Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH3:4])=O.[CH3:5][C:6]1([C:13](=O)[CH3:14])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1.[H-].[Na+]>CCOCC.CO>[CH3:5][C:6]1([CH:13]([CH:14]=[CH:4][OH:3])[CH2:14][CH2:13][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1
Reactant: CC(=O)C1(C)CC2(CCC2)C1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C=CO)C1(C)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A solution of 7.8 g (130.0 mmol) methyl formate and 4.91 g (32.4 mmol) of 2-methyl-2-acetylspiro[3.3]heptane in 8.0 ml of dry ether was dropped into a slurry of 1.2 g of sodium hydride in 180 ml of ether. A few drops of MeOH were added and the reaction mixture stirred for 1.5 hr at 25° C. The reaction mixture was cooled to -10° C and the reaction quenched by slow addition of water. The layers were separated and the aqueous layer extracted twice with ether. The combined organic extracts were washed with water and 1 N NaOH. The combined aqueous layers were acidified with 6 N HCl and extracted with ether. The ether extracts were washed with brine, then dried (MgSO4), filtered and evaporated in vacuo to yield 4.0 g of (2-methylspiro[3.3]hept-2-yl)(2-hydroxyvinyl)heptane as a yellow oil (69.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>>[CH3:15][O:16][C:17]([NH:19][C:20](=[S:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: CSCSc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)N=C=S
Product: COC(=O)NC(=S)Nc1ccc(SCSC)cc1[N+](=O)[O-]

Procedure:
The 1-amino-4-methylthiomethylthio-2-nitrobenzene prepared according to Example VIII is treated with methoxy carbonyl isothiocyanate according to the first paragraph of Example VI to afford 1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethylthio-2-nitrobenzene. This latter compound is treated according to the iron reduction technique set forth in the third paragraph of Example XIX to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethylthiobenzene. This latter compound is treated in accordance with the first paragraph of EXAMPLE XVII to afford 1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethylthio-2-succinamidobenzene.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:38][CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=1.Cl>S(Cl)(Cl)=O.O>[CH:1]([C:4]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([O:38][CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=1)=[O:10])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(OC)c1ccc(N)cc1
Reactant: Cc1ccc(C(C)C)c(OC(C)C(=O)O)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC(OC)c1ccc(NC(=O)C(C)Oc2cc(C)ccc2C(C)C)cc1

Procedure:
A solution of 150 mg (0.67 mmol) of 2-(2-isopropyl-5-methylphenoxy)propionic acid in 1 ml of thionyl chloride was boiled under reflux under argon for 30 minutes. The reaction mixture was concentrated, admixed with 2 ml of toluene and concentrated again. The residue was dissolved in 3 ml of acetonitrile under argon, admixed with 940 μl (0.67 mmol) of triethylamine and a solution of 150 mg (0.67 mmol) of ethyl 3-(4-aminophenyl)-3-methoxypropionate and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, adjusted to pH=6-7 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 287 mg of ethyl 3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 96.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.56 g (7.37 mmol) of 1-bromo-4,5-difluoro-2-[(4-methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.35 g (9.93 mmol) of 4-methylphenylboronic acid. Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.55 g (97%) of 1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 147.0-148.0° C.; NMR (CDCl3) δ 2.32 (s, 3H), 3.05 (s, 3H), 6.92 (d, J=8 Hz, 2H), 7.03 (d, J=8 Hz, 2H), 7.17-7.32 (m, 4H), 7.79 (d, J=8 Hz, 2H). MS (FAB): m/e 365 (M+Li). Anal. Calc'd for C20H16F2O2S: C, 67.03; H, 4.50. Found: C, 67.18; H, 4.48.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1ccc(Sc2ccc(CO)cc2)cn1
Product: CC(=O)c1ccc(OCc2ccc(Sc3ccc(C#N)nc3)cc2)c(C)c1O
Yield: 64.7 %

Procedure:
Using the method of Preparation 166 using 5-(4-(hydroxymethyl)phenylthio) picolinonitrile (1.90 g, 7.84 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.30 g, 7.84 mmol) affords the title compound (1.98 g, 65%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: N[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)=[O:11].N([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O.CC(C)=O.O>[OH:11][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C=O
Reactant: Cc1ccnc(C)c1N
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccnc(C)c1O
Temperature: 0 °C

Procedure:
To a solution of 3-amino-2,4-dimethylpyridine (25.0 g, 0.21 mol) in 10% sulfuric acid (405 mL) cooled to 0° C. by dry ice in acetone with stirring, a solution of sodium nitrite (16.2 g, 0.23 mol) in 160 mL of water was added dropwise at 0.5° C. over a period of 7 min. The solution was maintained at 0° C. for an additional 15 min and then heated in a steam-bath for 15 min. After cooling to room temperature, the solution was neutralized with K2CO3 to pH 7. The product was then extracted with chloroform (3×500 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The product was recrystallized from acetone, and the mother liquid was purified by silica gel column chromatography (EtOAc) to afford an additional amount of the pure product, 3-hydroxy-2,4-dimethylpyridine. The total yield was 12.7 g (51 %) as a colorless solid: mp 105°-106° C. (lit. 99°-101° C.); 1H NMR (90 MHz, CDCl3) δ 2.25 (s, 3H, 4-CH3), 2.50 (s, 3H, 2-CH3), 6.97 (d, 1H, 5-H, J5,6 =4.5 Hz), 7.95 (d, 1H, 6-H, J5,6 =4.5 Hz), 11.20 (s, 1H, 5-OH, D2O exchangeable).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[C:4](C(OCC)=O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]2.C(O)=O.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:10][CH:9]([CH3:11])[C:6]([CH3:12])([CH2:5][CH2:4][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]1[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1(C)C(C)CCN(C)C1C
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate (121 g, 389 mmol) at 0° C. was added formic acid (121 mL, 3.2 mol), followed by triethylamine (179 mL, 1.3 mol). The mixture was slowly heated to 160° C. over a period of 2 hours and was stirred at 160° C. for 20 minutes. The mixture was cooled to room temperature, and allowed to stand under nitrogen for 24 hours. The mixture was basified by the addition of saturated NaHCO3 and was extracted with ether (3X). The organic layers were combined, washed with saturated NaHCO3 then brine and were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was taken up in 0.5N HCl (500 mL) and washed with hexane (3X). The aqueous layer was basified with concentrated NH4OH and extracted with ether (3X). The ether layer was dried over MgSO4 and concentrated in vacuo to afford 34 g (36%) of ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate as a yellow oil. The combined aqueous phases were concentrated in vacuo and the residue was triturated with hot ethanol (800 mL at 70° C.). The solution was filtered, triturated with additional hot ethanol (300 mL) and filtered once again. The ethanol filtrates were combined, acidified with concentrated H2SO4 and refluxed for 24 hours under nitrogen. The solution was basified with concentrated NH4OH and extracted with ether (3X). The ether layers were combined, washed with saturated NaHCO3 (2X) and dried over MgSO4. The solvent was removed in vacuo to afford 28.5 g of additional product for a total yield of 62.5 g (67%). The product was treated with p-toluenesulfonic acid to afford ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate-4-methylbenzenesulfonate as a white powder, m.p. 171-171.5.C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](Cl)=[O:28])(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28])(=[O:22])=[O:23]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1ccc(C(=O)Cl)cc1S(C)(=O)=O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(C)c(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 3-methane-sulfonyl-4-methyl-benzoyl chloride. MS: 456.2 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl-].[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:19][C:18]=2[CH:42]=1)#[N:13].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[CH:22][C:20]2[O:21][C:17]3[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:42][C:18]=3[CH:19]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: O=Cc1ccc(CO)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(C=Cc3ccc(CO)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 189.6 %

Procedure:
911 mg of 4-hydroxymethylbenzaldehyde and 2.0 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride were dissolved in a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of ethanol, followed by the addition of 845 mg of 1,8-diazabicyclo[5.4.0]-7-undecene and by subsequent stirring at room temperature for 1 hour. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography, thereby obtaining 2.3 g of 2-[2-(4-hydroxymethylphenyl)vinyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. 2.3 g of the thus obtained E/Z mixture was dissolved in a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 7 hours in the presence of 800 mg of palladium oxide.1H2O.barium sulfate. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an elution solvent to obtain 835 mg of 2-[2-(4-hydroxymethylphenyl)ethyl]-5-benzofurancarbonitrile as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]([NH:16][C:17]1[C:18](Br)=[CH:19][C:20]2[C:24]3[CH:25]=[C:26](Br)[C:27]([NH:29][C:30](=[O:44])[CH:31]=[CH:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[C:34]=4[Cl:43])=[CH:28][C:23]=3[S:22](=[O:47])(=[O:46])[C:21]=2[CH:48]=1)=[O:15].C([O:52][P:53]([O-:57])[O:54][CH2:55][CH3:56])C>C(N(CC)CC)C>[CH2:55]([O:54][P:53]([C:18]1[C:17]([NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:3]2[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[CH:48][C:21]2[S:22](=[O:46])(=[O:47])[C:23]3[CH:28]=[C:27]([NH:29][C:30](=[O:44])[CH:31]=[CH:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[C:34]=4[Cl:43])[C:26]([P:53]([O:54][CH2:55][CH3:56])([OH:52])=[O:57])=[CH:25][C:24]=3[C:20]=2[CH:19]=1)(=[O:52])[OH:57])[CH3:56]
Reactant: CCOP([O-])OCC
Reactant: COc1ccc(C=CC(=O)Nc2cc3c(cc2Br)-c2cc(Br)c(NC(=O)C=Cc4ccc(OC)c(OC)c4Cl)cc2S3(=O)=O)c(Cl)c1OC
Solvent: CCN(CC)CC
Product: CCOP(=O)(O)c1cc2c(cc1NC(=O)C=Cc1ccc(OC)c(OC)c1Cl)S(=O)(=O)c1cc(NC(=O)C=Cc3ccc(OC)c(OC)c3Cl)c(P(=O)(O)OCC)cc1-2
Temperature: 90 °C

Procedure:
To a nitrogen flushed flask containing 2.45 g of the product of Example 16 was added, via syringe, 1.04 ml of diethylphosphite, 1.12 ml of triethylamine and 15 ml of N,N-dimethylformamide(DMF). The resulting stirred mixture was heated to 90° C. and 1.66 g of tetrakistriphenylphosphine palladium(0) was added, rapidly. The reaction was cooled, and the product precipitated by the addition of excess (200 ml) of 1N hydrochloric acid. The solid was collected, washed and lip dried in vacuo. The collected solid was dissolved in acetone; dry Silica Gel was added and the solvent was removed in vacuo. The Silica Gel/compound support was applied to a Silica Gel column which was eluted with 20% acetone, 79% hexane, 1% glacial acetic acid gradient to 50% acetone, 49% hexane, 1% glacial acetic acid). The product containing fractions were combined and concentrated in vacuo to give [3,7-bis-[3-(2-chloro-3,4-dimethoxyphenyl)acryloylamino]-8-(ethoxyhydroxyphosphoryl)-5,5-dioxo-5H-5λ6 -dibenzothiophen-2-yl]-phosphonic acid monoethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CN1CCCC1=O
Product: COc1cccc(Nc2ncc3ccc(-c4cc(Cl)ccc4OC)n3n2)c1
Temperature: 140 °C
Yield: 9.1 %

Procedure:
7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and [B] 3-methoxyaniline (57.4 mg, 0.000466 mol) were dissolved in N-Methylpyrrolidinone (2.0 mL) and the reaction was heated at 140° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 8.08 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-methoxy-phenyl)-amine as a lyophilated powder. (M+H)=381.09. 1H NMR (400 MHz, DMSO, d6) δ 9.44 (s, 1H), 8.98 (s, 1H), 7.89 (s, 1H), 7.49 (m, 1H), 7.37 (m, 1H), 7.24 (m, 3H), 7.01 (d, 1H, J=4.55 Hz), 6.94 (d, 1H, J=4.55 Hz), 6.50 (d, 1H, J=8.34 Hz), 3.80 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:39])[CH2:35][C:36]([OH:38])=O)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:36](=[O:38])[CH2:35][C:34]([NH:33][C:30]2[CH:29]=[CH:28][C:27]([N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[O:20])=[CH:32][CH:31]=2)=[O:39])[CH2:66][CH2:67]1)=[O:61]
Reactant: O=C(O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
HOBt (75 mg, 0.55 mmol) and DIPEA (213 mg, 1.65 mmol) were added to a stirred solution of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid (150 mg, 0.55 mmol) in DMF (2.0 mL). The reaction mixture was cooled to 0° C. and EDCI.HCl (126 mg, 0.66 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (185 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was recrystallized from ethyl acetate:hexane (1:1) to afford 180 mg (21%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-propionamide. LCMS: 524.09 (M+1)+9.7%, 1H NMR: (DMSO-d6): δ 7.7-7.2 (m, 8H), 6.5 (m, 1H), 6.3 (m, 1H), 3.8-3.6 (m, 5H), 3.6-3.34 (m, 3H), 3.2 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].O.O[N:22]1C2C=CC=CC=2N=N1.N>O1CCCC1>[C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])[NH2:22]
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cccc(C(N)=O)c2OCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.9 %

