Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:21])([O:19][CH3:20])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C(O)(=O)C.O.[Fe]>[C:1](=[O:21])([O:19][CH3:20])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH3:18]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 4-(3-(dimethylamino)prop-1-ynyl)-2-methyl-5-nitrophenyl methyl carbonate (120 mg; 0.41 mmol) in ethanol (2.7 mL) and glacial acetic acid (1.5 mL) was added Fe (92 mg, 1.64 mmol). The mixture was heated at 60° C. for 1 h and then cooled to room temperature. The mixture was diluted with water and carefully neutralized with solid Na2CO3. The resulting solution was extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to provide 5-amino-4-(3-(dimethylamino)prop-1-ynyl)-2-methylphenyl methyl carbonate (85 mg, 79% yield). LC/MS m/z 218.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([CH3:11])[CH:3]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:36]([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45]C2C=CC([N+]([O-])=O)=CN=2)[N:32]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:36]([C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)[N:32]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Product: Cc1cc(Cl)ccc1-c1nc(NCCNc2ccc(C(F)(F)F)cn2)ncc1-c1ncc[nH]1

Procedure:
[4-(4-chloro-2-methylphenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 4-chloro-2-methylbenzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[NH:20]1[C:28]2[N:23]3[C:24](=[N:29][CH:30]=[C:22]3[C:21]1=[O:31])[CH:25]=[CH:26][CH:27]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C.O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:20]2[C:28]3[N:23]4[C:24](=[N:29][CH:30]=[C:22]4[C:21]2=[O:31])[CH:25]=[CH:26][CH:27]=3)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=c1[nH]c2cccc3ncc1n32
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)c3cnc4cccc2n43)CC1
Yield: 43.5 %

Procedure:
A mixture containing 5.68 g (20.0 mM) of (1-tert-butoxycarbonylpiperidin-4-ylmethyl) methanesulfonate, 4.35 g (20.0 mM) of 1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one.2NaCl, and 3.58 ml (24.0 mM) of DBU in 50 ml of DMF was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured in 50 ml of iced water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of purified water twice and, then, with 50 ml of saturated aqueous NaCl solution and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=10:1) to provide 3.00 g (yield 42.1%) of the title compound as a brown amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3-hydroxypropyl)morpholine (0.623 mL, 4.5 mmol), triphenylphosphine (1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropyl azodicarboxylate (0.886 mL, 4.5 mmol). The mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the crude mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dichloromethane to give N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (890 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.36 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:8]2[C@@H:9]([OH:16])[C@H:10]([Br:15])[C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.[C:26]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:8]2[C@@H:9]([O:16][C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:26](=[O:28])[CH3:27])[C@H:10]([Br:15])[C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](O)[C@H](Br)C(C)(C)O2
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](OC(=O)[C@H](C)CSC(C)=O)[C@H](Br)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (±)-trans-7-acetylamino-3-bromo-4-hydroxy-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran, ethylene chloride and pyridine was added (S)-(-)-3-acetylthio-2-methylpropionyl chloride under ice-cooling over 5 minutes and stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give (±)-trans-7-acetylamino-3-bromo-3,4-dihydro-6-nitro-2,2-dimethyl-4-[(S)-(-)-3-acetylthio-2-methylpropionyloxy]-2H-1-benzopyran.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]\[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:3])[CH3:2].[CH2:25](N)[CH2:26][CH:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:25]([NH:21][C:19](=[O:20])[NH:18]/[N:17]=[C:10]1\[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])[C:16]2[C:11]\1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCN
Reactant: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)N/N=C1\C(=O)N(CCN(C(C)C)C(C)C)c2ccccc21
Temperature: 120 °C
Reaction time: 23 h
Yield: 84 %

Procedure:
A suspension of 1.10 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone and 0.29 g of isopentylamine in a mixture of 150 ml of dry toluene and 20 ml of dry N,N-dimethylformamide was stirred for 23 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) to obtain 1.12 g of (Z)-1-(2-diisopropylaminoethyl)isatin 3-(4-isopentylsemicarbazone) in a viscous oil.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]([CH3:23])[C:12]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.[Cu]I>[F:25][C:4]1[CH:3]=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]([CH3:23])[C:12]1=[O:24]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(Br)cc2F)c1=O
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(C#C[Si](C)(C)C)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
3-(4-Bromo-2-fluoro-5-nitrophenyl)-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (12.85 g), trimethylsilylacetylene (5.93 g), a palladium chloride-ditriphenylphosphine complex (1.06 g) and copper(I) iodide (0.302 g) were suspended in triethylamine (210 ml), and the mixture was stirred at room temperature for 5 hours. After the reaction, triethylamine was distilled off under reduced pressure. Ethyl acetate was added thereto, and insolubles were filtered. Then, ethyl acetate was distilled off, and the resulting residue was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 3-{2-fluoro-5-nitro-4-[2-(trimethylsilyl)-1-ethynyl]phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (11.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cnc(N)o1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) (1 g, 3.4 mmol), ethyl 2-amino-1,3-oxazole-5-carboxylate (0.82 g, 5.2 mmol), HOBt (0.708 g, 5.2 mmol), EDCI (1.005 g, 5.2 mmol) and NEt3 (730 μL, 5.2 mmol) in DMF (50 mL) was stirred at room temperature for 2 days. The reaction was not completed and 2.5 eq of EDCI and HOBt were added and the reaction was heated at 40° C. and stirred for a further 14 days. Again no completed reaction was obtained. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM/MeOH (90/10) to give after crystallisation from diisopropyl ether, the title compound as a yellow solid (98 mg, 6%). LC/MS: m/z 424 (M+H)+. Rt: 3.17 min.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
Isonicotinoyl chloride hydrochloride (320 mg, 1.80 mmol, commercially available product) and triethylamine (480 μl, 3.44 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 4-[2-amino-4-(trifluoromethyl)phenyl]morpholine (196 mg, 0.796 mmol), obtained as described in Referential Example 5-2. The resulting mixture was warmed to room temperature and stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-(4-morpholinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0346) (65.1 mg, 23.2%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[C@H:3]1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[C@H:3]1[C:4]([OH:6])=[O:5]
Reactant: CC1CC(=O)N(C)[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(=O)N(C)[C@@H]1C(=O)O
Reaction time: 5 h
Yield: 133.6 %

Procedure:
1,1-Dimethylethyl 1,3-dimethyl-5-oxoprolinate (0.770 g, 3.62 mmol) was suspended in dichloromethane (5 ml) and treated with trifluoroacetic acid (0.4 ml, 5.4 mmol). The mixture was stirred for 5 hrs and then evaporated. Azeotroping the resulting residue with toluene then gave unreacted starting material (0.600 g). This was again taken up in dichloromethane (2 ml) and treated with trifluoroacetic acid (2 ml) once more. After stirring for 2 hrs the mixture was evaporated and the residue again azeotroped with toluene (10 ml) to give crude 1,3-dimethyl-5-oxoproline (0.760 g) which was used without any additional purification.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 32.2 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 prepared in Example 1, indole (234 mg), potassium carbonate (1382 mg), and dimethylformamide (15 mg) were added and the mixture was reacted at 80° C. for 30 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column ghromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (42.3 mg; yield=32.2%) as crystals. Melting point: 157°-158° C. 1H-NMR(CDCl3, δ ppm): 6.46 (s, H3), 8.26 (dd, H5), 7.47 (t, H6), 7.72 (t, H7), 7.58 (d, H8), 7.55 (d, H2'), 6.80 (d, H3'), 7.66 (d, H4'), 7.28-7.42 (m, H5'), 7.28-7.42 (m, H6'), 7.99 (m, H7').
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C.S(=O)(=O)(O)O>[C:2]1([CH2:1][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: c1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of dibenzoylmethane (100 g) and 5% palladium on carbon (10.0 g) in ethyl acetate (600 ml) and concentrated sulfuric acid (15 ml) was hydrogenated at a hydrogen pressure of 60 psi and at room temperature. After 2 hours, the reaction was allowed to cool to room temperature. Reaction mixture filtered through talc. The filtrate was treated with water (2×250 ml) and phases separated. The organic phase was treated with saturated aqueous sodium bicarbonate (250 ml). The organic phase was dried over sodium chloride then magnesium sulfate, filtered, concentrated vacuo to give 75.34 g of 1,3-diphenylpropane.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH:58]([C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:73])[C@H:59]([C:69](O)=[O:70])[CH2:60][CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65]>C(#N)C.CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14]([O:15][C:69](=[O:70])[CH:59]([NH:58][C:72]([O:74][CH2:75][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)=[O:73])[CH2:60][CH2:61][C:62]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:68])=[CH:16][CH2:17][C@@:18]35[OH:21]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(OC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)=CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution comprised of oxycodone free base, 1-1, (517 mg, 1.64 mmol), DIEA (1.5 mL, 8.6 mmol) in 9 mL of anhydrous acetonitrile was stirred at rt for 20 min and mixed with a solution containing DMAP (400 mg, 3.3 mmol), DCC (1.01 g, 4.1 mmol), and HOBt (440 mg, 3.3 mmol) in 6 mL of anhydrous acetonitrile. Cbz-L-Glu(OtBu)-OH (1.1 g, 3.3 mmol) was then added to the combined solutions. The mixture was stirred for 45 h at rt, precipitated DCU removed by filtration, and the solution concentrated under reduced pressure to give a dark-brown oil. HPLC analysis indicated that 39% of the oxycodone had been converted to 3-1. The brown oil containing crude 3-1 was dissolved in 20 mL of acetone, cooled in an ice bath for 2 h, and filtered to remove precipitated DCU. The filtrate was concentrated to dryness, and subjected to flash chromatography using a gradient of 0–10% methanol in DCM. The fractions containing 3-1 were combined and concentrated to dryness. The residue was treated with 20 mL acetone and filtered to remove precipitated DCU. The filtrate was concentrated to dryness under reduced pressure to yield partially purified 3-1.
Reaction SMILES: NC[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N+]([O-])(O)=O.[C:18]([N:21]1C(C)=CC(C)=N1)(=[NH:20])[NH2:19].C(N(CC)C(C)C)(C)C.Cl>O1CCCC1>[NH:20]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)[C:18]([NH2:21])=[NH:19]
Reactant: NCc1ccc(CCC(=O)O)cc1
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: N=C(N)Nc1ccc(CCC(=O)O)cc1
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
3.70 g (19.14 mmol) of the oily methyl ester of 3-(4-aminomethylphenyl)propionic acid was dissolved in 150 ml of tetrahydrofuran. To the solution were added 5.80 g (28.71 mmol) of 1-amidino-3,5-dimethylpyrazole nitrate and 4.70 g (36.37 mmol) of N,N-diisopropylethylamine, and the mixture was heated overnight under reflux. The reaction mixture was concentrated under vacuum to give an oil. This oil was reacted with 70 ml of 5% HCl for 3 hours under reflux. The reaction mixture was passed through a filter and the filtrate was ice-cooled. The pH of the filtrate was adjusted to 6.4 by addition of 10% aqueous NaOH. The so adjusted filtrate was stirred for 30 minutes under ice-cooling. The precipitating crystal was recovered by filtration and washed successively with distilled water and tetrahydrofuran. Upon drying, 2.85 g of a pale yellow crystal was obtained (yield: 67.4%). m.p.≥300° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCOCC1

Procedure:
Oxalyl chloride (1384; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 2 (119 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10) afforded the title compound as a white solid.
Reaction SMILES: [NH3:1].[C:2]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[CH:3]1>>[C:2]([OH:7])(=[O:8])/[CH:3]=[CH:4]\[C:5]([NH2:1])=[O:6].[C:2]([OH:7])(=[O:8])/[CH:3]=[CH:4]/[C:5]([NH2:1])=[O:6]
Reactant: N
Reactant: O=C1C=CC(=O)O1
Product: NC(=O)/C=C/C(=O)O
Product: NC(=O)/C=C\C(=O)O

Procedure:
Components (a) and (b) can also be reacted in a system in which a liquid phase exists in addition to one or more solid phases. This takes place, for example, by reacting gaseous amines or ammonia with molten maleic anhydride. This reaction is carried out in the range from about 50 to 100° C. In this case, component (b) is added at a rate such that the temperature does not rise above 100° C. Several solid products are formed in the reaction, such as maleamic acid, fumaramic acid or their ammonium salts. After completion of the reaction, the products are in the form of powdered solids, and no liquid phase then exists.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:29][CH3:30].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>COCCOC>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([C:10]([NH:18][C:19]5[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=5[Cl:28])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]4)=[CH:8][C:7]=3[O:29][CH3:30])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(OCCCCl)c(OC)cc23)c(Cl)cc1Cl
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCCN4CCC(N5CCCCC5)CC4)c(OC)cc23)c(Cl)cc1Cl
Yield: 10.4 %

Procedure:
A mixture of 260 mg (0.56 mmol) of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) and 380 mg (2.24 mmol) of [1,4′]bipiperidinyl are heated in 3 mL of ethylene glycol dimethyl ether at 85° C. for sixteen hours to yield the crude product. Following removal of the solvent in vacuo, the crude product is purified by silica gel chromatography (eluting with 7:3 methylene chloride/methanol) to give 35 mg of 7-(3-[1,4′-bipiperidin]-1′-ylpropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a white solid, mp 130-132° C.