Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]1([O-])[CH:11]=[CH:10][CH:9]=[C:8]2[CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:7]=12>>[Cl:3][C:9]1[CH:10]=[CH:11][N:6]=[C:7]2[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][C:8]=12
Reactant: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1Cc2nccc(Cl)c2C1
Temperature: 50 °C
Yield: 45.9 %

Procedure:
POCl3. (20 mL, 218 mmol) was added into ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate N-oxide (1 g, 4.80 mmol) and heated to 35° C. for 12 hours and 50° C. for another 5 hours. The solvent was evaporated and poured into water. The material was extracted with CH2Cl2, washed with NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The residue was purified on silica gel to afford the title compound (0.5 g, 45.9% yield).
Reaction SMILES: [C-:1]#[N:2].[Na+].C1(C)C=CC(S(O[CH2:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16]2)(=O)=O)=CC=1.C(OCC)C>CN(C)C=O>[C:1]([CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1)#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCC1CCc2ccccc2O1
Temperature: 0 °C
Reaction time: 10 h
Yield: 58.2 %

Procedure:
10.6 g (0.216 mol) of sodium cyanide are added to a solution of 57.31 g (0.18 mol) of 2-(p-toluenesulphonyloxymethyl)chroman in 800 ml of absolute dimethylformamide and the whole is heated, while stirring, to 60°. After 10 hours, ice-water is added to the reaction mixture and extraction is carried out with diethyl ether. The combined ethereal phases are washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 30.0 g (96.2%) of crude product are obtained and are chromatographed on 1000 g of silica gel (0.040-0.063 mm) using toluene as the eluant. 18.16 g (58.2%) of 2-cyanomethylchroman are thus obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1ccc(C2CCCNC2)nc1
Reactant: Nc1nc(Cl)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCCC(c3ccccn3)C2)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-chloronicotinic acid (1.6 g, 9.248 mmol) in N,N-dimethylformamide (41 mL) was added 2-(piperidin-3-yl)pyridine (1.82 g, 11.098 mmol) and triethylamine (25.455 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography to afford 2-amino-6-(3-(pyridin-2-yl)piperidin-1-yl)nicotinic acid
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[CH:69][C:70]([N:73]3[CH2:77][CH2:76][CH:75]([N:78]([CH3:80])[CH3:79])[CH2:74]3)=[N:71][CH:72]=2)[C:56]=1[CH3:81].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:80][N:78]([CH3:79])[CH:75]1[CH2:76][CH2:77][N:73]([C:70]2[N:71]=[CH:72][C:67]([C:57]3[C:56]([CH3:81])=[C:55]([NH:47][C:46]4[C:41]([N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:42][CH:43]=[C:44]([N:48]5[CH2:49][CH2:50][O:51][CH2:52][CH2:53]5)[CH:45]=4)[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=3)=[CH:68][CH:69]=2)[CH2:74]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCC(N(C)C)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCC(N(C)C)C3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.022 g, 0.047 mmol), 2,5-dimorpholinopyridin-3-amine (0.093 g, 0.351 mmol), 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine (0.118 g, 0.29 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.070 g, 0.73 mmol) in toluene (2.9 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (1H, d, J=2.0 Hz), 7.85 (1H, dd, J=8.7, 2.4 Hz), 7.74 (1H, d, J=5.9 Hz), 7.59 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.39 (1H, ddd, J=13.3, 9.3, 2.4 Hz), 6.61 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=2.5 Hz), 3.58-3.82 (10H, m), 3.39 (1H, m), 3.21-3.10 (3H, br. m), 2.95-3.04 (4H, m), 2.90-2.75 (3H, br. m), 2.22 (6H, s), 2.18 (1H, m), 2.13 (3H, s), 1.83 (1H, m). Mass Spectrum (ESI) m/e=631.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.[Si:24]([O:31][CH2:32][CH2:33]Br)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[I-].[Na+]>O1CCCC1.C(OCC)C.C1C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>[Si:24]([O:31][CH2:32][CH2:33][C:5]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]=1[O:13][CH3:14])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Agent: [I-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCO[Si](C)(C)C(C)(C)C)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
126 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 2 ml of anhydrous tetrahydrofuran, then 0.2 ml of hexamethylphosphoric triamide was added to the solution and whole mixture was cooled to -78° C. in a dry ice-acetone bath. Under argon gas stream conditions, 0.5 ml of sec-butyllithium was added dropwise to the reaction mixture and stirred for 30 minutes. Then 140 mg of 2-bromoethyl tert-butyldimethylsilyl ether and 70 mg of anhydrous sodium iodide were added to the reaction mixture and was stirred at -78° C. for 4 hours, then the temperature was elevated to room temperature. The solvent was removed by evaporation under reduced pressure, then to the residue thus obtained were added 50 ml of benzene and 50 ml of diethyl ether, the organic layer was washed three times with 30 ml of water, then washed three times with 30 ml of a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, then the residue was treated on a silica gel thin layer chromatography, and purified by developing with 30% ethyl acetate-n-hexane mixed solvent to yield 15.0 mg of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethyl tert-butyldimethylsilyl ether. Colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[C:11](OC)(OC)(OC)[CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH3:7][C:4]1[C:3]2[C:8](=[O:9])[NH:10][C:11]([CH2:12][CH2:13][CH3:14])=[N:1][C:2]=2[S:6][N:5]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Cc1nsc(N)c1C(N)=O
Solvent: CC(=O)OC(C)=O
Product: CCCc1nc2snc(C)c2c(=O)[nH]1
Temperature: 130 °C
Yield: 40 %

