tetrahydrofuran (15 mL) and anhydrous chloroform (85 mL) under cooling with ice-water over five minutes under nitrogen atmosphere, and the mixture was stirred at room temperature for twenty four hours. After methanol (10 mL) was added to the mixture under cooling with ice-water, hydrogen chloride-methanol reagent (2.5 M; 5.0 mL) was added to adjust pH to below 1 and the mixture was heated under reflux for two hours. The solvent was removed under reduced pressure and to the residue was added chloroform (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL). The mixture was adjusted to pH 10 by using aqueous 2N sodium hydroxide solution (5 mL) and then separated, and the aqueous layer was extracted with chloroform. The organic layer was combined and washed with water and brine successively, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (Chromatorex NH™) (eluent; dichlorometane:methanol=20:1). The fractions were concentrated and the residue was washed with ethyl acetate and dried to obtain the titled compound (0.76 g) as crystals.
Reaction SMILES: [OH:1][C@H:2]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])[CH2:3][NH:4]C(=O)OC(C)(C)C.O[C@@H](CNS(C1C=CC=CN=1)(=O)=O)CNC(=O)OC(C)(C)C.Cl.[C:46](=[O:75])(OC1C=CC([N+]([O-])=O)=CC=1)[O:47][C@H:48]([CH2:53][N:54]1[C:58]2[CH:59]=[C:60]([Cl:64])[C:61]([Cl:63])=[CH:62][C:57]=2[N:56]=[CH:55]1)[C:49]([CH3:52])([CH3:51])[CH3:50].C(N(C(C)C)CC)(C)C>O1CCOCC1.CN(C)C=O>[OH:1][C@H:2]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])[CH2:3][NH:4][C:46](=[O:75])[O:47][C@H:48]([CH2:53][N:54]1[C:58]2[CH:59]=[C:60]([Cl:64])[C:61]([Cl:63])=[CH:62][C:57]=2[N:56]=[CH:55]1)[C:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(C)(C)OC(=O)NC[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)NC[C@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of 370 mg (1.12 mmol) of tert-butyl (2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 3.3 mL of anhydrous dioxane, 20 mL of a 4 N solution of hydrogen chloride in dioxane was added. The resulting solution was stirred for 60 min, during which time a white precipitate formed. The mixture was concentrated under reduced pressure and the resulting solid was dried under vacuum. A 54 mg (0.18mmol) sample of the residue was then added to a solution of 90 mg (0.2 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl 4-nitrophenyl carbonate in 2 mL of dimethylformamide. Addition of 0.22 mL (1.12 mmol) of diisopropylethylamine resulted in a light yellow solution, which was stirred for 1 d under nitrogen, and then concentrated. The residue was then partition between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a methanol:chloroform solution (1:9) to afford 44 mg (45%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1s)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ES-LCMS m/z 544 (M+H) retention time=3.60 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl-].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][C@@H:25]3[CH2:27][C@H:22]2[CH2:23][NH2+:24]3)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.C1COCC1>O1CCOCC1>[F:29][C:14]([F:13])([F:28])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][C@@H:25]3[CH2:27][C@H:22]2[CH2:23][N:24]3[C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cccc(N2C[C@@H]3C[C@H]2C[NH2+]3)c1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)s1
Yield: 95.3 %

Procedure:
A suspension of ethyl 2-bromothiazole-5-carboxylate (0.125 mL, 0.834 mmol), title compound 216 (425 mg, 1.525 mmol), and triethylamine (0.465 mL, 3.34 mmol) in dioxane (1.525 mL) was sonicated for 1 h. More THF (2 mL) was added and the mixture was sonicated for another 2 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water (×2) then with brine. The organic extract was dried (magnesium sulfate) and solvent evaporated. The residue was purified via ISCO (0-50% Hex/EtOAc; 40 g silica gel column) to obtain title compound 217 (316 mg, 95%) as a white foam. LRMS: (calc) 397.11. (found) 398.1 (MH)+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Fc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(F)cc2OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 3.14 mL) was added dropwise to a solution of 2-benzyloxy-1-bromo-4-fluorobenzene (1.4 g, 5.0 mmol) in THF (50 ml) at −78° C. and the mixture was stirred at the same temperature for 15 minutes. To this solution, a solution of 4-methoxybenzaldehyde (680 mg, 4.99 mmol) in THF (15 mL) was added dropwise at −78° C. and the mixture was stirred at the same temperature for 1.5 hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:dichloro-methane:acetone (12:3:1)] to obtain the title compound (1.41 g, 83%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([CH3:21])[C:14]=3[N:15]=2)=[CH:7][C:6]([CH2:22][CH3:23])=[C:5]([CH3:24])[N:4]=1.Cl.N1C=CC=CC=1>O>[CH3:21][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]3[C:3](=[O:2])[NH:4][C:5]([CH3:24])=[C:6]([CH2:22][CH3:23])[CH:7]=3)[O:12][C:13]=2[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: CCc1cc(CCc2nc3c(C)ccc(C)c3o2)c(OC)nc1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(CCc2nc3c(C)ccc(C)c3o2)c(=O)[nH]c1C
Temperature: 140 °C
Yield: 42.7 %

Procedure:
A mixture of crude 2-methoxy-3-[2-(4,7-dimethylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridine (161 mg, 0.49 mmol) and pyridine hydrochloride (574 mg, 4.97 mmol) was warmed in a pre-heated oil bath at 140° C. for 15 minutes. The cooled residue was diluted with water and the product extracted into chloroform. This extract was dried (Na2SO4), filtered and the solvent evaporated. This residue was chromatographed on silica gel and eluted with a 0.5 to 2.5% methanol/chloroform gradient to yield 65 mg of pure product. The product was crystallized from diethyl ether to give 38 mg, m.p. 151.5°-153° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[CH:7][CH:6]=[CH:5]2.C([O:19]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[CH:1]=[O:19])([O-:14])=[O:13]
Reactant: Cc1cc2cccnc2cc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: O=Cc1cc2cccnc2cc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 63.5 %

Procedure:
6-Methyl-7-nitroquinoline (Achylediani,R. et al. Izvestiya Akademii Nauk Gruzii, Seriya Khimicheskaya (1996), 22(1-4), 43-47) (14 g; 74 mmol) was dissolved in DMF (200 ml) and treated with tert.butoxy-bis(dimethylamino)methan (64.5 ml; 313 mmol) at 160° C. for 30 min. The reaction mixture was evaporated and purified by dissolving in THF (30 ml ), adding TBME (1.5 l) and filtering from the brown precipitate. The filtrate was evaporated to dryness and dissolved in THF (300 ml). NalO4 (95.6 g; 446 mmol) dissolved in water (5 l) was added under stirring within 45 min. The reaction mixture was extracted with EtOAc three times, the combined organic phases were dried over Na2SO4, evaporated to dryness and purified via chromatography (SiO2, toluene/TBME 96/10) to yield the title compound as yellowish crystals (9.5 g; 63%), which were used in the following step.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>O1CCOCC1.C(OCC)C>[Br:14][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[CH3:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
To a suspension of 4-acetamidoacetophenone (Lancaster, 5.32 g, 0.03 mol) in 1,4-dioxane/diethyl ether (100 mL, 1:2, v/v) was added bromine (1.53 mL, 0.03 mol) via a syringe. The reaction mixture was stirred at room temperature for 4 hours until the color of the mixture was changed from brown to white. The solid was collected by filtration, washed with diethyl ether, and dried under high vacuum to give the title compound as a white solid (4.8 g).