Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1>CN(C=O)C.O>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC1CCCCN1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCCC2C)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Clontech 01072, 1 g; 4.69 mmol; 1 eq.) and 2-methylpiperidine (1.395 g; 14.07 mmol; 3 eq.) in DMF (4 mL) was heated to 50° C. for 3 hours. The reaction was then allowed to return to RT and diluted with water. It was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo, affording ethyl 4-(2-methylpiperidin-1-yl)-3-nitrobenzoate as a yellow oil. The residue was taken up in THF (10 mL) and lithium hydroxide (561.73 mg; 23.46 mmol; 5 eq.) was added followed by water (10 mL). The reaction mixture was stirred at RT for 16 hours. It was concentrated and the residue was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 5 with acetic acid. It was extracted with Et2O and the organic phase was dried over magnesium sulfate and concentrated, affording the title compound as a yellow solid (1.17 g, 94%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.07 (s, 1H), 8.23-8.22 (d, J=2.13 Hz, 1H), 8.04-8 (dd, J=8.96 Hz, J=2.28 Hz, 1H), 7.44-7.41 (d, J=8.88 Hz, 1H), 3.64-3.60 (m, 1H), 3.25-3.17 (m, 1H), 2.90-2.84 (m, 1H), 1.82-1.43 (m, 6H), 1.06-1.04 (d, J=6.43 Hz, 3H). LC/MS (Method A): 265.0 (M+H)+; 263.0 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4](O)=[O:5])[CH3:2].C([N:15](CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([C@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4]([NH2:15])=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC[C@@H](C(=O)O)N1CCCC1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:19]([O:25][CH2:26][CH2:27][OH:28])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH:16]([NH:30][C:31]1[CH:32]=[C:33]2[C:34](=[CH:35][CH:36]=1)[C:37](=[NH:38])[NH:40][CH2:39]2)[C:12]1[NH:13][C:14](=[O:15])[N:10]([C:6]2[N:7]=[CH:8][S:9][C:5]=2[C:3]([OH:2])=[O:4])[N:11]=1
Reactant: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-5-methoxy-3-(2-hydroxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid methyl ester (31 mg) and methanol (2.0 mL) there was added a 5N sodium hydroxide aqueous solution (28 μL), and the mixture was stirred overnight at room temperature. After neutralizing the mixture with acetic acid, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, and then a 4N hydrogen chloride-ethyl acetate solution (500 μL) was added to the mixture prior to stirring at room temperature for 15 minutes. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (10 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:20][C:21]([Cl:28])([Cl:27])[CH2:22][O:23][C:24](Cl)=[O:25]>O.C(OCC)(=O)C>[Cl:20][C:21]([Cl:28])([Cl:27])[CH2:22][O:23][C:24](=[O:25])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A cooled (0° C.) biphasic solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (26.6 g, 100 mmol) in water (80 mL) and ethyl acetate (180 mL) was treated with NaOH (10 g, 250 mmol) followed by trichloroethylchloroformate (29.7 g, 140 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to provide 40.3 g of pale yellow solid (99% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:13]1[CH:14]=[C:10]([C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[NH:25][N:24]=2)[NH:11][CH:12]=1
Reactant: O=C(c1cc(-c2c(Cl)cccc2Cl)c[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1cccc(Cl)c1-c1c[nH]c(-c2n[nH]c3ncccc23)c1

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-[4-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone (150 mg) from above and hydrazine hydrate (0.5 mL) in ethanol (7 mL) was heated at 90–100° C. for overnight. The reaction was concentrated, the residue was washed with water, dried and triturated with ethyl acetate-hexane mixture to give 71 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH3:9])[CH2:5][N:6]=[N+]=[N-].[ClH:11]>O1CCCC1.[Pd]>[ClH:11].[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH3:9])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](C)CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)CN

Procedure:
2.7 g of 3-azido-2(R)-methylpropionic acid methyl ester are hydrogenated in the presence of 1.4 g of 10% Pd/C in 50 ml of tetrahydrofuran for 4 hours at room temperature at pH 6.0 (pH-stat; 2N hydrochloric acid). The reaction mixture is filtered and concentrated by evaporation. The title compound is obtained by crystallisation from isopropanol/diethyl ether: 1H NMR (DMSO-d6), δ (ppm)=7.95 (3H, bs), 3.65 (3H, s), 3.12-2.78 (3H, m), 1.15 (3H, d); m.p. 122°-125° C.
Reaction SMILES: [SH2:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH2:28][CH2:29][CH3:30])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.C(NCC)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH2:27])=[S:1])=[CH:22][C:21]=3[CH2:28][CH2:29][CH3:30])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: S
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 70 °C