Procedure:
A mixture of 29 (3.0 g, 19.1 mmol), trimethyl orthobutyrate (7.0 mL) in acetic anhydride (7.0 mL) was heated at 130° C. in an open flask for 3 h, then cooled to room temperature and poured into ice water. The mixture was extracted with EtOAc for 3 times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 30 (1.6 g, 40%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 12.15 (brs, 1H), 2.81 (s, 3H), 2.78 (t, J=7.68 Hz, 2H), 1.90 (m, 2H), 1.07 (t, J=7.37 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH2:6])=[O:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][C:70]([F:73])([F:72])[F:71])[CH:64]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:6][C:67]1[CH:68]=[CH:63][CH:64]=[C:65]([CH2:69][C:70]([F:71])([F:73])[F:72])[CH:66]=1)=[O:5]
Reactant: NC(=O)c1c(F)cccc1[N+](=O)[O-]
Reactant: FC(F)(F)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(Nc1cccc(CC(F)(F)F)c1)c1c(F)cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Under nitrogen, to 2-fluoro-6-nitrobenzamide (921 mg, 5.00 mmol, 1.00 equiv) in dioxane (5.0 mL) at 23° C. was added palladium acetate (225 mg, 1.00 mmol, 0.200 equiv), Xantphos (868 mg, 1.50 mmol, 0.300 equiv), cesium carbonate (2.28 g, 7.00 mmol, 1.40 equiv), and 1-bromo-3-(2,2,2-trifluoroethyl)benzene (1.31 g, 5.50 mmol, 1.10 equiv). After stirring for 16 hr at 100° C., the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with EtOAc/hexanes to afford 860 mg of the title compound (50% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][C:12]1[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:14][C:15]2[S:16]C3C(O[C:24]=2[CH:25]=1)=CC(Cl)=C(Cl)C=3>>[Cl:11][C:12]1[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:14][C:15]2[S:16][C:4]3[C:3]([O:10][C:24]=2[CH:25]=1)=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=3
Reactant: Oc1ccc(Cl)c(Cl)c1Cl
Reactant: O=C(O)CCCCCOc1cc2c(cc1Cl)Oc1cc(Cl)c(Cl)cc1S2
Product: O=C(O)CCCCCOc1cc2c(cc1Cl)Oc1c(cc(Cl)c(Cl)c1Cl)S2
Yield: 4.3 %

