Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3]1=[N:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cn1c(NS(=O)(=O)c2ccccc2)nc2ccccc21
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=NS(=O)(=O)c2ccccc2)n(Cc2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 120 °C

Procedure:
To a solution of N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide (100 mg, 0.35 mmol) in DMF (2 mL) was added 1-bromomethyl-3-trifluoromethyl-benzene (166.4 mg, 0.70 mmol) and potassium carbonate (48 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h and then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-[1-methyl-3-(3-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide (2nd compound to elute off the column, 99.0 mg, 64%). MS 446 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[CH2:19]([O:21][C:22]([C:24]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([N:34]=[CH:35][C:36]2[S:37][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:39][CH:40]=2)[S:26][C:25]=1[NH2:46])=[O:23])[CH3:20]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:32]([O:31][C:29]([C:28]1[C:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])=[C:25]([N:46]=[CH:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:26][C:27]=1[N:34]=[CH:35][C:36]1[S:37][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:39][CH:40]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1c(N)sc(N=Cc2ccc(N(CC)CC)s2)c1C(=O)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N=Cc2ccc(N(CC)CC)s2)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC
Yield: 71.2 %

Procedure:
5-Nitrothiophene-2-carbaldehyde (23 mg) was mixed in toluene under nitrogen at 0° C. with DABCO (16 mg), TiCl4 in solution in toluene (146 μL) and 2-amino-5-[(5-diethylamino-thiophen-2-ylmethylene)-amino]-thiophene-3,4-dicarboxylic acid diethyl ester (56 mg) and refluxed for seven hours. The reaction affords a purple-grey powder (53 mg, 72%) after purification by flash chromatography. 1H-NMR (300 MHz, [D] acetone): δ=8.55 (s, 1H), 8.36 (s, 1H), 8.06 (d, 1H, 3J=4.3 Hz), 7.66 (d, 1H, 3J=4.4 Hz), 7.55 (d, 1H, 3J=4.6 Hz), 6.19 (d, 1H, 3J=4.6 Hz), 4.36 (q, 2H, 3J=7.3 Hz), 4.25 (q, 2H, 3J=7.1 Hz), 3.55 (q, 4H, 3J=7.5 Hz), 1.39 (t, 3H, 3J=7.1 Hz), 1.34 (t, 3H, 3J=7.2 Hz), 1.28 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=173.0, 167.5, 164.1, 162.9, 149.7, 143.7, 132.9, 131.6, 131.3, 130.2, 130.1, 129.7, 129.1, 127.6, 114.0, 104.9, 61.4, 60.2, 39.2, 14.2, 13.8, 10.8. +TOF-MS: m/z 563.10838. Calculated for C24H26O6N4S3 563.10872.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]([CH2:14]O)O.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:9])[N:8]=[CH:14][CH:12]=[CH:11]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Fc1cc2ncccc2cc1Br
Temperature: 130 °C
Yield: 37.8 %

Procedure:
To a suspension of 4-bromo-3-fluoro-phenylamine (100.0 g, 526 mmol) in concentrated sulfuric acid (290 mL) was added glycerol (220.0 g, 2.39 mol, 4.5 eq.) followed by ferrous sulfate (30.0 g, 0.2 eq.). The reaction mixture was heated at 130° C. for 14 h, cooled to it and poured onto ice-water. The solution was adjusted with saturated aqueous ammonium hydroxide to pH 8 and extracted with DCM (2 L×3). The combined organic layers were washed with brine (1 L×3), dried over Na2SO4 and concentrated under reduced pressure to afford a crude product, which was purified by column chromatography (petroleum:EtOAc=10:1) to give the title compound as white solid (45 g, 39%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 8.56 (m, 1H), 8.45 (m, 1H), 7.90 (d, 1H), 7.71 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.CC(C)([O-])C.[Na+]>CS(C)=O.O>[O:11]1[CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ncccc1C1=CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-pyridine (see PREPARATION P13.1; 3.5 g, 17.9 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.8 g, 17.9 mmol) were dissolved in DMSO (20 mL) and sodium tert-butoxide (t-BuONa) (3.4 g, 35.8 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crud product was purified by silica gel column chromatography to give the title compound (2.3 g, 7.8 mmol, yield 75%). 1H NMR (DMSO-D6, 300 MHz) δ (ppm) 1.38 (s, 9H), 2.41-2.47 (m, 2H), 3.75-3.86 (m, 4H), 4.19-4.30 (m, 4H), 5.26-5.35 (m, 1H), 6.15-6.20 (m, 1H), 7.01 (dd, 1H, J=7.31 Hz, 4.97 Hz), 7.62 (d, 1H, J=7.45 Hz), 8.02 (d, 1H, J=4.82 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:5]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])[C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc([N+](=O)[O-])cc1N
Product: COc1ccc([N+](=O)[O-])cc1N(Cc1ccccc1Br)Cc1ccccc1Br

Procedure:
2-Methoxy-5-nitroaniline and 1-bromo-2-(bromomethyl)benzene were processed as described in Example 2A to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].[NH3:21].[Cl-].[NH4+]>C(O)C>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH2:21])=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: N
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCc1ccc(Cc2ccc(C(N)=O)cc2O)cc1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a mixture of methyl 4-(4-ethylbenzyl)-3-hydroxy-benzoate (0.20 g) and 28% aqueous ammonia solution (6 mL) in ethanol (3 mL) was added ammonium chloride (0.079 g), and the mixture was stirred in sealed tube at 100° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. A mixed solvent of dichloromethane and methanol (10:1) was added to the residue, and an insoluble material was collected by filtration and dried to give 4-(4-ethylbenzyl)-3-hydroxybenzamide (0.065 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.O>C(Cl)(Cl)Cl>[C:17]1([S:27]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NC1CCC(O)CC1)c1cccc2ccccc12
Reaction time: 15 h
Yield: 89 %

Procedure:
To 18.6 g of trans-4-aminocyclohexanol hydrochloride suspended in 700 ml of chloroform are added, at 5° C., 34 ml of triethylamine, followed by a solution containing 18.6g of 1-naphthylsulfonyl chloride in 100 ml of chloroform. After reacting for 15 hours, the reaction mixture is poured onto 500 ml of water. The expected product is obtained by filtration of the precipitate.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][C:6]1([CH3:41])[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)[N:20]=[C:19](Cl)[N:18]=2)[CH2:9][C:8]([CH3:40])([CH3:39])[NH:7]1>C1(C)C=CC=CC=1>[CH2:2]([O:3][C:19]1[N:20]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:34])([CH3:35])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[N:22]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:10]2[CH2:9][C:8]([CH3:40])([CH3:39])[NH:7][C:6]([CH3:41])([CH3:5])[CH2:11]2)[N:18]=1)[CH3:1]
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1nc(NCCCCC2CC(C)(C)NC(C)(C)C2)nc(NCCCCC2CC(C)(C)NC(C)(C)C2)n1
Temperature: 25 °C
Yield: 74 %

Procedure:
g)1. 63.5 g (0. 195 mol) of a 21% solution of sodium ethylate in toluene are added dropwise at room temperature under nitrogen to a solution of 69.7 g (0.13 mol) of 2,4-bis[N-(2,2,6,6-tetramethyl-4-piperidinyl)butylamino]-6-chloro-1,3,5-triazine [EP-A-314 472, Sankyo] in 400 ml of toluene. The reaction mixture is then refluxed for 20 hours. After cooling to room temperature, the reaction mixture is washed successively with water, 1N sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phases are combined, dried over potassium carbonate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from acetonitrile gives 52.2 g (74%) of 2-ethoxy-4,6-bis[N-(2,2,6,6-tetramethyl-4-piperidinyl)butylamino]-1,3,5-triazine, m.p. 95°-104° C., in the form of a white powder. 1H-NMR (300 MHz, CDCl3): δ=4.345 ppm (q, J=7 Hz) --OCH2CH3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:23]=[CH:22][C:16](/[CH:17]=[CH:18]/B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd]Cl>[F:12][C:13]1[CH:23]=[CH:22][C:16](/[CH:17]=[CH:18]/[C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccnc(/C=C/c2ccc(F)cc2)c1
Temperature: 100 °C
Yield: 47.1 %

