Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:50][CH2:49][C:46]3[CH:45]=[CH:44][C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:48][CH:47]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: NCc1ccc(CN2CCCC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and 1-[4-(pyrrolidin-1-ylmethyl)phenyl]methanamine (37 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-n2nccc2N)cc1OC(F)F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15 g (0.065 mol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole was dissolved in 60 ml acetic acid and treated with 7.35 g (0.072 mol) acetic anhydride. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 10° C. 4.95 g (0.078 mol) Fuming nitric acid was added dropwise and the mixture treated with 8.0 g (0.078 mol) acetic anhydride. After stirring for 18 hours at room temperature, the reaction mixture was added to 500 ml ice-water. It was extracted three times with ethyl acetate, the organic phases were washed with water and concentrated. The residue was treated with 80 ml ethanol and 40 ml concentrated hydrochloric acid. After heating for 8 hours under reflux, the ethanol was removed and the residue extracted with ethyl acetate. The concentrated ethyl acetate phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether and ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:33]([O:34][CH3:35])[CH3:32])=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(C(=O)O)cc1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1

Procedure:
The product from Example 88A and N,O-dimethylhydroxylamine hydrochloride were processed as described in Example 68D to provide the title compound. MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:5])[OH:4])[CH3:2].[CH3:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29]Cl)=[O:27].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:4])[O:5][CH2:29][O:28][C:26](=[O:27])[C:25]([CH3:32])([CH3:31])[CH3:24])[CH3:2]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCP(=O)(O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedures of Example 1, P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinic acid (0.30 g, 0.80 mmol) and chloromethyl 2,2-dimethylpropanoate (0.24 g, 1.6 mmol) are reacted together in the presence of triethylamine (0.23 ml) and DMF (3 ml) to give 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinate.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[Al+3].[Cl-].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask with a stir bar was charged with the product of Example 1B (3 g, 12.2 mmol) and 60 mL of dichloromethane. The reaction solution was cooled to 0° C. and AlCl3 (4.86 g, 36.5 mmol) was added in portions. The mixture was allowed to stir for 20 min, and then acetyl chloride (954 μL, 13.4 mmol) was added dropwise. After stirring for 15 minutes, the reaction mixture was slowly pored into a beaker with ice water and diluted with 120 mL of ethyl acetate. The layers were separated and the organic layer washed with 1 N NaHCO3 (×2), brine (×2), dried over Na2SO4, and filtered. Evaporation of the solvents afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.17 (m, 2 H), 1.18 (t, 3 H), 1.39-1.62 (m, 3 H), 1.68-1.88 (m, 5 H), 2.17-2.26 (m, 2 H), 2.52-2.57 (s, 3 H), 4.07 (q, J=7.12 Hz, 2 H), 7.25-7.46 (m, 2 H), 7.77-7.94 (m, 2H); MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 99.8 %

Procedure:
A solution of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate (1.33 g, 2.29 mmol) and 10% Pd/C (cat.) in MeOH (20 mL) was stirred under a hydrogen atmosphere (15 psi) for 1.5 h. The solution was filtered through celite and evaporated to afford the title compound (1.26 g, quant.) as a light yellow solid that was used without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2C(OC(C)(C)C)=O)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][NH:38]2)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Yield: 89.1 %

Procedure:
N-[(1R)-2-(4-(2-[(2-aminoethyl)amino]phenyl)piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl] ((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide was prepared according to Preparation XVI using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]-ethyl}amino)phenyl]-piperazinyl}-1-[(4-chlorophenyl)-methyl]-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (150 mg, 0.18 mmol) and 25 mL of EtOAc satd with HCl. The crude product was concentrated to provide the desired product (90 mg). MS (ESI, pos. ion) m/z: 561 (M+H), (ESI, neg. ion) m/z: 559 (M−H). Calc'd for C31H37ClN6O2: 560.27.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C>[CH:27]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:3][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:9][CH:8]=4)[O:14][N:13]=3)=[CH:20][N:19]=2)[CH2:26][CH2:25]1)([CH3:29])[CH3:28]
Reactant: C1CCNCC1
Reactant: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CCl)cc4)n3)cn2)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CN5CCCCC5)cc4)n3)cn2)CC1
Yield: 100 %