Procedure:
Hydrogen sulfide was passed through a solution of methyl{5-[3-(4-cyano-2-propylphenoxy)propoxy]-1H-indol-1-yl}acetate (Example 51, 787 mg, 1.94 mmol) in DMF (15 mL) for 30 minutes at rt. Diethyl amine (0.3 mL, 2.90 mmol) was added, and the solution was heated to 70° C. for 3 h. The reaction mixture was cooled to rt, and the residual H2S was removed by passing argon through the reaction mixture for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of solvent yielded a brown oil which was used in the next step without further purification. LC/MS m/z 441.2 (M+H)+; RT 3.35 min.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][CH2:8]Cl)[CH3:5].[CH3:10][N:11]1[C:17]2=[CH:18][S:19][CH:20]=[C:16]2[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[CH:23][CH:24]=[N:25][C:12]1=2.Cl([O-])(=O)(=O)=O>O.CN(C)C=O>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][CH2:8][N:14]1[C:15](=[O:21])[C:16]2=[CH:20][S:19][CH:18]=[C:17]2[N:11]([CH3:10])[C:12]2[N:25]=[CH:24][CH:23]=[CH:22][C:13]1=2
Reactant: CN1c2cscc2C(=O)Nc2cccnc21
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCN1C(=O)c2cscc2N(C)c2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 0.69 g. of 55% sodium hydride-mineral oil dispersion and 0.9 ml. of dimethylaminopropylchloride in 30 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.70 g. of 5,10-dihydro-10-methyl-6H-pyrido[3,2-b]thieno[3,4-e] [1,4]diazepin-6-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an amber oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent to give a semi-solid. The perchlorate salt is preparaed by standard procedures and is recyrstallized from water to give a white solid, m.p. 263°-265°C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH:28]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:29][OH:30]>>[OH:30][CH2:29][CH:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: NC(CO)C1CCOCC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(c1)cc(C(=O)NC(CO)C1CCOCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 2-amino-2-(tetrahydropyran-4-yl)ethanol in a manner similar to that described in Example 11.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:23]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1
Reaction time: 1 h

Procedure:
A solution of 3-cyanophenylisocyanate (6.4 g, 1 eq) in DCM (100 ml), was added to 4-amino-N-benzylbenzenesulfonamide (10.4 g, 1 eq), dissolved in DCM (100 ml), at 4° C. in small portions, stirred for 1 h. Afterwards the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was recrystallized from ethanol/water (1/1). The product was filtered, washed 2 times with ethanol/water (1/1) at 4° C., and dried in vacuo to give N-benzyl-4-[3-(3-cyanophenyl)-ureido]-benzenesulfonamide. Yield 90% N-benzyl-4-[3-(3-cyanophenyl)-ureido]-benzenesulfonamide (22 g, 1 eq) was dissolved in ethanol (150 ml). Hydrochloric acid was bubbled through the solution for 2 h at 4° C. Then the solution was stirred for 1 h at rt. The solvent was removed in vacuo. The product was washed with ethanol/water (1/1) at 4° C., and dried in vacuo to give 3-[3-(4-benzylsulfamoylphenyl)-ureido]-benzimidic acid ethyl ester. Yield 75%.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH3:47])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH3:47])[CH3:46])[CH3:45]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 120 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([OH:23])[CH2:21][N:22]=1>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:18][CH:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]([O:23][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:21][N:22]=1
Reactant: OC1CN=C(c2ccccc2F)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccccc2F)OC1c1ccccc1
Yield: 39.7 %