Procedure:
A solution of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) in tetrahydrofuran (10 ml) was cooled in an ice bath. To this solution was added 1-hydroxybenzotriazole hydrate (0.57 g) and 1-(3-dimethylaminopropyl)-3-ethylcarboxiimide hydrochloride (0.80 g). Thereto aqueous ammonia (0.28 ml) was added dropwise at 5° C. The reaction mixture was stirred for 7 hours at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) to give ethyl 2,3-dihydro-9-carbamoyl-1-benzoxepin-4-carboxylate (0.31 g).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([CH3:58])=[N:47][O:48][C:49]=2[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][C:51]=2[OH:57])=[CH:41][CH:40]=1.C(OCC)(=O)C>ClCCl>[Br:1][C:54]1[CH:55]=[C:50]([C:49]2[O:48][N:47]=[C:46]([CH3:58])[C:45]=2[C:42]2[CH:41]=[CH:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=2)[C:51]([OH:57])=[CH:52][C:53]=1[OH:56]
Reactant: [Br-]
Reactant: COc1ccc(-c2c(C)noc2-c2ccc(O)cc2O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)noc2-c2cc(Br)c(O)cc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyltrimethylammonium tribromide (3.95 g, 10 mmol) was added portion-wise to an ice cooled suspension of 4-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol (Example 1) (2.95 g, 10 mmol) in dichloromethane (50 ml) and the mixture stirred for ˜60 mins, at room temperature. Ethyl acetate (300 ml) was added and the mixture washed with water (3×200 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown solid. Crude product was purified by column chromatography, on silica, eluting with ethyl acetate/hexane (1:2), to give 4-bromo-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol as a white solid, dried in vacuo, (3.42 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[CH3:13][NH2:14]>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:14][CH3:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,2-Dichloro-4-fluoro-5-nitrobenzene (5.00 g, 23.8 mmol) in DMF (5.0 mL) was added to methylamine (10% in toluene, 80.0 g, 258 mmol) and stirred at rt overnight. The reaction mixture was filtered through a pad of ALOX B, washed with DMF/MeOH and concentrated to give the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cc(F)ccc2c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc(F)ccc2c1Cl

Procedure:
A mixture of 7-fluoro-4-hydroxyquinoline-3-carbonitrile (2.02 g, 10.7 mmol) and a few drops of N, N-dimethylformamide in 16.0 mL of thionyl chloride is heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo and toluene (20 mL) is added and the mixture is again concentrated in vacuo to provide 2.18 g of 4-chloro-7-fluoroquinoline-3-carbonitrile as a yellow solid, mp 163-165° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1>C(O)C.[Pd]>[F:13][C:2]([F:1])([F:12])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[CH:5][N:4]=1
Reactant: FC(F)(F)c1ncc2cnccn12
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ncc2n1CCNC2
Yield: 99.4 %

Procedure:
3-Trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of anhydrous ethanol under stirring, then 10% Pd/C (500 mg) was added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through a pad of coarse silica gel and concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (12.2 g, yield 99%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:28])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:27])[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:4])[CH3:3].CN(C1C=CC=CN=1)C.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].CC=C(C)C>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6](=[O:28])[N:7]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C@@H:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[O:27][C:38]1=[O:39])[CH3:8])([CH3:1])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2nccc([C@@H](O)CNCCCN(C)C(=O)OC(C)(C)C)c2c1
Agent: CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H]3CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.3 %

Procedure:
A mixture of {3-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethylamino]-propyl}-methyl-carbamic acid dimethyl-ethyl ester (830 mg, 2.1 mmol), 4 (dimethylamino)pyridine (DMAP) (329 mg, 2.66 mmol), 1,1′-carbonyldiimidazole (CDI) (454 mg, 2.77 mmol) and methylene chloride stabilized over amylene (20 ml) was stirred under argon, at room temperature, for 4 days. The solution was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (95-5) to give {3-[(R)-5-(6-methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl}-methyl-carbamic acid dimethyl-ethyl ester (770 mg, 88%).