Procedure:
Methyl 2-chloroisonicotinate (5.5 g, 32.05 mmol), (E)-4-fluorostyrylboronic acid (7.98 g, 48.08 mmol), potassium phosphate (3.93 mL, 48.08 mmol) and PdCl2 (dppf) (0.464 g, 0.64 mmol) were split into 5 equal portions and each portion was placed in a microwave reaction vessel. The vessels were evacuated and backfilled with nitrogen. Methanol (15 mL) was added to each vessel, the vessels were sealed and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vessels was pooled and water and DCM were added, the phases separated and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 6:1 to 4:1 of EtOAc in heptane over 15 CV was used as mobile phase. (E)-Methyl 2-(4-fluorostyryl)isonicotinate (3.88 g, 47%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.04-7.18 (m, 3H), 7.52-7.62 (m, 2H), 7.63-7.71 (m, 2H), 7.93 (s, 1H), 8.74 (d, 1H). MS m/z 258 (M+H)+
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[BrH:24]>CC(O)=O>[Br:24][C:17]1[CH:16]=[C:15]([C:12]2[N:11]([CH3:22])[C:10](=[O:23])[C:9]([OH:8])=[CH:14][N:13]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Br
Reactant: Cn1c(-c2ccnc(Cl)c2)ncc(OCc2ccccc2)c1=O
Solvent: CC(=O)O
Product: Cn1c(-c2ccnc(Br)c2)ncc(O)c1=O
Temperature: 100 °C
Yield: 623 %

Procedure:
A mixture of 5-(benzyloxy)-2-(2-chloropyridin-4-yl)-3-methylpyrimidin-4(3H)-one (3.5 g, 10.7 mmol), conc. aq. HBr (10 mL), and HOAc (50 mL) was heated at 100° C. for 2 h with stirring. After cooled to rt, the solid was filtered, washed with EtOAc several times, dried to give 5 g of crude compound, which was purified by prep-HPLC to give pure 2-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one (1.9 g, 623%). 1H-NMR δ (400 MHz, d6-DMSO): 9.88 (s, 1H), 8.52 (dd, J=5.6, 0.4 Hz, 1H), 7.86 (dd, J=5.2, 0.4 Hz, 1H), 7.65 (dd, J=5.2, 1.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 3.33 (s, 3H); MS (ESI) m/z. (M+H)+ 282.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.C1(P(=[CH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[CH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29]
Reactant: CC(=O)C(F)(F)F
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: CC(=CC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 72 h

Procedure:
1,1,1-Trifluoroacetone (680 mg, 6.1 mmol) was added to an ambient temperature solution of benzyl (triphenylphosphoranylidene)acetate (2.5 g, 6.1 mmol) in methylene chloride (10 mL). After stirring in a sealed tube for 72 h, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-20% ethyl acetate/hexane afforded benzyl 4,4,4-trifluoro-3-methylbut-2-enoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].C([O-])(=O)C.[NH4+]>C(O)C>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 4 was repeated using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.9 g of ethyl cyanoacetate and 0.15 g of ammonium acetate in 10 ml of ethanol. Yield 0.87 g (57%), m.p. 205°-210° C.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-fluoro-benzylamine (0.137 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.149 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.75 (s, 2H) 7.02 (t, 2H), 7.27 (t, 2H), 7.36 (s, 1H), 7.92 (s, 1H). GC-MS: m/z 401 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[N:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:4]([CH2:7][NH:8][C:9](=[O:16])[C:10]2C=CC=NC=2)=[N:5][N:6]=1.NCC1C(=NNC2C=CC=C(F)C=2)C(N)=NN=1.Cl.C(Cl)(=O)C1C=CC=NC=1.[C:53]([O:56]CC)(=[O:55])[CH3:54]>>[NH2:1][C:2]1[C:3](=[N:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:4]([CH2:7][NH:8][C:9]([CH:10]=[CH:54][C:53]([OH:56])=[O:55])=[O:16])=[N:5][N:6]=1
Reactant: CCOC(C)=O
Reactant: NC1=NN=C(CNC(=O)c2cccnc2)C1=NNc1cccc(F)c1
Agent: Cl
Agent: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: O=C(Cl)c1cccnc1
Product: NC1=NN=C(CNC(=O)C=CC(=O)O)C1=NNc1cccc(F)c1
Yield: 41 %

