Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([S:40](=[O:59])(=[O:58])[N:41](CC3C=CC(OC)=CC=3OC)[C:42]3[S:46][N:45]=[CH:44][N:43]=3)=[CH:35][C:34]=2[F:60])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:12]=3[CH:31]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:13]1[C:12]2[CH:31]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:32][C:33]3[C:34]([F:60])=[CH:35][C:36]([S:40]([NH:41][C:42]4[S:46][N:45]=[CH:44][N:43]=4)(=[O:58])=[O:59])=[C:37]([F:39])[CH:38]=3)[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate (1.70 g, 1.92 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The residue was taken up in methanol (15 mL) and filtered. The filtrate was concentrated in vacuo and triturated with dichloromethane/diethyl ether (2:1 v/v, 15 mL) to afford 4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless solid in 63% yield (0.65 g): 1H NMR (300 MHz, DMSO-d6) δ8.49 (s, 1H), 7.95 (s, 1H), 7.72-7.66 (m, 1H), 7.62-7.59 (m, 2H), 7.49-7.42 (m, 2H), 7.26-7.24 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 1H), 6.47-6.40 (br s, 2H); MS (ES+) m/z 535.8 (M+1), 537.8 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1

Procedure:
A solution of 2.7 g of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 40 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 3.75 g of (E)-2-[2-[3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 209°-210° C. from tetrahydrofuran.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:30][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: CCOC(=O)CCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 4-bromobutanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.95 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.10-3.95 (m, 4H), 3.91 (s, 3H), 2.54 (t, 2H), 1.90 (m, 2H), 1.16 (t, 3H); MS (ESI): 466.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:35]2[CH:36]=[C:37]([C:39]([F:41])([F:40])[F:42])[CH:38]=[C:33]([F:32])[CH:34]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15, step (e-f) using 3-fluoro-5-trifluoromethylphenylboronic acid in step (e).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:18]([CH3:20])[CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cc1C=O
Yield: 98.7 %

Procedure:
To a solution of 5-bromosalicylaldehyde (5.0 gm, 0.025 mol) in DMF (40 mL) were added powdered potassium carbonate (5.15 gm, 0.037 mol) and 2-iodopropane (3.5 mL, 0.035 mol) dropwise with stirring. The mixture was stirred overnight at room temperature, partitioned between diethyl ether and water. The aqueous was extracted with ether, and the combined organic layers were washed with water, saturated brine solution, dried (Na2 SO4), and evaporated to afford 6.0 gm of pure title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:43])([F:42])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[C@@H:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:23]2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH3:20])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>ClCCl>[F:42][C:8]([F:7])([F:43])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH:28]=[O:29])[C@@H:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:23]2[C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH3:20])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](CO)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C=O
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
To a solution of oxalyl chloride (0.22 mL, 2.6 mmol) in 40 mL dichloromethane was slowly added under nitrogen DMSO (0.13 mL, 1.8 mmol) at −78° C. The mixture was stirred for 5 min at the same temperature. Intermediate alcohol obtained from Step B (0.46 g, 8.6 mmol) in 15 mL dichloromethane was added by injection. Stirring continued at −78° C. for 20 min. Triethylamine (0.48 mL, 3.4 mmol) was added. The cooling bath was removed and the mixture was stirred until the temperature rose to −0° C. The reaction was quenched with sat. aq. NH4Cl. The organic layer was separated and the aqueous was extracted with dichloromethane (40 mL×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum to give 0.45 g title compound which was used without further purification. 1H-NMR (CDCl3): δ: 9.64 (1H, s), 7.71 (1H, s), 7.22 (2H, s), 7.00 (2H, m), 6.86 (2H, m), 4.43 (1H, q, J=6.4 Hz), 3.80 (2H, q, J=7.1 Hz), 3.34 (1H, m), 2.84 (2H, m), 2.66 (1H, m), 2.46 (1H, m), 2.32 (1H, m), 1.64 (2H, m), 1.42 (1H, m), 1.35 (3H, d, J=6.4 Hz), 0.82 (3H, t, J=7.1 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11](=[O:22])[N:12]([CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:8]=2[CH:7]=1)[CH3:4].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([S:35]([C:28]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:37])=[O:36])[C:11](=[O:22])[N:12]([CH2:13][CH2:14][N:15]([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20])[C:8]=2[CH:7]=1)[CH3:4]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(CCN(C(C)C)C(C)C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(CCN(C(C)C)C(C)C)c(=O)n2S(=O)(=O)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
0.05 g of sodium hydride as a 60% dispersion in oil is added in portions to a solution of 0.5 g of 5-ethoxy-1,3-dihydro-3-[2-(N,N-diisopropylamino)ethyl]-2H-benzimidazol-2-one in 7 ml of THF and the mixture is stirred for 30 minutes at RT. 0.42 g of 2,4-dimethoxybenzenesulfonyl chloride is then added and the mixture is stirred for 1 hour at RT. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.7 g of the expected product after crystallization from iso ether. M.p.=132° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:16]=2[N+:26]([O-])=O)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:16]=2[NH2:26])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-((1-acetylpiperidin-4-yl)methyl)-3-(2-nitro-5-(thiophen-2-yl)phenyl)urea (0.09 g, 0.22 mmol) in methanol was added Pd/C (0.03 g, 0.028 mmol, 1.2 equiv.). The reaction mixture was degassed then stirred at room temperature under H2 atmosphere for 1 h. The reaction was filtered through celite and concentrated. The crude solid was washed with ether, and dried under reduced pressure to obtain of pure 1-((1-acetylpiperidin-4-yl)methyl)-3-(2-amino-5-(thiophen-2-yl)phenyl)urea (0.05 g, 60% yield). ESI+ MS: m/z 373 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ 7.66 (d, J=2.0 Hz, 1H), 7.58 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.10 (dd, J=3.5 Hz, 1H), 7.04-7.02 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.31 (t, J=6.0 Hz, 1H), 4.89 (bs, 2H), 4.36 (d, J=13.0 Hz, 1H), 3.81 (d, J=13.5 Hz, 1H), 3.0-2.96 (m, 3H), 1.90 (s, 3H), 1.71-1.64 (m, 3H), 1.10-1.07 (m, 1H), 0.98-0.95 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:40].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COCCC#Cc1cc(F)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 57.6 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-fluoro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (154 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.25 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (183 mg, 57%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.46 (t, 2H), 2.72 (t, 2H), 3.33 (s, 3H), 3.52 (t, 2H), 3.60 (m, 4H), 3.93 (s, 3H), 4.19 (t, 2H), 6.14 (s, 2H), 6.84 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 539.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH3:18])=[O:16].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:15]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([O:17][CH3:18])=[O:16]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)N1CCN(Cc2ccccc2)CC1
Yield: 81.8 %

