Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([SH:33])=[N:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)=[N:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cnc(S)n1C
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCSCC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:22][N:21]([C:23]3[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[CH3:32])[CH2:20][CH2:19][C:4]=2[N:5]=[C:6]([C:8]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:18])=[N:11][NH:12]3)[N:7]=1.C[CH2:34][N:35]([CH:39](C)C)[CH:36]([CH3:38])[CH3:37].CC([N:45](C)C)=O>>[CH3:14][C:13]1[C:9]2[C:10](=[CH:18][CH:15]=[C:16]([CH3:17])[C:8]=2[C:6]2[N:7]=[C:2]([N:45]3[CH2:38][CH:36]([N:35]([CH3:39])[CH3:34])[CH2:37]3)[C:3]3[CH2:22][N:21]([C:23]4[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=4[CH3:32])[CH2:20][CH2:19][C:4]=3[N:5]=2)[NH:11][N:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(Cl)c2C1
Reactant: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(N3CC(N(C)C)C3)c2C1

Procedure:
A solution of 4-chloro-2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (30 mg, 0.07 mmol), N,N-dimethylazetidin-3-amine bistrifluoroacetate salt (20.0 mg, 0.2 mmol) and DIEA (0.06 mL, 0.35 mmol) in DMA (1.5 mL) was heated to 180° C. for 3 min in a microwave reactor. The reaction mixture was filtered through a 0.45 μM PTFE filter and the filtrate was purified by reverse phase HPLC (C18, 10-100% acetonitrile-H2O with 0.1% NH4OH) to afford 1-(2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethylazetidin-3-amine 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.43 (d, J=8.46 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.13 (d, J=7.83 Hz, 1H), 7.04 (d, J=1.39 Hz, 1H), 6.91 (dd, J=1.52, 7.71 Hz, 1H), 4.36 (t, J=8.21 Hz, 2H), 4.08-4.20 (m, 4H), 3.32-3.38 (m, 2H), 3.18-3.27 (m, 1H), 2.79-2.97 (m, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.18 (s, 6H), 2.04 (s, 3H), 1.24 (d, J=6.95 Hz, 6H); MS (ESL) m/z 510.5 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[C:10](=[N:19][OH:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)Cl>[C:32]([O:20][N:19]=[C:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:9]1[CH:21]=[CH:22][CH:23]=[C:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:24])(=[O:5])=[O:4])[CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=NO)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=NOC(C)=O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Yield: 29.8 %

Procedure:
A suspension of 3-[N-(dimethylaminosulfonyl)amino]-4'-methoxybenzophenone oxime (1.5 g) and triethylamine (650 mg) in dry methylene chloride (15 ml) is stirred under icy water cooling. A solution of acetyl chloride (337 mg) in dry methylene chloride (3 ml) is dropwise added to the suspension, and 30 minutes later the reaction mixture is mixed with icy water, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of Lobar Lichroprep Si 60, which is eluted with benzene:ethyl acetate (2:1). The eluates from the fraction No. 5-18 are combined and concentrated to give 3-[N-(dimethylaminosulfonyl)amino]-4'-methoxybenzophenone O-acetyloxime (500 mg) as an oil.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[H-].[Na+].Br[CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:27][CH2:28][CH3:29])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CCCBr
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(CCCCCO)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Yield: 77.7 %

