Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:34]([NH:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:35])[CH:11]=2)[C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 1 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 1 g 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized from isopropanol, giving 1.6 g of 1,3-bis[[1-cycloheptyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[H][H]>C(O)C.[Pd]>[NH2:10][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([CH3:9])=[CH:6][C:4]=1[NH2:5]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(N)c(N)c1
Yield: 99.9 %

Procedure:
2.50 g (15.0 mmol) of 3,5-Dimethyl-2-nitroaniline are dissolved in 50 ml ethanol. To this solution 250 mg (0.23 mmol) of palladium (10% on carbon) are added under argon. The mixture is treated for 24 h with hydrogen at ambient pressure and ambient temperature. The mixture is filtrated over celite and washed with ethanol. The solvent is evaporated under vacuum to yield 2.04 g (97.1% of th.) of 2-Amino-3,5-dimethylphenylamine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]([C:8]#[N:9])=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:12])[CH3:15]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCOCC1

Procedure:
A mixture of tetrahydropyran-4-one (12 g), ethyl cyanoacetate (13.6 g), ammonium acetate (1.2 g), glacial acetic acid (2.4 ml) and toluene (15 ml) is stirred at reflux for 16 hours. The mixture is diluted with toluene and the organic layer is separated, washed with water, then brine, and dried over magnesium sulfate. It is concentrated at reduced pressure to an oil which solidifies. It is further purified by flash chromatography through silica gel with methylene chloride as eluent. The desired fractions are combined and concentrated to dryness at reduced pressure to afford 4-(alpha-ethoxycarbonyl-cyanomethylene)-tetrahydropyran.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:19]=[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: OB(O)c1cccc(Br)c1
Product: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1

Procedure:
4-[1-(3-Bromo-phenyl)-piperidin-4-yl]-morpholine was prepared from 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol) and 3-bromophenylboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a tan resin (0.238 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=7.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.75-3.68 (m, 6H), 2.79-2.70 (m, 2H), 2.60-2.55 (m, 4H), 2.37-2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.68-1.56 (m, 2H). MS=325, 327 (MH)+. 57b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-[1-(3-bromo-phenyl)-piperidin-4-yl]-morpholine (100.0 mg, 0.3075 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 25%). MP=230-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.08 (d, J=7.1 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.24-7.18 (m, 1H), 7.01 (d, J=6.7 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.81 (d, J=11.7 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.78 (t, J=11.8 Hz, 2H), 2.63-2.58 (m, 4H), 2.40-2.30 (m, 1H), 1.97 (d, J=12.7 Hz, 2H), 1.74-1.62 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[C:5]([C:25]2[CH:44]=[CH:43][C:28]([O:29][C@H:30]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([O:29][C@H:30]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]([OH:33])=[O:32])=[CH:43][CH:44]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2-c2ccc(OCCCCCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1-c1ccc(OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixed solution of ethyl (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate (520 mg, 0.884 mmol) in THF (20 ml) and methanol (20 ml) was added 1N aqueous potassium hydroxide solution (5 ml, 5 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 336 mg (yield: 67.9%)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][P:15]([CH2:20][NH2:21])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][P:15]([CH2:20][NH:21][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CCOP(=O)(CNc1cc(F)ccc1[N+](=O)[O-])OCC
Yield: 75.6 %

Procedure:
1.1 g of 2,4-difluoronitrobenzene is heated with 2.8 g of aminomethanephosphonic acid diethyl ester for 2 hours to 40° C. Then, it is chromatographed on silica gel with methylene chloride:ethanol=10:1. 1.6 g of N-(2-nitro-5-fluorophenyl)aminomethanephosphonic acid diethyl ester is obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[Cl-].[NH4+]>C1COCC1>[CH3:10][C:3]1[C:2]([B:16]([OH:19])[OH:17])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(C)c(Br)c(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-bromo-2,4,6-trimethylpyridine (CAS No. 23079-73-4; Prasenjit Mal etc., Journal of Organic Chemistry, 68(9), pp. 3446-3453) (1 g) was added to THF (20 mL). The solution was cooled to −78° C., and n-butyllithium (1.63 M solution in n-hexane, 3.37 mL) was added, followed by stirring at the same temperature for 30 minutes. Trimethyl borate (0.78 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between oil and water by adding water and DCM. The aqueous layer was concentrated under reduced pressure. DCM and ethanol were added to the resulting residue. The insoluble matter was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (242 mg). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.50 (s, 3H), 2.63 (s, 3H), 2.67 (s, 3H), 7.52 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]ccnc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccnc1-c1ccccc1

Procedure:
A 0.01 mol. sample of 3-phenylpyrazin-2(1H)one is mixed with 9.0 ml. of phosphorous oxychloride (POCl3) and refluxed for 5-6 hr. The excess phosphorous oxychloride is removed by distillation at reduced pressure and 25 ml. of methylene chloride added to the residue. The resultant solution is stirred with a few milliliters of ice water, dried, evaporated and the residue recrystallized to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NC1CCCCC1N1CCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CC#N
Solvent: CCO
Product: Clc1ccc2c(NC3CCCCC3N3CCCC3)ccnc2c1

Procedure:
3.87 g from 3.6 g of 4,7-dichloroquinoline and 3.06 g of (2-pyrrolidin-1-yl-cyclohexyl)-amine (reaction duration 24 hours at 120° C.); colourless crystals from acetonitrile/ethanol, m.p.: 228°-231° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=1)[C:5]([NH:7][C:8]1[S:12][N:11]=[C:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31](Cl)=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=3)[C:5]([NH:7][C:8]3[S:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[O:6])=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: Cc1nsc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Reaction time: 10 h
Yield: 17.7 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (237 mg, 0.77 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (151 mg, 0.77 mmol) and potassium carbonate (213 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and at 160° C. for 10 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (64 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH3:11][C:12]([S@:15](/[N:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:16])([CH3:14])[CH3:13]>C1COCC1.BrCCBr>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@H:18]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[NH:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[CH:3][C:4]=1[F:9]
Reactant: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cn1cc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(Cl)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a mixture of 4-bromo-1-chloro-2-fluorobenzene (11.7 g, 56.0 mmol) and magnesium turnings (2.1 g, 84 mmol) in THF (150 mL) at RT was added a few drops of 1,2-dibromoethane (1.1 g, 5.6 mmol). The mixture was stirred at RT for 1.5 h. After cooling to −78° C., (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (4.00 g, 18.7 mmol) was added and stirred at −78° C. for 6 h. The reaction was quenched with aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1) to afford the 2.9 g (45%) of (R)—N—((S)-(4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (48). LCMS (ESI) m/z: 344.1 [M+H]+.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BH4-].[Na+].CS(O[CH2:17][CH:18]([O:39][CH3:40])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=O)=O>O1CCCC1.CO>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4][CH2:17][CH:18]([O:39][CH3:40])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: OCCCCS
Reactant: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCCCO)OC
Reaction time: 1.5 h

Procedure:
To 40 ml of a methanol solution of sodium methoxide (1 M solution) are added 3.1 g of 4-mercaptobutanol and 0.5 g of sodium borohydride, to which is added dropwise a solution of 4.36 g of 2-methoxy-3-octadecyloxypropyl methanesulfonate in 40 ml of tetrahydrofuran at room temperature with stirring. The mixture is stirred at room temperature for 14 hours and then at 40° C. for 1.5 hours. The solvent is distilled off under reduced pressure and the residue is acidified with hydrochloric acid and extracted with hexane. The extract layer is washed with water, dried and concentrated to leave crude 2-methoxy-3-octadecyloxypropyl 4-hydroxybutyl sulfide. This sulfide is dissolved in 75 ml of dichlromethane, to which 7.6 g of m-chloroperbenzoic acid is added little by little at room temperature with stirring. The mixture is then stirred at room temperature for 1 hour and is filtered to remove precipitates. The filtrate is washed with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution and water, dried and concentrated to leave a residue which in turn is purified by silica gel column chromatography to obtain 2.5 g of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 174.7 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.218 g) and aminoguanidine hydrochloride (94 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 129) (0.255 g) as crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.I[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 84 mg (0.22 mmol) (6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone and 0.15 mL (0.88 mmol) DIPEA were combined in 2.5 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was mixed with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[OH:7][CH2:8][C:9]([S:12]([CH2:15][CH:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10]>N1C=CC=CC=1>[CH:1]1([C:4]([O:7][CH2:8][C:9]([S:12]([CH2:15][CH:16]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)C1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in paragraph (d) above, by reacting cyclopropanecarbonyl chloride and benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate in pyridine there was obtained benzyl rac-[[[2-[(cyclopropylcarbonyl)oxy]-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 367 (M-benzyl)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[CH3:12][C:13]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc(O)cc1
Product: Cc1nnc(-c2ccc(O)cc2)o1
Yield: 99 %

Procedure:
A mixture of 9.6 parts of 4-hydroxybenzoic acid hydrazide and 44 parts of 1,1',1"-[ethylidynetris(oxy)]trisethane is stirred and refluxed overnight. The precipitated product is filtered off and crystallized from 1-butanol, yielding 10.5 parts (99%) of 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol; mp. 238.8° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18](CC[Si](C)(C)C)[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29]CC2C=CC=CC=2)[CH:10]=1.[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[OH:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[NH:18][S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and ethanesulfonyl chloride analogous to Example 205, steps B, C and D. MS (M−1)−=430; HPLC retention time=0.91 min. (Method A).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])[CH3:36]>>[C:35]([C:18]1[C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:37])[CH3:36]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Solvent: CCCCCC
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Yield: 69 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 161, the title compound was synthesized in the same manner as in Example 38. Yield: 69%. Melting point: 218-219° C. (hexane-ethyl acetate).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:13]([C@H:10]1[CH2:11][CH2:12][C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O[C@@H]1CC[C@H](OC2CCCCO2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(O[C@H]2CC[C@H](OC3CCCCO3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of (1R,3S)-3-tetrahydropyranyloxycyclopentanol (2.00 g, 10.7 mmol), phenol (1.20 g, 12.0 mmol) and triphenylphosphine (3.20 g, 12.0 mmol) in dry THF (40 ml) cooled to 0° C. was added dropwise a solution of diethyl azodicarboxylate (2.60 g, 15.0 mmol) in dry THF (10 ml). The mixture was stirred for 1 h at room temperature and then the volatiles removed under reduced pressure. Chromatographic purification of the residue {SiO2, 150 g; hexane/ethyl acetate (20:1)} provided 2.16 g (77 %) of the title compound as a colorless oil: 1H NMR δ7.33-7.22 (m, 2H), 6.99-6.83 (m, 3H), 4.98-4.81 (m, 1H), 4.70-4.60 (m, 1H), 4.55-4.41 (m, 1H), 4.00-3.85 (m, 1H), 3.58-3.47 (m, 1H), 2.30-1.45 (m, 12H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CBr)[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution, prepared at 30° C., of 7β-bromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid (about 0.15 mmol), prepared according to the process described in Example 43, in 10 ml of ethanol and 0.3 ml of water is mixed with a solution of 0.03 g of sodium azide in 0.5 ml of water. The reaction mixture is stirred for 15 hours at room temperature with exclusion of light and is then worked up according to the process described in Example 41. 7β-Azidoacetylamino-3-methoxy-3-cephem-4-carboxylic acid is thus obtained, which in a thin layer chromatogram (silica gel; system: n-butanol/pyridine/acetic acid/water, 42:24:4:30) shows an Rf value of 0.40; ultraviolet absorption spectrum (in ethanol): λmax at 264 mμ; infrared absorption spectrum (in mineral oil): characteristic bands at 4.65μ and 5.64μ.