Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:19]([NH2:20])=[N:18][C:12]3[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: COc1cccc(-c2cc3cnc(N)nc3nc2N)c1
Reactant: CC(C)(C)N=C=O
Product: COc1cccc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1

Procedure:
The title compound was prepared from 0.50 g of 6-(3-methoxy-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 102 and 0.23 mL tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1) to EtOAc; mp 275°-280° C.; MS(CI).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>C(OCC)(=O)C>[CH2:23]([C:15]1[CH:14]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C(=O)OCC)cc1
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OCC)ccc1O
Temperature: 200 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
A mixture of ethyl 4-allyloxybenzoate (10.0 g, 48.5 mmol) and N,N-dimethylaniline (20 ml) was left under stirring at 200° C. for 48 h, then diluted with ethyl acetate (150 ml) and washed with 1M HCl. After drying and evaporating off the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 95:5, thereby recovering 6.85 g of the title compound (69% yield).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][N:7]2[C:10](=[O:23])[CH:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:12](=[O:13])[N:6]2[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][N:3]1[CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[C:10]([O:23][C:32](=[O:33])[O:34][CH2:35][CH3:36])[N:7]2[CH2:8][CH2:9]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Oc1c(-c2c(C)cc(C)cc2C)c(=O)n2n1CCN(OC)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (106 mg, 0.33 mmol), triethylamine (0.070 ml, 51 mg, 0.50 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (2 ml) at 0° C. was added ethyl chloroformate (0.035 ml, 40 mg, 0.37 mmol) dropwise. The suspension was stirred at 0° C. for 20 minutes, treated with more triethylamine (0.070 ml, 51 mg, 0.50 mmol) and ethyl chloroformate (0.035 ml, 40 mg, 0.37 mmol) dropwise, and further stirred at 0° C. for 10 minutes. The solvent was evaporated, the residue diluted with ethyl acetate, the organic phase washed with water and brine, dried over sodium sulfate and concentrated. The gummy residue was triturated in cyclohexane and diethyl ether, stirred at room temperature, filtered and dried. Yield: 100 mg of carbonic acid ethyl ester 3-methoxy-9-oxo-8-(2,4,6-trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl ester (title compound P1.2) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:31].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:32])[C:2]([CH3:33])([CH3:34])[CH3:1])=[C:7]([CH3:31])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2o1
Yield: 99.3 %

Procedure:
Methanesulfonic acid 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-yl ester (100 mg, 0.206 mmol) and NaBH4 (8.0 mg, 0.206 mmol) in THF (5.0 mL) are reacted analogous to Example 19 to give the title compound (100 mg, 100%). MS (ES) m/e: 506.2 (M+18).
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20](I)[CH3:21].O>CN(C)C=O>[CH2:20]([O:18][C:17](=[O:19])[CH2:16][C:15]1[C:10]2[C:11](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][N:9]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:21]
Reactant: O=C(O)Cc1cccc2c(-c3ccccc3)onc12
Reactant: CCI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc2c(-c3ccccc3)onc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.9 %

Procedure:
To a stirred slurry of 0.7 g (0.014 mole) of washed (petroleum ether), 50% sodium hydride/oil in 5 ml of dry dimethylformamide was added a solution of 2.9 g (0.012 mole) of 3-phenyl-2,1-benzisoxazol-7-acetic acid in 15 ml of dimethylformamide. The mixture was stirred at ambient temperature for 10 minutes and then 2.0 g (0.013 mole) of ethyl iodide was added. The dark solution was stirred at ambient temperature for 1 hr and then poured into 500 ml of water and let stand overnight. The mixture was filtered and the collected solid was recrystallized from 2-propanol to give 0.2 g (6%) of solid, m.p. 97°-98° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](OS(C)(=O)=O)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Solvent: C1CCOC1
Product: CC(=O)O[C@H](C)c1nccc(N2CCNCC2)n1
Yield: 88 %

Procedure:
A mixture of (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Six, 24.1 g, 92 mmol) and piperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated at reflux for 1 h. This mixture was cooled, filtered, concentrated, and purified by flash column chromatography (9:1 dichloromethane/methanol) to give 24.4 g (88%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz) δ1.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 251 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].[C:34](#[N:37])[CH:35]=[CH2:36]>C1(C)C=CC=CC=1>[C:34]([CH2:35][CH2:36][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])=[CH:19][CH:20]=2)[CH2:25]1)#[N:37]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Reactant: C=CC#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(CCC#N)CC4)c2)cc1OC
Temperature: 80 °C
Yield: 68.2 %

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 3 mL of toluene and added acrylonitrile (0.04 mL, 0.600 mmol). The mixture was heated at 80° C. for 2 h. LC-MS indicated the desired material. Concentrated to dryness and applied to a SiO2 prep plate. Eluted with (5% MeOH/1% NH3/CH2Cl2) to give 40.8 mg of N-{3-[2-(2-Cyano-ethyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-benzyl}-3,4-dimethoxy-benzamide. MS, electrospray 499.5 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[O:26][C:25](=O)[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=2)[CH2:13][CH2:12]1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=c1oc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc12
Product: O=c1c2ccccc2nc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)n1Cc1ccccc1
Temperature: 250 °C
Yield: 64.8 %

Procedure:
A mixture of 207 mg of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)-butyl]-3,1-benzoxazin-4-one as synthesized in above Step 7-15-B and 150 mg of benzylamine was stirred at 250° C. for an hour. Cooling the solution, the residue was purified on silica gel column chromatography (dichloromethane:methanol=15:1) to provide 163 mg (65%) of 3-benzyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:10]1[N:11]=[C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(CC(C)C)c1csc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1csc(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
A solution comprised of the ethyl 4-methyl-2-(2-phenylthiazol-4-yl)pentanoate in methanol (5 mL) was treated with sodium hydroxide (0.1 gm, 2 mmol). The mixture was stirred for 4 hours, basified with 0.1 M sodium hydroxide solution, washed with ethyl acetate (10 mL), acidified and extracted with ethyl acetate (50 mL). The extract was washed with water, dried (MgSO4) and concentrated. Product was purified from the residue by flash chromatography on silica gel (60° A) with 33% ethyl acetate in hexane as an eluent to provide 4-methyl-2-(2-phenylthiazol-4-yl)pentanoic acid (200 mg, 1.44 mmol). Rf 0.41. 1H NMR (DMSO-d6): 1.01 (m, 6H), 1.61-1.79 (m, 3H), 3.63 (m, 1H), 7.04 (d, 1H), 7.22-7.34 (m, 5H). LCMS: 276.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([CH:21]=1)[C:17]([O:19]C)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-:24])=[O:23])=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 75.7 %

Procedure:
To a solution of methyl 5-(2-benzyloxy-ethoxy)-2-nitro-benzoate (8.26 g, 24.93 mmol) in methanol (200 ml) was added LiOH (1N, 80 ml), and the reaction mixture was heated to 50° C. for 2 h. The solvent was evaporated, water was added (100 ml), and the solution was cooled in an ice bath. 3N HCl was added slowly to pH=2.5. The aqueous layer was salted with NaCl and extracted with ethyl acetate (4×75 ml). The aqueous layer was reacidified and extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO4, filtered and evaporated to give an oil that solidified upon standing. The solid was washed with ether (30 ml), filtered and air dried to give 5-(2-benzyloxy-ethoxy)-2-nitro-benzoic acid (5.99 g, 75%). 1H NMR (CDCl3) 7.96 (1H, d, J=9.0), 7.36-7.25 (5H, m), 7.17 (1H, d, J=2.7), 7.05 (1H, dd, J=9.0, 2.7), 4.62 (2H, s), 4.22 (2H, m), 3.84 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:26](=[O:27])[NH:11][C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a cold solution of N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbo hydrazonamide (0.050 g, 0.146 mmol) in CHCl3 was added pyridine (0.5 mL) and phosgene (1.0 mL) at 0-5° C. The reaction mass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched in water, neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=8.7 Hz, 1H), 7.56-7.71 (m, 4H), 7.89 (d, J=9.3 Hz, 2H), 12.69 (s, 1H). MS (m/z): 368.15 (M)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][O:35][C:30]1[C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:21][CH2:22]3)=[CH:24][CH:25]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: COc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 111.9 %

Procedure:
A solution of the compound (315 mg, 0.59 mmol) obtained in Example 43-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (279 mg, quant.) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]([O:12][C@@H:13]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:14]1[O:15][C:16]1[CH:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1)(=[O:11])[CH3:10]>>[C:9]([O:12][C@@H:13]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:14]1[O:15][C:16]1[CH:17]=[N:18][C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:20][CH:21]=1)(=[O:11])[CH3:10]
Reactant: Cc1cncc(Br)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cncc(C)c2)nc1

Procedure:
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methylpyridine and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a white solid (yield=38%).
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14](=[O:47])/[C:15](/[N:20]1[CH:23]([S:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]1=[O:46])=[C:16](/[O:18][CH3:19])\[CH3:17].COC(=O)/C(/N1C(SS(C2C=CC(C)=CC=2)(=O)=O)C(NC(=O)COC2C=CC=CC=2)C1=O)=C(\OC)/C>O1CCCC1.C(Cl)Cl>[CH3:12][O:13][C:14]([C@@H:15]1[N:20]2[C:21](=[O:46])[C@@H:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:23]2[S:24][CH:17]=[C:16]1[O:18][CH3:19])=[O:47]
Reactant: COC(=O)/C(=C(\C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Agent: COC(=O)/C(=C(/C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12

Procedure:
302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to a solution of 534 mg (1 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel using toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8.25 μ, followed by pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90 and 7.10 μ, in the form of colourless foams.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:20]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=CNCCc1cnn2c1NCC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=CNCCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 15.6 %

Procedure:
To a solution of 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (1.67 g) in pyridine (15 ml) was added triphenylmethyl chloride (3.1 g) at room temperature. The mixture was stirred at 60° C. for 5.5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 2-(1-trityl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (610 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH:6]=1.CS(OC1CCOC1)(=O)=[O:13]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH2:9][O:13][CH2:8]2)[CH:6]=1
Reactant: CS(=O)(=O)OC1CCOC1
Reactant: Brc1cnn(C2CCC2)c1
Product: Brc1cnn(C2CCOC2)c1

Procedure:
The title compound was prepared in the same manner as 4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-yl methanesulfonate (prepared according to procedures known in the art).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH:9]1(N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>CN1CCCC1=O>[CH:9]1([N:8]2[C:6](=[O:7])[NH:5][NH:4][C:1]2=[O:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: NC(=O)NNC(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1C1CCCCC1

Procedure:
118 g of hydrazodicarbonamide and 100 g of cyclohexyl amine are stirred in 100 ml of N-methyl pyrrolidone for 2 hours at 160° C., for 7 hours at 175° C. and for 10 hours at 200° C. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of a 10% sodium hydroxide solution. The deposit is isolated by filtration under suction and the filtrate is neutralised with 10% hydrochloric acid. A deposit is precipitated and is isolated by filtration under suction, washed with water and dried in vacuo, giving 132 g (76% of the theoretical yield) of 4-cyclohexyl-1,2,4-triazolidine-3,5-dione (identical with the compounds produced in accordance with Example 2).
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[S:13])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2[nH]cnc2[nH]1
Yield: 354.5 %

Procedure:
6.59 g (19 mM) of xanthine and 5.07 g (22.8 mM) of phosphorus pentasulfide were heated under reflux in 102 ml of pyridine for 3 days. At 0° C., 25.1 ml of 2N NaOH were added. The solid was filtered off and washed with pyridine. The solvents were evaporated in vacuo, the residue suspended in water, collected, redissolved in 100 ml of 1N NaOH and 50 ml of isopropanol, treated twice with 0.3 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The isopropanol was removed in vacuo and the solid collected, washed and dried to give 6.80 g (98.7%) of 6-thioxanthine, mp 188-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][C:13]([O:15]CC)=O)([CH3:11])[CH2:5][NH:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:11][C:4]12[CH2:5][NH:6][C:7]3[C:3]1=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1][C:13](=[O:15])[CH2:12]2
Reactant: CCOC(=O)CC1(C)CNc2cccc(N)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC12CNc3cccc(c31)NC(=O)C2

Procedure:
A mixture of (±)-ethyl (4-amino-3-methyl-2,3-dihydro-1H-indol-3-yl)acetate from Step B (2.50 g, 10.7 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol) was heated in xylenes (50 mL) at reflux for 13 h, then concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:N4OH—100:0:0 to 90:4.5:0.5, to give the racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak AD column and eluting with hexane:i-PrOH:Et2NH—75:25:0.1. The first major peak to elute was 2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer A, the title compound, and the second major peak to elute was 2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B. MS: m/z=189 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[N:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:4]=2[NH:3]1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>>[OH:13][CH2:12][C:10]1[CH:9]=[N:8][C:5]2[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[CH:11]=1
Reactant: O=C1CSc2ncc(C(=O)O)cc2N1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CSc2ncc(CO)cc2N1
Yield: 56.2 %

Procedure:
2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acid (2.48 g) was reacted with iso-butylchloroformate and sodium borohydride by the method of Preparation (14b) to afford a solid (1.3 g), after recrystallisation from chloroform-methanol (9:1). MS (ES) m/e 197 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21]C(OCC3C=CC=CC=3)=O)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4].C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:21])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
cis-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (322 mg, 0.71 mmol), 10% palladium on carbon (32 mg) and cyclohexene (9 ml) in 16 ml ethanol was heated to 80° C. for 1.25 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 1% isopropanol-dichloromethane afforded the title product (208 mg, 91%). 1H NMR (DMSO-d6)δ 1.02 (d, 3H), 6.68 (s, 1H).