Procedure:
Similar procedures were carried out using 2,3,4-trichlorophenol instead of 3,4-dichlorophenol used in the above (1) to obtain 6-(3,6,7,8-tetrachlorophenoxathiin-2-yloxy)hexanoic acid in an overall yield of 4.3%.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([OH:10])=[O:9].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(O)(=O)C>[Cl:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:13](=[O:14])[CH2:12][Cl:11])[C:3]=1[C:8]([OH:10])=[O:9]
Reactant: Nn1ccc(Cl)c1C(=O)O
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=C(CCl)Nn1ccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of 1-amino-3-chloro-1H-pyrrole-2-carboxylic acid (12.51 g, 55% purity, 0.04 mol) in 500 mL of glacial acetic acid were added under argon 17 mL of chloroacetyl chloride (0.21 mol) and the mixture was stirred at room temperature during 1.5 hours. Afterwards, the reaction mixture was poured into ice-water and extracted with ethyl acetate (2×400 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuum giving a dark oil that was crystallized from a 1/1 diethyl ether/petroleum ether mixture. Filtration of the solid obtained afforded 7.28 g of a white solid corresponding to the title compound (61% yield, 85% purity). This solid was used in the next step without further purifications.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
A solution of 0.544 g (2.103 mmol) (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid, 0.440 g (2.313 mmol) 4-piperidin-1-ylmethyl-phenylamine, 0.736 g (2.313 mmol) TBTU, 0.313 g (2.313 mmol) HOBt and 1.025 mL (7.361 mmol) triethylamine in 10 mL DMF was stirred for 3 h at RT and then poured onto ice water and a little EtOAc. The precipitate was filtered off, washed with water and dried at 80° C. i. vac.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1[CH2:15]C)=[O:4].CNC(NC1C2C=CSC=2CCC1CCC)=O>>[CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1[CH3:15])=[O:4]
Reactant: CCC1CCc2sccc2C1NC(=O)NC
Agent: CCCC1CCc2sccc2C1NC(=O)NC
Product: CNC(=O)NC1c2ccsc2CCC1C

Procedure:
Similarly, alkylation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one with ethyl iodide, propyl iodide, and butyl iodide affords the corresponding 5-alkyl ketones, which are converted in the above manner to 1-methyl-3-(5-ethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-methyl-3-(5-propyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, and 1-methyl-3-(5-butyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)yrea, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH:9]1[C:24](=[O:28])[NH:25][O:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:24](=[O:28])[NH:25][O:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CONC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CONC(=O)C1CNCCN1C(=O)OC(C)(C)C

Procedure:
A mixture of 2-Methoxycarbamoyl-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (0.23 g, 0.58 mmol) and activated 10 wt. % palladium on carbon (0.048 g) in methanol (8 mL) was stirred vigorously under 40 psi hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through a microglass filter paper and the solid washed abundantly with methanol. The solvent was evaporated in vacuo to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18].C(=O)=O.[OH-].[K+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:15]/[NH:16][C:17](=[NH:18])[NH2:19])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Agent: O=C=O
Product: N=C(N)N/N=C/c1ccc(F)cc1
Yield: 91.3 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 15.8 mmol), 20% hydrochloric acid (4 mL) was added to an aminoguanidine bicarbonate (2.2 g, 15.8 mmol) aqueous solution. After completion of the liberation of carbon dioxide, the mixture was heated for 4 h. A solution of 40% aqueous potassium hydroxide (7 mL) was added and the mixture was heated at reflux for additional 10 min. The resulting solution was filtered, washed with water until the wash water was at pH=7, dried and recrystallized from ethanol to give 2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (2.6 g, 91%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:40][CH2:41][O:42]C)(=[N:29]C(OCC3C=CC=CC=3)=O)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:40][CH2:41][OH:42])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: COCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-methoxyethyl)-N-benzyloxycarbonyl sulfoximide (0.3 g, 0.00046 mol) in DCM (3 mL) was added 1M solution of BBr3 in DCM(0.33 g, 0.00138 mol) at −70° C. under nitrogen atmosphere. Reaction mixture was stirred for 3 hr at 25-30° C. Subsequent work up and column purification (2% methanol in chloroform and 100-200 mesh silica gel) gave 65 mg of desired product in 28% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][C:10]([O-:12])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[Na+].[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([NH:18][C:10](=[O:12])[CH2:9][C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(N)cccc1Br
Reactant: COc1cccnc1CC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccnc1CC(=O)Nc1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of sodium 2-(3-methoxypyridin-2-yl)acetate (0.166 g, 0.871 mmol), 3-bromo-2-methylaniline (0.118 mL, 0.958 mmol), DIEA (0.608 mL, 3.48 mmol) and HATU (0.397 g, 1.05 mmol) in DMF (4.0 mL) was stirred at room temperature. After 1 h, the mixture was diluted with EtOAc and washed twice with 10% aqueous LiCl, then with brine, dried and concentrated. The residue was purified by column chromatography on silica gel to provide N-(3-bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide as a pale yellow solid (0.213 g, 73% yield). Mass spectrum m/z 335, 337 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C#N)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:20]([OH:21])=[O:23])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N#CCc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 4 h