Procedure:
In a similar manner, N-{5-amino-4-[(3-fluorophenyl)hydrazono]4H-pyrazol-3-ylmethyl}nicotinamide was prepared by reacting 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg, 0.25 mmole) with nicotinoyl chloride hydrochloride (46.3 mg, 0.26 mmole). The reaction was worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:MeOH=9:1) to yield 36 mg (41%) of the title compound as a yellow powder. MS (m/z, ES+): 340 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 9.01 (br s, 2H), 8.70 (d, 1H), 8.20 (d, 1H), 7.30-7.70 (m, 4H), 6.85-7.25 (m, 3H), 4.70 (br s, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 3-[(aminooxy)methyl]piperidine-1-carboxylate 152 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 153 (0.37 g, 84%) as a white foam.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>CCO.O>[CH:7]1[CH:6]=[CH:5][C:3](=[O:4])/[C:2](=[CH:1]/[NH:12][CH2:11][CH2:10][NH:13]/[CH:1]=[C:2]2/[CH:8]=[CH:7][CH:6]=[CH:5][C:3]/2=[O:4])/[CH:8]=1
Reactant: O=Cc1ccccc1O
Reactant: NCCN
Solvent: O
Solvent: CCO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of salicylaldehyde (24.42 g, 0.200 molc) in 80 ml of EtOh was added to a stirred solution of ethylenediamine (6.070 g, 0.100, olc) in a mixture of 50 ml EtOH and 50 ml of H2O over a period of 5 minutes. The reaction mixture was refluxed for 1 hour and stirred at room temperature overnight. The yellow crystalline product was separated by filtration and washed with 2×30 ml of cold 60% EtOh and air dried to yield 25.733 g (95.9%) of salen.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C@@H:11]([CH3:24])[C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13](O)=[O:14].CN1C=CN=C1.CS(Cl)(=O)=O>C(#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:13](=[O:14])[C@@H:12]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:11]([CH3:24])[NH:10][C:3]=2[CH:4]=1)#[N:9]
Reactant: C[C@H](Nc1cc(C#N)ccc1N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CC#N
Product: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
A mixture of (2S,3S)-3-(2-amino-5-cyanophenylamino)-2-(tert-butoxycarbonylamino)butanoic acid (4.9 g, 14.7 mmol) in acetonitrile (96 ml), was cooled in an ice water bath, then 1-methylimidazole (3.5 ml, 44.0 mmol) was added and the reaction was stirred at 0° C. for 20 min, then methanesulfonyl chloride (1.31 ml, 16.9 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at RT for 2 h, then concentrated to 13 volume and treated with water (˜200 ml, dropwise addition). The resulting solid was separated by filtration, washed with H2O, and dried under vacuum at 50° C. for 3 h to afford tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (4.2 g). The aqueous solution was extracted with EtOAc, dried over Na2SO4, and purified by flash chromatography (0-60% EtOAc in DCM) to afford additional product (0.4 g). MS m/z 339 (MNa)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:43]=[C:44](/[C:46]1[CH:63]=[CH:62][C:49]([CH2:50][N:51]2[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]2)=[CH:48][CH:47]=1)\[NH2:45]>C(#N)C>[C:1]([C:5]1[C:6]([C:16]2[O:18][N:45]=[C:44]([C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:52][CH:53]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:54]4)=[CH:62][CH:63]=3)[N:43]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1c(C(=O)O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(C)(C)C)n3)cc2)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 4-tert-butyl-5-phenylisoxazole-3-carboxylic acid (25 mg, 0.102 mmol), HOBt (28.1 mg, 0.183 mmol), and diisopropylethylamine (0.071 mL, 0.408 mmol) in acetonitrile (1 mL) was added EDC (45.9 mg, 0.240 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 31.1 mg, 0.102 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-tert-butyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylate.