Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[C:10]([CH3:17])([CH3:16])[C:11](OCC)=[O:12].C(NC(C)C)(C)C>CN(C=O)C>[CH3:16][C:10]1([CH3:17])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:11]1=[O:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC1(C)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
A mixture of 1,2-phenylenediamine (II, 7.55 g), ethyl 2-bromoisobutyrate (III, 12.8 ml), diisopropylamine (15.5 ml) and DMF (30 ml) is heated at 110° for 5 hr, after which an additional ethyl bromoisobutyrate (III, 0.5 ml) and diiopropylethylamine (0.8 ml) is added. After heating for 2 more hours, the reaction is cooled and the DMF is removed in under reduced pressure. The residue is stored overnight in the freezer and then partitioned between ethyl acetate, water, and saline. The phases are separated and the organic phase is dried over magnesium sulfate, the organic phase is removed under reduced pressure. The residue is chromatographed eluting with ethyl acetate/dichloromethane (20/80). The product crystallizes out in the column. The product is recrystallized from dichloromethane/hexane to give the title compound, mp 173°-174°; NMR (CDCl3) 1.41, 3.72, 6.67, 6.76, 6.87 and 8.50 δ.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>ClCCCl>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: Clc1cccc(Cl)c1Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1Nc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-phenyl)-amine (0.72 g; 1.74 mmol) in 1,2-dichloroethane (5 mL) was added, drop wise, ACE-Cl (0.40 mL; 3.66 mmol) at 0° C. The resulting mixture was stirred at room temperature, overnight, and subsequently concentrated in vacuo. To the residue was added toluene and the mixture was concentrated in vacuo. This last step was repeated twice. To the final residue was added MeOH (5 mL), and this mixture was stirred overnight at RT. Once more the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2 M Aqueous NaOH. The layers were separated, and the organic layer dried (Na2SO4), filtered, and concentrated in vacuo to afford (2,6-dichloro-phenyl)-(4-morpholin-2-yl-phenyl)-amine (0.34 g); which was used as such.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:6]=[O:7].[I-].[K+]>CN(C=O)C.O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[CH2:2][C:3]2[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][CH2:13]1
Reactant: O=Cc1ccc(OCCNc2ccccn2)c(CCl)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(c1)CN(c1ccccn1)CCO2
Temperature: 130 °C

Procedure:
To a solution of 3-chloromethyl-4-[2-(pyridin-2-yl-amino)-ethoxy]-benzaldehyde [compound of step II] (7.45 g, 25.7 mmol) in 340 mL DMF, was added potassium iodide (8.53 g, 51.4 mmol) and the reaction mixture was heated to 130° C. for 1 hour. The reaction mixture was cooled, diluted with 1 L water and extracted with 2×500 mL of ethyl acetate. The ethyl acetate extract was washed with 250 mL brine, dried over anhydrous sodium sulfate and concentrated under vacuum at 40° C. to give 5.9 g crude material. This crude material was purified by silica chromatography using 15% ethyl acetate in petroleum ether to give 4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo [f][1,4]oxazepine-7-carbaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[NH2:43][CH2:44][CH2:45][C:46]1[O:50][N:49]=[C:48]([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=2[CH3:60])[CH:47]=1>C(Cl)Cl>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:43][CH2:44][CH2:45][C:46]2[O:50][N:49]=[C:48]([C:51]3[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=3[CH3:60])[CH:47]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NCCc2cc(-c3ccc(C#N)c(Cl)c3C)no2)[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (31 mg; 0.203 mmol) and DIPEA (0.106 ml) were dissolved in 5 ml of dry DCM. HOBt hydrate (47 mg; 0.304 mmol) and EDCI (58 mg; 0.304 mmol) were added at RT. 4-(5-(2-aminoethyl) isoxazol-3-yl)-2-chloro-3-methylbenzonitrile (53 mg; 0.203 mmol) was added and the reaction was stirred at RT for 4 h. DCM 10 ml of was added and organic layer washed with 1M HCl, saturated NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was triturated with n-heptane to give the title product 32 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 2.51 (s, 3H), 3.12 (t, 2H), 3.63 (m, 2H), 6.75 (s, 1H), 7.30 (bs, 1H), 7.62 (d, 1H), 7.94 (d, 1H), 8.73 (bs, 1H), 14.20 (s, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.CN1C(=O)N(C)CCC1.[CH3:22]/[C:23](=[CH:31]\[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)/[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CI>C1COCC1>[CH3:1][CH:25]([CH2:24]/[C:23](/[CH3:22])=[CH:31]/[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC/C(C)=C/c1ccc(C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCOC(=O)C(C)C/C(C)=C/c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
n-Butyl lithium (1.6 M in hexanes from Fluka, 70 ml, 0.111 mol) was added rapidly to a solution of diisopropylamine (11.7 g, 0.116 mol) in dry THF (200 ml) under nitrogen, maintaining the temperature below −20° C. by cooling in a dry ice-acetone bath. After cooling to −78° C., dry DMPU (14.9 g, 0.116 mol) was added drop-wise for 5 minutes. Then, ethyl (4E)-4-methyl-5-(4-methylphenyl)-4-pentenoate (21.5 g, 0.092 mol) was added in 10 minutes. The reaction was warmed up to 0° C. and kept for 20 minutes at this temperature before cooling back to −78° C. Methyl iodide (66 g, 0.46 mol) was added drop-wise. The reaction was warmed up to room temperature and stirred overnight. It was then poured onto water and extracted twice with diethyl ether. Each organic fraction was washed with water and brine. Combined extracts are dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether. Solvents are removed under vacuum and the product was purified by bulb-to-bulb distillation (125° C./0.04 mbar). 18.5 g of colorless liquid were obtained (yield=81%).
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15]CC(C)C)=[O:14])[CH2:7][CH2:6][CH:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH2:6][CH2:7]1
Reactant: COCCOC1CCC(C)(C(=O)OCC(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOC1CCC(C)(C(=O)O)CC1
Temperature: 100 °C

Procedure:
A mixture of isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (D68, 27 g, 49.6 mmol), 1,4-dioxane (100 mL) and 3M aqueous sodium hydroxide (100 mL, 300 mmol) was heated at 100° C. for 18 h then cooled and partitioned between water and diethyl ether. The aqueous phase was acidified and extracted with ethyl acetate to give the desired product. Unreacted starting material remained in the ether wash, so the ether was evaporated and the residue dissolved in a mixture of THF (100 mL), methanol (100 mL), and 6M aqueous sodium hydroxide (100 mL) and heated at 65° C. for 18 h then worked up as before to give additional product, which was combined to give 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (9.5 g, 43.9 mmol, 89% yield) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C(C)=CC=CC=1.CCCCCC>[N:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(O)c1ccc(N2CCCCCC2)nc1
Temperature: 140 °C
Reaction time: 30 h

Procedure:
A suspension of 6-chloronicotinic acid (5.0 g) and perhydroazepine (7.16 mL) in xylene (20 mL) was stirred at 140° C. for 30 hours under an atmosphere of argon. The reaction mixture was cooled to room temperature, diluted with hexane and filtrated. The insoluble material was dissolved in ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.19 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:52]([OH:60])(=[S:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:59][C:52](=[O:60])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCCn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (12.5 g) in tetrahydrofuran (125 ml) were added successively triphenylphosphine (17.6 g) and diethyl azodicarboxylate (10.6 ml) at -10° C. and the solution was stirred at the same temperature for 30 minutes. Then thiobenzoic acid (9.5 ml) was added at the same temperature and the solution was stirred for 3 hours. To the solution was added ethyl acetate (125 ml) and washed with saturated aqueous sodium hydrogen carbonate (125 ml×2) and brine (250 ml). The solution was dried over magnesium sulfate and the solvent was evaporated to give a yellow oil. The oil was chromatographed on a 500 g of silica gel to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[3-(imidazol-1-yl)propyl]pyrrolidine (15.3 g) as a yellow paste.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:21]=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Sodium hydride (225.6 g, 5.64 mol) is dispersed into THF (3 L) and the temperature is lowered to 0-5° C. A solution of (R)-3-hydroxy-1-boc piperidine (891.6 g, 4.43 mol) in THF (3 L) is added over 1 h while maintaining the temperature between 0-5° C. The reaction is stirred for 1 h. 2,6-Dichloropyrazine (600 g, 4.03 mol) as a solution in THE (3 L) is added dropwise over 1.5 h maintaining the same temperature. The reaction is stirred for 2 h at 25-30° C., and then poured onto ice. The mixture is diluted with water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate, filtered, and concentrated. The residual oil is triturated with 5% dichloromethane in hexane to give the product as a white solid. The solid is collected by filtration and dried, to give 1538 g crude material. The crude product is retriturated with 5% dichloromethane in hexanes to give a white solid in quantitative yield. ES/MS m/z 314.1 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C>[CH2:9]([C:13]1[NH:14][C:15]([Cl:1])=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1nc(CO)c[nH]1
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)c(Cl)[nH]1
Reaction time: 8 h

Procedure:
9.52 g (0.071 mol) of N-chlorosuccinimide are introduced, at a temperature of between 0° and 5° C., into 10 g (0.065 mol) of 2-butylimidazole-4-methanol in suspension in 200 ml of ethyl acetate. The mixture is stirred overnight while maintaining this temperature. The solution is filtered and the solid is washed with 20 ml of ice-cold ethyl acetate, drained and washed with water in order to remove traces of succinimide and starting product, and then dried.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(OCC)(OCC)OCC.C(O)(=O)C>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: c1ccncc1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: CCOP(OCC)OCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
In 2 ml of acetonitrile was suspended 103 mg of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 0.10 ml of pyridine, 0.21 ml of triethyl phosphite and 0.2 ml of acetic acid. The mixture was stirred at 20 to 25° C. for 8 hours, followed by concentration under reduced pressure. To the concentrated solution was added 10 ml of tetrahydrofuran, then precipitating powdery product was collected by filtration, followed by concentration under reduced pressure to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(1 -pyridinio)methyl-3-cephem-4-carboxylate.
Reaction SMILES: C(OC(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31].[OH-].[Na+]>O.O1CCCC1>[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]
Reactant: COC(=O)CCCCCCCCCCCCCCCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: NCCCCCCCCCCCCCCCCO
Reaction time: 8 h

Procedure:
In a mixed solvent of 75 ml of isopropyl ether and 25 ml of tetrahydrofuran was suspended 1.0 g of lithium aluminum hydride and to the suspension was added with stirring at room temperature 2.45 g of crystalline methyl 16-aminohexadecanoate and the mixture was stirred overnight. To the reaction solution were added successively 1 ml of water, 1 ml of a 10% aqueous solution of sodium hydroxide and 3 ml of water and the insolubles thus precipitated out were filtered off. The insolubles were extracted with a mixed solvent of chloroform and methanol. Then, the extract was combined with the filtrate and the mixture was distilled to afford the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].[C:21](#[N:25])[CH2:22][C:23]#[N:24].II>CO>[C:23]([C:22]([C:21]#[N:25])=[C:9]1[CH:10]=[C:11]2[C:6](=[N:5][C:4]3[C:13]([S:12]2)=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[CH:7]=[CH:8]1)#[N:24]
Reactant: N#CCC#N
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: CC(=O)[O-]
Agent: II
Agent: [K+]
Solvent: CO
Product: N#CC(C#N)=c1ccc2c(c1)Sc1ccc(Cl)cc1N=2
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 26.2 %

Procedure:
A solution of 2-chlorophenothiazine (1.0 g; 4.26 mmol) and potassium acetate (KOAc) (2.5 g) in boiling methanol (MeOH) (70 mL) was allowed to cool to 40° C. then treated with malononitrile (0.42 g; 1.5 eq). This solution was treated at once with a solution of I2 (2.16 g) in MeOH (25 mL) and allowed to stir at ambient temperature for 3.5 h. The dark green solid that separated was collected by filtration, washed with MeOH and dried in vacuo to give 4 (0.33 g, 26%). MS (70 eV) m/e (rel. intensity) 295 (100), 260 (26).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH:20]1[CH2:25]CCC[CH2:21]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([N:20]([CH3:25])[CH3:21])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: C1CCNCC1
Solvent: CCO
Product: CN(C)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with piperidine in ethanol gives 4-(3-bromoanilino)-6-dimethylaminopyrido[3,4-d]pyrimidine.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:9](=O)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:12][OH:13].O.C(O)C.C([O-])(=O)C.[Na+]>C(O)C>[N:12](=[C:9]1[CH2:8][CH2:7][S:6][C:5]2[S:1][CH:2]=[CH:3][C:4]1=2)[OH:13]
Reactant: O=C1CCSc2sccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCSc2sccc21

Procedure:
To a solution of 5,6-dihydrothieno[2,3-b]thiopyran-4-one (5.0 g, 29.4 mmol) in ethanol (98 ml) was added a solution of hydroxylamine hydrochloride (4.9 g, 70.6 mmol) in 2:1 water-ethanol (27 ml). Sodium acetate.3H2O (9.6 g, 70.6 mmol) in 2:1 water-ethanol (27 ml) was added and the solution was heated at reflux for 2 hours. The reaction mixture was concentrated to dryness, water was added and the solid product (5.3 g, 98%) was collected and dried. An analytical sample was prepared by recrystallization from acetonitrile; m.p. 123°-124° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(I)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(p-iodophenyl)-butyric acid (45.0 g, 0.155 mol) in methanol (1.3 L), was added sulfuric acid (concentrated, 8.4 mL) dropwise and it was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (700 mL) and saturated sodium bicarbonate aqueous solution (500 mL). The organic phase was separated, washed with brine (2×200 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil that was used in step B without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:28])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:28])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Br)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Br)cc21
Yield: 83.2 %

Procedure:
A solution of ethyl 2-[7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (3.0 g) and 1N aqueous sodium hydroxide (5.83 ml) in methanol (69.6 ml) was refluxed for 1 hour with stirring. After cooling, the solvent was evaporated to give a residue, which was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried. Removal of the solvent gave a residue, which was recrystallized from a mixture of ethyl acetate and n-hexane to afford 2-[7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetic acid (2.36 g).
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28]C(=O)C)[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:8]([CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH:6]([OH:28])[CH2:5][CH:4]([C:1](=[NH:2])[NH2:3])[CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(=N)N)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of acetic acid 3-carbamimidoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester in methanol is added 2.0 equivalents of potassium carbonate, stirred for approximately 5 hours, and concentrated. The crude product is dissolved in ethyl acetate and water. The organic layer is then washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gives the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CC(C)CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 37.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), 4-methylvaleryl chloride (1.5 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (23 mL) provided 4-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-pentanamide (0.54 g). Mp 145.5-146.0° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.46; H, 8.14; N, 4.92.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:24].C(O)C>C(O)(=O)C>[BrH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1
Yield: 16 %

Procedure:
The title compound was prepared in 16% yield from the (R)-1-(3-phenylpropyl)-3-(3-methoxyphenyl)piperidine from Preparation 4 by treatment with 48% aqueous hydrobromic acid in glacial acetic acid, using the procedure of Example 3. The product melted at 181°-183° C., [alpha]D25 =+10.4° (c=1; C2H5OH).