Procedure:
A mixture of 1-(5-(5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropylpiperazine, hydrochloride (280 mg, 0.65 mmol, prepared as described in Example 41, 96% ethanol (20 mL) and piperidine (0.2 mL, 2.1 mmol) heated at reflux temperature for 4 h. The mixture was evaporated to give a solid residue which was purified by column chromatography on silica gel (75 g, Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of dichloromethane and methanol (7:3). Collecting the proper fractions afforded 310 mg (100%) of 1-isopropyl-4-{5-[5-(4-piperidin-1-ylmethylphenyl)[1,2,4]oxadiazol-3-yl]pyridin-2-yl}piperazine. The free base (310 mg) was dissolved into ethanol (20 mL) and a 1 N hydrochloric acid solution (1.5 mL) was added. When dissolved, the mixture was evaporated and the solid residue was re-crystallised from ethanol to give 240 mg (67%) of the title compound.
Reaction SMILES: Br[CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].[NH3:30].Cl>ClCCCl.C(OCC)(=O)C>[NH2:30][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4]
Reactant: N
Reactant: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
23.04 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine was dissolved in 65 ml of 1,2dichloroethane and 65 ml of ethyl acetate, into which ammonia gas was passed at -15° C. for 1 hour. This solution was placed in a sealed tube and reacted at 110° C. for 2 hours. In order to complete the reaction, ammonia was again passed into the solution at -15° C. for 30 minutes in the sealed tube where the reaction was continued at 110° C. for 1.5 hours. After ice-cooling, the reaction solution was charged into ice-cooled 2N hydrochloric acid, to which ethyl acetate was added, from which the resultant aqueous phase was collected. sodium carbonate was added to the aqueous phase under ice-cooling conditions so that the pH was adjusted to 8, followed by extraction with chloroform under salting-out conditions. The extract was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. followed by filtration and concentration to obtain 12.97 g (yield 64%) of the intended compound.
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[NH:9])C=CC=CC=1.[NH2:42][OH:43].Cl.NO.[OH-].[Na+]>CO>[Br:35][C:33]1[CH:34]=[C:29]2[CH2:28][CH2:27][C:26]3[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]=3[CH:24]([CH:21]3[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][CH:12]4[CH2:13][CH2:14][N:10]([C:8](=[NH:9])[NH:42][OH:43])[CH2:11]4)[CH2:23][CH2:22]3)[C:30]2=[N:31][CH:32]=1
Reactant: NO
Reactant: N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(NO)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve the product of Example 9 (1 equivalent) in CH3OH. Prepare an aqueous solution of hydroxylamine by dissolving hydroxylamine hydrochloride (1 equivalent) in 50% (w/v) NaOH (1 equivalent) and add to the mixture; stir at 25° C. for 18 h. Evaporate the solution to dryness and triturate with water. Filter off the solid and purify on silica gel to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].CCCCCCC>CO>[CH3:20][CH2:19][N:21]([C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:16])[C:13]=2[C:14]=1[OH:15])=[O:4])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Reactant: CCNc1ccccc1
Solvent: CO
Solvent: CCCCCCC
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Laquinimod acid was prepared according to the method described in U.S. Pat. No. 6,875,869: 5-Chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq 2-2.88 ml), and heptane (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during 6 hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield laquinimod acid (3.94 g, 98%) as white to off-white crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC1c2cc3c(cc2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCO3
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reaction time: 1.25 h
Yield: 81 %