Procedure:
To a flask containing 2-(4-bromo-3-(trifluoromethyl)phenyl)acetonitrile 46-5 (880 mg, 3.3 mmol) were added water (4.5 mL) and dropwise concentrated sulfuric acid (4.5 mL). The reaction mixture was stirred at 115° C. for 4 hours. After cooled down to room temperature, the reaction mixture was poured into water (100 mL). The resulting solution was neutralized with powder sodium carbonate to pH 12, treated with 1N HCl aqueous solution to pH around 2, and extracted with dichloromethane (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and then taken to dryness by rotary evaporation give 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 as pale yellow solid. MS m/z 283.1 (M+1)
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[CH:3]([N:17]1[CH:20]([Cl:21])[CH:19]([NH:22]C(=O)COC2C=CC=CC=2)[C:18]1=[O:33])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5].P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[Cl-].[Na+]>C(O)CC.C(Cl)(Cl)Cl>[CH3:34][C:2](=[CH2:1])[CH:3]([N:17]1[CH:20]([Cl:21])[CH:19]([NH2:22])[C:18]1=[O:33])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(N)C1Cl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5 mmoles of p-nitrobenzyl 3-methyl-2-(2-oxo-4-chloro-3-phenoxyacetamido-1-azetidinyl)-3--butenoate in 20 ml. of chloroform cooled to -10° C. were added 30 mmoles of phosphorus pentachloride and an excess of quinoline (30 mmoles plus). The reaction mixture was stirred for 30 min. and was then cooled to -30° C. To the cold mixture were added 2 ml. of n-propyl alcohol with stirring and the reaction mixture was allowed to stand in an ice bath for about 3 min. Thereafter 5 ml. of a saturated aqueous solution of sodium chloride were added followed by the addition of 100 ml. of petroleum ether. The product precipitated as a gum from which the liquid phase was decanted. The gum solidified on treatment with 5 ml. of saturated aqueous sodium chloride. The product was filtered and dried. There were obtained 400 mg. of the deacylated product as the hydrochloride salt represented by the following formula. ##STR56## wherein pNB=p-nitrobenzyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:12].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=[N:14][OH:15])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1c(C)cc(C=O)cc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1c(C)cc(C=NO)cc1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methoxy-3,5-dimethylbenzaldehyde (1.86 g, 11.3 mmol) was dissolved in ethanol (30 mL) and stirred with hydroxylamine hydrochloride (2.4 M aq. solution, 5.65 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.65 mL, 0.6 eq.) at room temperature for 2.5 hours. The mixture was then heated to 60° C. and additional hydroxylamine hydrochloride and Na2CO3 was added. The mixture was again stirred overnight at 60° C., transferred to a separatory funnel, diluted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by ISCO chromatography with EtOAc/hexanes eluent to yield 1.55 g (8.56 mmol) of 4-methoxy-3,5-dimethylbenzaldehyde oxime as a white solid. M+1=180.0.
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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>[C:26]1([CH:32]2[CH:5]([C:4]3[CH:15]=[CH:14][CH:1]=[CH:2][CH:3]=3)[C:6]3[CH:7]=[CH:8][C:9]([C:15]4[C:8]5[C:7]6=[C:16]7[C:11](=[CH:10][CH:9]=5)[CH:12]=[CH:13][CH:14]=[C:1]7[CH:2]=[CH:3][C:6]6=[CH:5][CH:4]=4)=[CH:10][C:32]=3[C:26]3[C:31]2=[CH:30][CH:29]=[C:28]([C:14]2[C:1]4[C:16]5=[C:7]6[C:6](=[CH:3][CH:2]=4)[CH:5]=[CH:4][CH:15]=[C:8]6[CH:9]=[CH:10][C:11]5=[CH:12][CH:13]=2)[CH:27]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(C2c3ccc(-c4ccc5ccc6cccc7ccc4c5c67)cc3-c3cc(-c4ccc5ccc6cccc7ccc4c5c67)ccc3C2c2ccccc2)cc1
Temperature: 60 °C
Yield: 69 %

Procedure:
As illustrated in Formula 7, the product 4a in Formula 6 (1.0 g, 2.05 mmol), 1-pyreneboronic acid (1.53 g, 6.2 mmol), potassium carbonate solution (2.0 M, 10 mL), and dried toluene (30 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (243 mg, 0.21 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting mixture was cooled to room temperature to precipitate a solid, and the solid was collected by filtering. The solid was sublimated at a temperature of 330° C. to obtain a white solid of 1.03 g (yield=69%).