Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6].[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: Cc1ccc(CN)cc1C
Product: Cc1ccc(CNC(=O)Cc2cccc(Br)c2)cc1C
Yield: 93 %

Procedure:
The title compound was prepared from 3,4-dimethylbenzylamine and 3-bromophenylacetic acid, using a method similar to that of preparation 27, as a white solid in 93% yield. 1H NMR (400 MHz, CDCl3) δ: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1H, brs), 7.60–7.80 (7H, m); LRMS ESI 332 [M]+
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][O:40][CH2:41][CH2:42][NH2:43]>C(N(CC)CC)C>[CH3:39][O:40][CH2:41][CH2:42][NH:43][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Reactant: COCCN
Solvent: CCN(CC)CC
Product: COCCNCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-methoxyethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=61-62° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.75 (m, 3 H), 7.56 (t, 1 H), 7.49-7.40 (m, 3 H), 7.27 (d, J=7.6 Hz, 1 H), 7.17-7.15 (m, 2 H), 6.76 (d, J=7.2 Hz, 1 H), 4.64 (t, J=7.2 Hz, 1 H), 3.39-3.35 (m, 3 H), 3.23 (s, 3 H), 3.21-3.11 (m, 2 H), 2.76-2.64 (m, 6 H). LCMS 519 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[OH-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].Cl>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:16][C:17]([OH:19])=[O:18])[N:11]=[C:4]2[N:3]=1
Reactant: O=C(O)CCl
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)n2nc(SCC(=O)O)nc2n1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (1.0 g, 5.6 mmol), sodium hydroxide (0.44 g, 11.1 mmol), and water (22 mL) was added to a 100 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and the mixture was warmed to reflux in a 120° C. oil bath for 30 min. The mixture was removed from the oil bath and allowed to cool, and chloroacetic acid (0.525 g, 5.6 mmol) was added. Warming to reflux was continued for 6 h. The mixture was allowed to cool to ambient temperature, and the pH was adjusted to 2 with 1 M aqueous hydrochloric acid (5 mL). A solid precipitate was isolated by filtration, rinsed with 1 M hydrochloric acid (2 mL) and water (5 mL), and allowed to dry. The title compound was obtained as a tan solid (1.16 g, 88% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 12.85 (br s, 1H), 7.12 (s, 1H), 4.08 (s, 2H), 2.66 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:23])[CH2:9]1)(C)(C)C.CO.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:23][C:14]1[N:13]([C@H:10]2[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]2)[C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[N:15]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](N)C1
Reaction time: 0.25 h

Procedure:
The trans-[3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester prepared above (320 mg, 0.95 mmol) was dissolved in HCl (4M) in dioxane (5.0 mL) and the solution was stirred for 15 minutes. Solids came out of solution and 1 mL of methanol was added to dissolve the precipitate. Stirring was continued for 60 minutes and the reaction mixture was evaporated to a sticky solid which was stirred with ethyl ether. The resulting solid was filtered to provide trans-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride salt as an off white powder (250 mg). LR-MS calcd for C14H19N3 (m/e) 229.1579, obsd 230.2 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][CH:7]=1.[C:21](O)(=[O:24])[CH:22]=[CH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([NH:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:9]=[CH:8][CH:7]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)O
Reactant: CN(CCN)c1cccc(NC(=O)OC(C)(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NCCN(C)c1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 110c (1.2 g, 4.5 mmol), acrylic acid (0.37 mL, 5.4 mmol), HATU (2.05 g, 5.4 mmol) and DIPEA (4.6 mL, 10.8 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give tert-butyl 6-((2-acrylamidoethyl)(methyl)amino)pyridin-2-ylcarbamate 110d (1.2 g, 75%) as a brown oil. The material was used for the next step directly. ESI-LCMS: m/z=321.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(COc2ccc(F)cn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccc(F)cn2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 90.4 %

Procedure:
A mixture of 4-(5-fluoro-pyridin-2-yloxymethyl)benzaldehyde (2.71 g, 11.7 mmol) described in Manufacturing Example 56-1-2, nitromethane (1.26 mL, 23.4 mmol), ammonium acetate (1.35 g, 17.6 mmol) and acetic acid (30 mL) was stirred for 10 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.9 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([CH:18]2[S:32][C:25]3([CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)[CH:15]=[CH:16][CH:17]=1>ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH:18]2[S:32][C:25]3([CH2:26][CH2:27][N:28]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:29][CH2:30]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To 5.0 g of phenyl chloroformate in 80 ml of dichloromethane is added 7.89 g of the free base, 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 55, in 10 ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of 10% aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatographed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine], m.p. 134°-142° C. A portion is recrystallized twice from toluene:hexane, m.p. 144°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][CH2:15][C:16](=O)[CH3:17])[CH:7]=1)[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:25]3[C:24](=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[NH:28][C:16]=2[CH3:17])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: [4-methoxy-3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12](=[O:13])[C:7]2=[C:6]([OH:22])[C:5]=1[C:23]([O:25]CC)=O)(=O)[CH3:2].[CH3:28][NH:29][NH2:30].C(O)(=O)C>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]3[C:7](=[C:6]([OH:22])[C:5]4[C:23](=[O:25])[N:29]([CH3:28])[N:30]=[C:1]([CH3:2])[C:4]=43)[C:12]2=[O:13])=[CH:16][CH:17]=1
Reactant: CNN
Reactant: CCOC(=O)c1c(O)c2n(c1C(C)=O)CCN(Cc1ccc(F)cc1)C2=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(C)c(=O)c2c(O)c3n(c12)CCN(Cc1ccc(F)cc1)C3=O

Procedure:
A mixture of ethyl 6-acetyl-2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (75 mg, 0.2 mmol), methylhydrazine (46 mg, 1 mmol), and a drop of acetic acid in ethanol (4 mL) was heated in a sealed tube at 105° C. overnight. The product mixture was concentrated under vacuum. The residue was recrystallized from methanol to provide the titled product.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[CH3:7][N:6]1[C:2]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and p-tolylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H14N4, 275. Found, 275.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[C:12]([CH3:20])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH3:13])=[CH:7][CH:6]=1.[CH2:22]([S:26][CH2:27][C:28](=[CH2:32])[C:29](O)=[O:30])[CH2:23][CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C.C(OCC)(=O)C>CC(N(C)C)=O>[CH3:20][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:13])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH2:3][CH2:2][O:1][C:29](=[O:30])[C:28]([CH2:27][S:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH2:32])=[CH:6][CH:7]=1)=[O:21]
Reactant: C=C(CSCCCC)C(=O)O
Reactant: CC(C)(C(=O)c1ccc(SCCO)cc1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(CSCCCC)C(=O)OCCSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
1.0 g (3.2 mmol) of 1-[4-(2-Hydroxyethylthio)phenyl]-2-methyl-2-morpholin-4-yl-propane-1-one and 0.56 g (3.2 mmol) of 2-(butylthiomethyl)acrylic acid are dissolved in 20 ml of dry dimethylacetamide and cooled to −20° C. To the solution is added 0.68 g (3.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 5 ml of dry dimethylacetamide. The mixture is gradually warmed to room temperature and stirred overnight. To the mixture is added ethyl acetate. The mixture then is washed with saturated sodium chloride solution and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][P:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[C:19]1([P:18]([Cl:17])[O:11][C:10]2[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH3:16])=[CH:8][C:9]=2[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP(Cl)c2ccccc2)c(C(C)(C)C)c1

Procedure:
To a solution of 110 grams of 2,6-di-tert-butyl-p-cresol in 252 grams of triethylamine was added at 25°-26° C. over a 15-minute period 89.5 grams of dichlorophenylphosphine. The reaction mixture was heated for 31 hours at 95°-97° C. The excess triethylamine solvent was then removed by distillation under vacuum, the resulting residue was triturated with 200 ml of dry benzene, and the white crystalline solid triethylamine hydrochloride was separated by filtration. The desired product named above was isolated from the filtrate by distillation of the benzene under vacuum and crystallization of the residue from acetonitrile. The product was obtained as white crystals melting at 103°-106° C.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]([O:29][CH3:30])=[C:22]([O:31][CH3:32])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:36]([C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[NH2:37].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:36]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=2)[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]=1[O:29][CH3:30]
Reactant: NNc1ncccn1
Reactant: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(OC)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 169 mg of [2-(3,4-dimethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 40 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(3,4-dimethoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (89 mg) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1,1-dimethylethyl (4RS,5RS)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (3.7 g, 8.42 mmol) in methanol (20 ml) was gradually added a solution of sodium hydroxide (0.40 g, 10.10 mmol) in methanol (20 ml) under ice-cooling. The reaction solution was stirred for 1 hr, diluted with 1N hydrochloric acid (15 ml) and water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (2.24 g, 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:10][CH:11](Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CC(C)([O-])C.[K+]>CN(C)C=O>[Br:10][CH:11]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOC(=O)C(Br)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Br)c1ccc([N+](=O)[O-])cc1

Procedure:
Nitrobenzene was treated with ethyl dibromoacetate in dimethylformamide containing potassium tertiarybutoxide at -20° C. to give ethyl 2-bromo-2-(4-nitrophenyl)acetate (1.37 parts) which was dissolved in methanol (50 parts). To this methanol solution was added dropwise separately a solution of bromine (1.72 parts) in methanol (40 parts) and a solution of sodium methoxide (0.56 parts) in methanol (40 parts). The reaction mixture was poured into dilute aqueous hydrochloric acid solution and extracted with dichloromethane. The dichloromethane solution was evaporated to give methyl 2,2-dibromo-2-(4-nitrophenyl)acetate (1.44 parts, 50%).
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5]1.CO>CN(C)C=O>[C:1]([CH2:5][C:6]1([OH:4])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by reacting potassium cyanide (20.7 mmol) with (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (13.8 mmol) in 60 ml 5:1 methanol: dimethylformamide mixture under stirring. The reaction was stirred for 12 hours at 25° C. and quenched with saturated ferrous sulfate solution. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate, organic layer was washed with brine and dried over sodium sulfate. Evaporation of organic solvent under vacuum and silica gel chromatographic purification afforded the titled product in 44% yield. M.P. 88-90° C. and MS (M+1)=373 (MH+, 100%) for M.F.=C19H24N4O4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1O
Solvent: CO
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a suspension of 2-amino-4-chlorophenol (1.43 g, 10.0 mmol) in methanol was added acetic anhydride (0.945 mL, 10.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo to give the subtitled compound (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N,N-dimethylacetamide. The filtrate is poured onto water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 191.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:31]2[N:30]=[C:29]([C:22]3[C:23]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][CH:21]=3)[CH:34]=[CH:33][N:32]=2)=[C:5]([CH3:10])[CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c(C)c1
Yield: 20.1 %

Procedure:
Using the procedure of example 1, 4-methoxy-2-methylaniline, (111 mg) was reacted with compound 1f (100 mg) to provide compound 27 (18 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=7.2 Hz, 1H), 8.20 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 7.03 (m, 1H), 6.90 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 332 (M+H)+.
Reaction SMILES: ClCCO[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].[Cl:30]CCOCCOCCOCCN1C(=O)C2C(=CC=CC=2)C1=O>>[Cl:30][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCCl
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCOCCCl
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCCl
Yield: 92 %

Procedure:
2-{2-[2-(2-{2-[2-(2-Chloroethoxy)-ethoxy}-ethoxyl-ethoxy)-ethoxy]-ethyl}-isoindole-1,3-dione. The title compound was prepared according to the synthesis of 2-(2-{[2-(2-Chloro-ethoxy)-ethoxy]-ethoxy}-ethyl)-isoindole-1,3-dione in 92% yield: 1H NMR (CDCl3) δ 7.84 (dd, 2 H), 7.71 (dd, 2H), 3.90 (t, 2H), 3.74 (q, 4 H), 3.67-3.58 (m, 18H). Mass spectrum, m/e Calcd for C20H29ClNO7+: 430.16 (100.0%). Found: 429.85.