Procedure:
To a reaction vessel, 5 g (0.012 mol) compound XIII, 30 ml ethanol and 100 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction was kept at room temperature for 1-1.5 h, filtered, the filter cake was washed with ethyl acetate, dried, and 3.4 g compound II-3 was obtained, with yield of 81%. 1H NMR (D2O): δ 1.24 (d, 3H, J=7.0 Hz), 1.44-1.58 (m, 5H), 1.98 (m, 2H), 2.96 (m, 2H), 3.21-3.25 (m, 1H), 3.44 (d, 2H, J=12.4 Hz), 3.64-3.72 (m, 1H), 4.34 (q, 1H, J=6.6 Hz), 5.94 (s, 2H), 6.72 (s, 1H), 6.79 (s, 1H); MS (ESI): m/z 303 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]COCC.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[N:34]S(C(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[NH2:34][C:22]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[C:23]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:24]=2[O:30][C:31]2[C:21]1=[CH:20][C:19]([Br:18])=[CH:33][CH:32]=2
Reactant: CCOCOc1ccccc1Br
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1(c2ccccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Butyllithium solution, 2.5m in hexanes (1.257 mL, 3.14 mmol) was added dropwise to a solution of 1-bromo-2-(ethoxymethoxy)benzene (0.726 g, 3.14 mmol) in THF 20 mL at −78° C. The reaction was stirred for 25 min. Then N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (1.0 g, 2.417 mmol) in THF was added. The reaction was warmed up to RT and stirred for an hour. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with gradient of 15-50% EtOAc/Hexane. The resulting material was dissolved in dry MeOH 10 mL and cooled in an ice bath. Hydrochloric acid, 4.0M solution in 1,4-dioxane (20 mL, 80 mmol) was added and mixture was stirred at RT for 4 h. The reaction was quenched with 10% sodium carbonate solution and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated to give the desired product which was used without further purificationMS m/z=402.8 [M+H]+.
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:15][C:16](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:7]([N:15]=[C:16]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCNC(=N)N
Agent: [Na]
Product: CCCCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in Example 18A, and using 2.3 g. of sodium, 22 g. of n-octylguanidine sulfate, and 15.5 g. of n-octyl isocyanate, there was obtained 26 g. of 1 -n-octylamidino-3-n-octylurea having the structural formula ##EQU69## as a white crystalline solid which melted at 60°-62°C. The solubility of this base in water at 25°C. was less than 0.25 per cent. IN 95 per cent ethyl alcohol it was soluble to the extent of 5 per cent; a precipitate formed when the 5 per cent ethanolic solution was diluted with four volumes of water.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:25]>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])[CH2:38][CH2:37]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1ccccc1N1CCN(C(=O)Nc2nc3ccccc3nc2OCC)CC1
Yield: 76.5 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-ethoxyphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: C1(C=[CH:8][C:9]([C:11]2[CH:16]=C[CH:14]=[CH:13][CH:12]=2)=[O:10])C=CC=CC=1.[Li].C(=O)C.C(#[N:23])C>>[C:9]([C:11]1[CH:16]=[N:23][CH:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:8]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CC#N
Agent: CC=O
Agent: [Li]
Product: CC(=O)c1cccnc1

Procedure:
In a variation on this chalcone procedure, the lithium compound IV can be reacted with acetonitrile or with acetaldehyde followed by oxidation to give the corresponding 3-acetylpyridine. This acetylpyridine is then reacted with an appropriate substituted aldehyde in a Claisen-Schmidt condensation to give a chalcone as described earlier although it would be an isomeric ("reverse") chalcone. That is, reduction of the carbonyl group of the chalcone would give an alcohol of type III which would be similar to that obtained according to scheme I discussed earlier.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[N:3]=[CH:2][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Yield: 94.9 %

Procedure:
To a solution (60 ml) of 4,6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs. The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give tert-butyl 4-(6-chloropyrimidin-2-yl)piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(N2CCC(F)(F)CC2)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: FC1(F)CCN(C2CC=C(N3CCCC3)CC2)CC1
Yield: 96.2 %

Procedure:
Heat a solution of 4-(4,4-difluoro-piperidin-1-yl)-cyclohexanone (1.93 g 8.88 mmol), pyrrolidine (0.89 mL, 10.7 mmol) and p-toluenesulfonic acid (1 crystal) in cyclohexane (50 mL) to reflux with a Dean-Stark trap for 7 h. Cool the solution and filter through a plug of cotton wool. Evaporate to give 2.31 g, 96% yield of 4,4-difluoro-1-(4-pyrrolidin-1-yl-cyclohex-3-enyl)-piperidine as an oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=[CH:23][C:24]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:26]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCOC(=NC(=O)c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and biphenyl-4-carboxylic acid chloride, there is obtained ethyl N-(4-biphenylylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 52°-58° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C1COCC1.C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate (900 mg, 3.76 mmol) in THF/ethanol (1:1, 30 mL) was slowly added 10% Pd/C (93 mg) at room temperature. The mixture was hydrogenated for 1 hour at 46 psi and then filtered with celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=2/1.