Procedure:
To a solution of 35.2 g (0.20 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 17.0 g (0.18 mole) of methyl chloroformate in 110 ml of CHCl3. The mixture was allowed to reflux during 2.5 hours and was made basic with 16 g of sodium hydroxide in 100 ml of water. The nonaqueous layer was separated, dried over magnesium sulphate and concentrated. The residue was distilled b.p. 108°-10° C. at 0.1-0.2 mmHg to give 34.5 g of 1-carbomethoxy-4-benzylpiperazine.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH3:5].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].N1C=CC=CC=1>CCOCC>[C:6]([O:9][CH:3]([CH2:4][CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=CCCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=CC(CC)OC(C)=O
Temperature: 0 °C

Procedure:
The above pentene derivative (9.0 g, 25 mmols) and acetic anhydride (3.0 g, 30 mmols) are dissolved in ether (200 ml), followed by dropwise adding pyridine (5 ml), while stirring the solution under ice cooling, stirring the reaction liquid under ice cooling for one hour, elevating the temperature up to room temperature, stirring for 3 hours, pouring the reaction mixture into ice water after completion of the reaction, extracting with toluene (150 ml), washing the organic layer with water, drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 5-(4-(4-propylphenyl)phenyl)cyclohexyl)-3-acetyloxy-1-pentene pale yellow oil.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:10]=1)=[O:8])C.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:43]([N:6]1[CH:5]=[CH:4][C:13]2=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:10]=[C:9]2[C:7]1=[O:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) and p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml) was heated to reflux in round bottom flask fitted with a Dean-Stark condenser. After 1 hour, the reaction was cooled to room temperature, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), a concentrated, in vacuo. The crude material (0.49 g) was purified on a Biotage™ Flash 40S column using 10–20–40% ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg, 16%): +ES MS (M+1) 480.1; 1H NMR (500 MHz, CD2Cl2) δ 7.50 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38–7.27 (m, 7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz, 1H), 5.21 (s, 2H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](OCC)=[O:6].[CH2:14]([O:21][CH2:22][C:23](=[NH:25])[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O(C)[Na].Cl>CO>[CH2:14]([O:21][CH2:22][C:23]1[N:24]=[C:5]([OH:6])[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][N:25]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(N)COCc1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)[N+](=O)[O-]
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(COCc2ccccc2)nc1O

Procedure:
To a mixture of step A product, 3-c, (24 g, 127 mmol) and 2-(benzyloxy)acetimidamide (25.9 g, 127 mmol) in CH3OH (30 mL) was added with NaOCH3 (14.2 g, 254 mmol) and 30° C. overnight. The pH of reaction mixture was adjusted to 7 by addition of concentrated HCl. The solids were filtered to afford the crude product, 3-d, (25 g). LC-MS (M+H)+ 262.1
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1>C1COCC1.CCO.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/CCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 6 h
Yield: 100.8 %

Procedure:
tert-Butyl 4-[(E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-butenyl]benzoate (15.1 g) was dissolved in 1:1 THF/EtOH (150 mL). 10% Pd on carbon (6.0 g) was added and the reaction placed on a Parr hydrogenator under 50 psi of H2. The reaction was shaken for 6 h. The reaction was filtered through a pad of celite and the celite washed with ethanol (3×100 mL). The organic extracts were concentrated to afford 15.3 g of tert-butyl 4-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]benzoate: 1H NMR (CDCl3, 400 MHz) 7.88 (d, 2H, J=8.1 Hz), 7.82 (dd, 2H, J=3.0, 3.1 Hz), 7.77 (dd, 2H, J=3.0, 3.2 Hz), 7.2 (d, 2H, J=8.1 Hz), 3.7 (t, 2 h, J=6.9 Hz), 2.7 (t, 2H, J=6.9 Hz), 1.7 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][Cl:19])[CH:11]=[C:10]([CH3:16])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(CO)nc(Nc2ccccc2)n1
Product: Cc1cc(CCl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
Phosphorus oxychloride (10 ml) was added to 1.5 g of 2-anilino-4-hydroxymethyl-6-methylpyrimidine and the mixture was heated under reflux for 15 minutes. After completion of the reaction, excessive phosphorus oxychloride was removed by distillation under reduced pressure. After dissolving the residue in dichloromethane, a 10% aqueous solution of sodium hydroxide was gradually added until the solution became alkaline under reflux of dichloromethane. After cooling to room temperature, the organic layer was washed with water, dried over magnesium sulfate and concentrated. The residual solid was recrystallized to obtain 1.2 g (yield: 73%) of 2-anilino-4-chloromethyl-6-methylpyrimidine having a melting point of 100°-101° C.
Reaction SMILES: [C:1]1([CH:11]=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O.[CH:22]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])=[CH2:23].C(N(CC)CC)C>>[C:1]1([C:11]2[CH2:23][CH:22]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ON=Cc1cccc2ccccc12
Reactant: C=CP(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2cccc3ccccc23)=NO1

Procedure:
Preparation is carried out in analogy to Example 1 from 31.2 g (0.2 mol) of 1-naphthaldoxime, 29.4 g (0.22 mol) of N-chlorosuccinimide, 29.2 ml (0.22 mol) of dimethyl vinylphosphonate and 30.6 ml (0.22 mol) of triethylamine, with 56 g of oily compound being obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:31][CH2:30][C:18]3([CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][C:18]3([CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(F)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (0.6 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.31 mmol, 1.0 eq.) in methylene chloride (2 ml) and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-22).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 9, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O1CCCC1.O>[OH:20][C:16]1([CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH2:15]1
Reactant: CN1CCCC(=O)C1
Reactant: Cc1cc(C)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC2(O)CCCN(C)C2)on1
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethylisoxazol (4.86 g, 50 mmol) in dry tetrahydrofuran (15 ml) cooled to -78° C was added butyllithium (2.5 M in hexane, 50 mmol). The reaction mixture was stirred for 0.5 h. 1-methyl-piperidin-3-one (2.70 g, 23.9 mmol) dissolved in tetrahydrofuran (25 ml) was added. The reaction mixture was stirred for another 2 h at -78° C. Water (50 ml) was added and the reaction mixture was acidified with concentrated hydrochloric acid. The water phase was extracted with ether (2×50 ml), then made alkaline with potassium carbonate and extracted with methylene chloride (4×50 ml). The combined methylene chloride phases were dried over magnesium sulphate and evaporated giving the title compound in 4.18 g (83%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)c(Cl)cc1F
Temperature: 90 °C
Yield: 77.4 %

Procedure:
A suspension of 2-chloro-4-fluoro-5-nitrophenol (21.8 g, 124 mmol), calcium chloride (30.6 g, 248 mmol) and reduced iron (20.8 g, 372 mmol) in ethanol (500 mL)/water (50 mL) was stirred with heating at 90° C. for 4 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethyl acetate. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (500 mL), washed with water (250 mL×2), 5% aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (15.5 g, 77%) as a black powder. This was used for the next reaction without further purification.