Procedure:
Phenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2.3 g) in 1,2-dichloroethane (30 cc). The solution obtained is stirred under reflux for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (7:3 by volume)], collecting 20-cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.3 g), m.p. 128° C., is obtained.
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:32]1[CH2:33][CH2:34][O:30][C:31]1=[O:35])=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: O=C1NCCO1
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Product: COc1ccc2c(CN3CCOC3=O)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in the example 369d was used, starting from Methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester and Oxazolidin-2-one to give 5 mg of 3-[6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylmethyl]-oxazolidin-2-one as a yellow solid. LC-MS m/e 354 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][C:28](C)([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2c(C(CC(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methyl-4-methylpentanoate (0.114 g; 0.27 mmol) in methanol (2.7 mL) and water (0.27 mL) was added a solution of sodium hydroxide 10 N (0.27 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.083 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]>CO>[CH3:1][O:2][C:9](=[O:4])[CH2:8][CH2:7][CH2:6][CH2:5][OH:10]
Reactant: C[O-]
Reactant: O=C1CCCCO1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of sodium methoxide (71.3 mg, 1.32 mmol) in anhydrous MeOH (4 ml), tetrahydro-pyran-2-one (1.32 g, 13.2 mmol) is added dropwise at room temperature under nitrogen. The mixture is stirred at 50° C. for 4 hours and filtered through a silica gel short column (eluent: diethyl ether). Collected filtrate is concentrated under reduced pressure to give 5-hydroxy-pentanoic acid methyl ester; 1H NMR (400 MHz, chloroform-d) ppm 1.57-1.76 (m, 4H), 2.35 (m, 2H), 3.65 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CCCC)=O.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=1>>[Cl:29][C:25]1[N:24]=[C:23]([NH:22][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:28]=[N:27][CH:26]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from butyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [O-]CC.[Na+].C(O[C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([C:23](=[O:25])C)[CH:20]=[CH:21][CH:22]=1>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of 1.96 g (0.0275 mol) sodium ethoxide (95%) and 22 ml ethanol was stirred 20 minutes at room temperature and was then cooled with an ice bath. 3.65 g (0.025 mol) diethyloxalate followed by 4.7 g (0.025 mol) 1-(3-trifluoromethyl-phenyl)-ethanone were added slowly. The mixture was stirred for 30 min. at 0-5° C., then allowed to warm to room temperature and additional 25 ml ethanol were added. After 1 d at room temperature the solvent was evaporated. Water and diethylether were added to the residue. The organic phase was separated and the aqueous phase was extracted one more time with diethyl ether. The aqueous phase was acidified with 2M HCl to pH2 and extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate, the solvent was evaporated and the residue triturated with petrol ether to give 5.35 g (0.0185 mol) 3-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:33][CH3:34])=[C:13]([CH:19]2[CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O>[Pd].CO>[NH:21]1[CH2:22][CH:19]([C:13]2[C:12]([O:33][CH3:34])=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:16]=[C:15]([Cl:17])[C:14]=2[CH3:18])[CH2:20]1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (720 mg, 1.5 mmol) (second peak from chiral separation of previous step) and 5% palladium on carbon (100 mg) were combined in methanol (40 mL), to which was added 0.25 M HCl in water (11 mL, 2.8 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 1 hour. The suspension was then filtered, neutralized with sat. NaHCO3 solution, concentrated, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.4 g). LCMS calculated for C18H28ClN2O3 (M+H)+: m/z=355.2. found: 355.1.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]#[N:52])[CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]2[NH:52][N:7]=[N:6][N:5]=2)[CH:27]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc(Cl)ccc1NC(=O)c1cccc(-c2cccc3cccnc23)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1-c1nnn[nH]1)c1cccc(-c2cccc3cccnc23)c1
Temperature: 100 °C
Reaction time: 66 h
Yield: 54 %

Procedure:
240 mg (2.08 mmol) of trimethylsilyl azide and 25.9 mg (0.10 mmol) of dibutyl tin oxide were added to a toluene (50 mL) solution comprising 400 mg (1.04 mmol) of N-(4-chloro-2-cyanophenyl)-3-(quinolin-8-yl)benzamide, and the mixture was stirred at 100° C. for 66 hours. The reaction mixture was condensed, and ethyl acetate was added thereto. Solids were collected by filtration. The obtained solids were recrystallized using DMF/IPE. The resulting solids were suspended in H2O, and stirred at 80° C. for 6 hours. Thereafter, diluted hydrochloric acid was added, and solids were collected by filtration and dried, thereby giving 242 mg of the target N-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3-(quinolin-8-yl)benzamide (yield: 54%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:23][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-methoxybenzaldehyde yields the (E)-1-methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=255 (M+H)+.