Procedure:
5.1 g of 5-trimethylsilyloxy-2-(4-[5-hydroxy-1-pentyl]phenyl)pyridine, 0.7 g of sodium hydride (60-65 wt. %), 2.5 g of 1-bromopropane and 100 ml of tetrahydrofuran were reacted analogously to Example 1(f) to give 3.6 g of 5-hydroxy-2-(4-[5-(propyloxy)-1-pentyl]phenyl)pyridine.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-chloro-4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.54 (t, J=8.8 Hz, 1H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 8.24 (ddd, J=8.6, 4.6, 2.0 Hz, 1H), 8.39 (dd, J=7.0, 2.2 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.9, 1.5 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:55]1[CH2:60][CH2:59][S:58](=[O:62])(=[O:61])[CH2:57][CH2:56]1>CN(C=O)C.O>[O:61]=[S:58]1(=[O:62])[CH2:59][CH2:60][N:55]([C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:23])[CH2:56][CH2:57]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) in DMF (8 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (227 mg, 0.70 mmol), N,N-diisopropyl ethyl amine (550 μL, 3.2 mmol) and thiomorpholine 1,1-dioxide (0.104 g, 0.77 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 6:4) afforded the title compound (176 mg, 63%) as a white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.P(Cl)(Cl)(Cl)(Cl)Cl.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O>[C:23]1([O:5][S:2](=[O:4])(=[O:3])[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccccc1
Reactant: Nc1cccc2cccnc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
Chlorosulfonic acid (210 mg, 1.8 mmol) in DCM was added dropwise to solution of 8-aminoquinoline (250 mg, 1.7 mmol) and TEA (260 mg, 2.6 mmol) in DCM (5 ml) at 0° C. and the mixture was stirred for 30 min. The reaction was allowed to warm to room temperature and stirring was continued for 1 h. PCl5 (370 mg, 1.8 mmol) was added and the mixture was heated at 50° C. for 1 h. The reaction was cooled to room temperature, phenol (310 mg, 3.4 mmol) and TEA (340 mg, 3.4 mmol) were added and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM, the organic phase dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (4:1) as the eluent to give the title compound (40 mg, 8%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14](=[O:28])[C@H:15]([NH2:27])[CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:45])[CH2:31][CH2:30]1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:28])[C@H:15]([NH:27][C:1]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:45])[CH2:33][CH2:34]1)=[O:2])[CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@H](N)Cc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CC(=O)N2)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phosgene in toluene (2M, 0.158 mL, 0.30 mmol) was added to a vigorously stirred mixture of (R)-2-amino-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)-propionic acid methyl ester (70 mg, 0.25 mmol) in methylene chloride (15 mL) and saturated sodium bicarbonate (7.5 mL). After the mixture was stirred at room temperature for 30 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (58 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 h, diluted with ethyl acetate, and washed with 0.25 N hydrochloric acid that had been saturated with solid sodium chloride. The organic layers were dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a tan viscous oil. LC/MS: tR=2.01 min, 492.10 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCl)ccn1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(2-Methyl-pyridin-4-yl)-methanol (40 mg, 0.33 mmol) described in Manufacturing Example 47-1-1, thionyl chloride (0.047 ml, 0.65 mmol) and methylene chloride (4.0 ml) were stirred for 5 minutes at 60° C. Sodium bicarbonate solution and ethyl acetate were added to separate the reaction solution, and the ethyl acetate layer was dried over sodium sulfate. The solvent was evaporated under a reduced pressure to obtain 4-chloromethyl-2-methyl-pyridine as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[C:19]([O:25][CH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CC(O)C>[CH3:23][C:21]1[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[C:20]=1[C:19]([O:25][CH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])=[O:24]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cccc(Cl)c1Cl
Yield: 47.7 %

Procedure:
A mixture of 175 mg of 2,3-dichlorobenzaldehyde, 126 mg of methyl 3-aminocrotonate and 320 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 1 ml of 2-propanol was refluxed for 8 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel to provide 260 mg of the desired compound (134).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH3:29])[CH:24]=2)[N:19]=1)([C:5]1[N:9](COCC[Si](C)(C)C)[N:8]=[N:7][CH:6]=1)[OH:4].[F-].[Cs+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][CH:2]([CH3:30])[C:3]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH3:29])[CH:24]=2)[N:19]=1)([C:5]1[N:9]=[N:8][NH:7][CH:6]=1)[OH:4]
Reactant: CSc1ccc2nc(C(O)(c3cnnn3COCC[Si](C)(C)C)C(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc2nc(C(O)(c3c[nH]nn3)C(C)C)ccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
To a stirred solution of 2-methyl-1-(6-(methylthio) quinolin-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-yl) propan-1-ol (AL) (1 g, 2.25 mmol) in THF (20 mL) was added CsF (1.02 g, 6.75 mmol) followed by TBAF (2.24 mL, 2.25 mmol) (1M solution in THF) at RT under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using 30% EtOAc/Hexane as eluent to afford 7 (70 mg, 0.22 mmol, 9.9%). 1H NMR (500 MHz, CDCl3): δ 11.65-11.63 (br s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.80 (br s, 2H), 7.59 (dd, J=2.0, 9.0 Hz, 1H), 7.52-7.51 (m, 1H), 6.54 (s, 1H), 2.82-2.80 (m, 1H), 2.58 (s, 3H), 0.97 (d, J=6.5 Hz, 3H), 0.63 (d, J=6.5 Hz, 3H). HPLC: 95.12%. MS (ESI): m/z 315 [M++1].
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][CH2:21][CH2:22][CH2:23][Si:24]([O:25][CH2:26][CH3:27])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[Si](CCCI)(OCC)OCC
Reactant: O=C(Oc1ccc(CO)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[Si](CCCOCc1ccc(OC(=O)c2ccccc2)cc1)(OCC)OCC
Yield: 30.1 %

Procedure:
4-(Hydroxymethyl)phenyl benzoate (1 g, 4.39 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran and cooled in an ice bath. A suspension of sodium hydride (60% suspension, 175 mg, 4.39 mmol) in 5 mL of anhydrous tetrahydrofuran was added dropwise under stirring. The resultant mixture was stirred at 0° C. for 1 hour. (3-Iodopropyl)triethoxysilane (1.46 g, 4.39 mmol) was added and the mixture was refluxed for 36 hours. The reaction crude was filtered, the solvent was removed under reduced pressure, and the resultant oil was chromatographed (hexane/ethyl acetate 8:2) thus affording 570 mg (1.32 mmol, yield=30%) of the title compound (HPLC purity=99.2%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C@@H:10]2[C@@:4]([C:24]([O-:26])=[O:25])([N:5]3[C@H:8]([S:9]2)[C@H:7]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]3=[O:23])[O:3]1.[Na+].[C:28](OCC)(=O)C.[N+](=C)=[N-].Cl>O.CCOCC>[O:1]=[C:2]1[CH2:11][C@@H:10]2[C@@:4]([C:24]([O:26][CH3:28])=[O:25])([N:5]3[C@H:8]([S:9]2)[C@H:7]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]3=[O:23])[O:3]1
Reactant: CCOC(C)=O
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1S[C@@H]1CC(=O)O[C@@]12C(=O)[O-]
Agent: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@]12OC(=O)C[C@H]1S[C@@H]1[C@H](NC(=O)COc3ccccc3)C(=O)N12
Reaction time: 0.5 h

Procedure:
30 mg of the compound obtained in Example 4 was dissolved in 3 ml water. To this solution 3 ml ethyl acetate and 5 ml of diazomethane in ether were added, while cooling the solution with ice. After adding 83 μl of 1N hydrochloric acid, the resulting mixed solutio was stirred for 30 minutes, while cooling with ice. After 30 minutes of stirring, 8 ml of a solution of diazomethane in ether was added; the resulting mixed solution was stirred for 20 minutes, while cooling with ice. The reaction mixture, after dilution with water, was extracted with ethyl acetate. The organic layer was dried (MgSO4), then the solvent was evaporated under reduced pressure. The resulting residue was passed through a silica gel column and eluted with n-hexane-ethyl acetate (2:1), then the eluted fraction containing the desired product was collected and concentrated under reduced pressure to yield 13.5 mg of the subject compound in the form of a white crystal. Melting point: 182° to 184° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][N:4]([C:6]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])=[O:7])[C:3]1=[O:13].C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.[C:39]1([CH2:45][C:46](O)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[NH2:12][S:9]([NH:8][C:6]([N:4]1[CH2:5][C@H:2]([NH:1][C:46]([CH2:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:47])[C:3]1=[O:13])=[O:7])(=[O:10])=[O:11]
Reactant: O=C(O)Cc1ccccc1
Reactant: N[C@H]1CN(C(=O)NS(N)(=O)=O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Product: NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 34.1 %

Procedure:
(S)-3-Amino-N-(aminosulfonyl)-2-oxo-1-azetidinecarboxamide (see example 22, or prepared by hydrogenating 140 mg of (S)-N-(aminosulfonyl)-3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinecarboxamide in dimethylformamide used 50 mg of 5% palladium on charcoal catalyst) was acylated with 100 mg of dicyclohexylcarbodiimide, 20 mg of hydroxybenzotriazole and 55 mg of benzeneacetic acid. The mixture was stirred at 0° C. for 6 hours and dicyclohexylurea was filtered off. Dimethylformamide was distilled off, the residue was dissolved in 5 ml of acetone and the solution was, after standing for about 16 hours, filtered and then evaporated. The crude material was chromatographed on an HP-20 column eluting with water/acetone (6:4) to give 45 mg of the title compound, melting point 137° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[C:7]([C:10]1([CH2:21][C:22]([OH:24])=[O:23])[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11]1)([OH:9])=[O:8].[OH-:25].[Na+].[OH2:27]>>[C:7]([C:10]1([CH2:21][C:22]([OH:24])=[O:23])[C:15]2[CH:16]=[C:17]([C:20]([OH:27])=[O:25])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11]1)([OH:9])=[O:8]
Reactant: O
Reactant: Cc1ccc2c(c1)C(CC(=O)O)(C(=O)O)CCO2
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)CC1(C(=O)O)CCOc2ccc(C(=O)O)cc21
Reaction time: 8 h

Procedure:
Potassium permanganate (7.52 g, 48 mmol) is added to a mixture of 4-carboxy-3,4-dihydro-6-methyl-2H-benzopyran-4-acetic acid (3.50 g, 14 mmol) and sodium hydroxide (0.84 g, 21 mmol) in water at 50° C. The reaction mixture is stirred at 50° to 60° C. overnight and filtered through diatomaceous earth. The filtrate is acidified to pH 1 with hydrochloric acid, washed with an ether/methylene chloride solution and filtered to obtain the title product as a white solid (0.62 g, mp 198°-200° C.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[N:6][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:15])=[N:6][C:7]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ncco2)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-nitro-6-(1,3-oxazol-2-yl)pyridin-2-amine (0.127 g, 0.62 mmol) in dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (0.115 g, 0.65 mmol) and the mixture was warmed to room temperature. After 3 days, further N-bromosuccinimide (0.058 g, 0.33 mmol) was added and stirring was continued for 3 hours. The solution was poured into water and the precipitate was filtered, washed with water and dried to give the title compound (0.18 g, 70%) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[S:30])[CH2:27][C:28]#[N:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NCCC(O)=O>C(O)C>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:27](/[C:26]([NH:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:30])\[C:28]#[N:29])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCC(=S)NCCCc1ccccc1
Agent: NCCC(=O)O
Solvent: CCO
Product: CC(C)c1cc(/C=C(\C#N)C(=S)NCCCc2ccccc2)cc(C(C)C)c1O

Procedure:
0.6 g of 3,5-diisopropyl-4-hydroxybenzaldehyde, and 0.6 g of N-3-phenyl-n-propylcyanothioacetamide and 40 mg β-alanine in 40 ml ethanol were refluxed 4 hours. Evaporation and chromatography gave 0.6 g of M24 as an orange viscous oil that did not crystalyze. NMR CDCl3 δ 8.76(1H, S, vinyl), 7.78(2H, S, H2.6), 7.25(5H, m), 5.60(1H, S, OH), 3.90(2H, q, J=7.0 Hz), 3.17(2H, Septet, J=7.0 Hz), 2.76(2H, t, J=7.0 Hz), 2.11(2H, quintet, J=7.0 Hz), 1.29(12H, d, J=7.0 Hz). MS—407(M+1,55), 406(M+, 70), 373(M-CH3-H2O, 100), 363(M-isopropyl, 72), 272(M-NH(CH2)3 Ph. 20), 259 (58), 230 (28), 91 (28), m/e.
Reaction SMILES: [CH3:1][N:2]1[C:17](=[O:18])[C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:5]=3[C:4]=2[C:3]1=[O:26].[C:27]([NH2:31])(=[O:30])[CH:28]=[CH2:29].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:27]([CH2:28][CH2:29][N:19]1[C:6]2[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]3[C:17](=[O:18])[N:2]([CH3:1])[C:3](=[O:26])[C:4]=3[C:5]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:30])[NH2:31]
Reactant: C=CC(N)=O
Reactant: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN1C(=O)c2c(c3c4ccccc4n(CCC(N)=O)c3c3[nH]c4ccccc4c23)C1=O

Procedure:
500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals.