Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[CH:16]1([NH:15][P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[S:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CN(CP(=S)(NC1CCCCC1)NC1CCCCC1)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)CNCP(=S)(NC1CCCCC1)NC1CCCCC1
Yield: 40.8 %

Procedure:
N-trifluoroacetyl-N-[bis(cyclohexylamino)phosphinothioylmethyl]glycine, ethyl ester (4 g, 8.49 mm), was dissolved in ethanol (40 ml). The solution was stirred and sodium tetrahydrido boron (322 mg, 8.49 mm) was added portionwise over a ten minute period. The solution was stirred for an additional 30 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel with ether to yield N-[bis(cyclohexylamino)phosphinothioylmethyl]glycine, ethyl ester (1.3 g), m.p. 74°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][NH:13][CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+]>CO.C(Cl)Cl.C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3ccc(Br)cc31)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reaction time: 1 h
Yield: 88 %

Procedure:
7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and CH2Cl2 (5 mL) and formaldehyde (0.56 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc)3 (1.98 g, 9.34 mmol) was added and the mixture stirred for a further 10 minutes. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH:26]1([CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([CH2:32][CH2:33][S:34]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Reactant: O=S(=O)(Cl)CCC1CCCCC1
Product: CC(C)(C)OC(=O)NCCCc1cccc(NS(=O)(=O)CCC2CCCCC2)c1

Procedure:
Sulfonation of aniline 17 by 2-cyclohexylethanesulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(2-cyclohexylethylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:12][CH3:13])[C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])[CH3:4].C([Li])CCC.[CH:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O1CCCC1.CCCCCC.O>[CH2:12]([N:5]([CH2:3][CH3:4])[C:6](=[O:11])[CH2:7][C:8](=[O:9])[CH2:10][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:26])[CH3:13]
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)C(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CC(=O)CC(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
1.53 g of 80% sodium hydride (51.0 mmol) in 60 cm3 of tetrahydrofuran are introduced into a three-necked, round-bottomed flash equipped with a septum and a dropping funnel. The mixture is cooled to -10° C. and then 5.5 g of 97% N,N-diethylacetoacetamide (34.0 mmol) are slowly added. The mixture is stirred for 15 minutes. 21.25 cm3 of n-butyllithium in solution in hexane at 1.6 mol/liter are then slowly added and the mixture is then stirred for 15 minutes. 3.05 g of benzaldehyde (28.5 mmol) are introduced. The mixture is stirred for 25 minutes and then 6 cm3 of concentrated hydrochloric acid and 35 cm3 of water are added. Extraction is carried out with 3 times 25 cm3 of dichloromethane. The combined organic phases are washed with 2 times 100 cm3 of water and dried over sodium sulphate. After filtration and concentration to dryness under reduced pressure, there is obtained, with a yield of 97.7%, 7.33 g of N,N-diethyl -5-phenyl-5-hydroxy-3-oxopentanamide, the structure of which is confirmed by the proton nuclear magnetic resonance spectrum.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:24]([O:26]CC)=[O:25])=[N:10]2)=[CH:5][CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[CH:12][C:11]([C:24]([OH:26])=[O:25])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(OC)cc2)n1
Agent: I
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(O)cc2)cc1
Yield: 48 %

Procedure:
A mixture of ethyl 1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (2 g) and hydriodic acid (57%, 5 ml) in acetic acid (10 ml) was refluxed for 5 hours. The reaction mixture was concentrated and the residue was triturated in an aqueous solution of sodium bisulfite giving a powder. This crude powder was purified by column chromatography on silica gel (80 g) eluting with a mixture of chloroform and methanol to give a powder of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (0.86 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nccc2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(C)n2ncc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5,7-Dimethyl pyrazolo[1,5-a]pyrimidine [1.0g (6.8 mmoles)] was dissolved in H2SO4 (10 ml) keeping the temperature below 5°. Fuming HNO3 [4 ml; sp. gr. 1.5] was added dropwise to the cold H2SO4 solution, with good stirring. The temperature during this addition was maintained below 10°. After the addition was complete, the solution was stirred at room temperature for 45 minutes and then added to 100 g of ice. The precipitated product was separated by filtration, washed well with H2O, and dried. Recrystallization from CH3OH afforded 0.75 g (57%) of analytically pure product; mp 156°-7°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1

Procedure:
To a solution of 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (5.0 g) in dimethylformamide (DMF) (25 ml) was portionwise added sodium hydride (60% in oil) (1.29 g) with stirring under ice-cooling. The mixture was successively stirred at ambient temperature for 30 minutes, stirred at 60° C. for 1 hour and cooled with an ice bath. To the reaction mixture was added 1,5-dibromopentane (6.72 ml), and the mixture was stirred at ambient temperature for 3 hours. The reaction solution was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate (80 ml) and n-hexane (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-bromopentyloxy)-1-N-t-butyloxycarbonylpiperidine (2.44 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:36])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[N:18]=3)[CH:15]=2)[N:10]([C:32](=[O:34])[CH3:33])[C@@H:9]([CH3:35])[CH2:8]1)[CH3:3].[ClH:37]>O1CCOCC1>[ClH:37].[C:32]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][CH2:23][NH2:24])[N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:36])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N1c2ccc(-c3nc(CCNC(=O)OC(C)(C)C)no3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3nc(CCN)no3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.45 %

Procedure:
To a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{3-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,2,4-oxadiazol-5-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 66) (100 mg, 0.199 mmol) in 1,4-dioxane (0.5 mL) at room temperature was added HCl (4N in 1,4-dioxane, 2 mL, 8.00 mmol) and the resulting mixture was stirred at this temperature for 3 h then was left standing at 4° C. for 16 h before being warmed to room temperature. The residue was triturated with Et2O then purified using MDAP (modifier: ammonium bicarbonate). The residue obtained was dissolved in 1,4-dioxane (2 mL) and treated with HCl (4N in 1,4-dioxane, 1 mL). The resulting mixture was concentrated in vacuo and the residue triturated with Et2O to give 1-methylethyl {(2S,4R)-1-acetyl-6-[3-(2-aminoethyl)-1,2,4-oxadiazol-5-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (10 mg, 0.023 mmol, 11.45% yield) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])CC4)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC(N1CCNC1=O)=[O:30].CN1CCN(C(Cl)=O)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][C:27]4=[O:30])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Agent: CN1CCN(C(=O)Cl)CC1
Product: O=C1NCCN1C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 51.3 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 104, replacing 1-chlorocarbonyl-2-imidazolidinone for by 4-methyl-1-piperazinecarbonyl chloride. After evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient EtOAc-MeOH from 95:5 to 8:2) to afford a yellowish solid. Yield: 51.3%.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C[N+]1C=CN([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])C=1.[CH:25]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([C:43](=[O:45])[CH3:44])[CH2:39][CH2:38]3)=[CH:33][C:32]=2[F:46])[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:43]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:29]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[S:15](=[O:17])(=[O:16])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:32]([F:46])[CH:33]=2)[CH2:42][CH2:41]1)(=[O:45])[CH3:44]
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Reactant: C[n+]1ccn(S(=O)(=O)Oc2ccccc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Oc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a solution of 3-methyl-1-(phenoxysulfonyl)-1H-imidazol-3-ium triflate (143 mg, 0.6 mmol) and 1-(4-(4-((cyclobutylamino)methyl)-3-fluorophenyl)piperazin-1-yl)ethanone (150 mg, 0.49 mmol) in DCM (20 mL) was added diisopropylethylamine (1 mL). The mixture was stirred at ambient temperature for 16 h. After the solvent was removed, the residue was purified by prep-HPLC to provide the title compound (67.3 mg, 29.6%). 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.40 (m, 2 H), 7.34-7.24 (m, 4 H), 6.79-6.67 (m, 2 H), 4.46 (s, 2 H), 4.20-4.17 (m, 1 H), 3.73-3.66 (m, 4 H), 3.26-3.17 (m, 4 H), 2.19-2.15 (m, 2 H), 2.14 (s, 3 H), 2.03-1.98 (m, 2 H), 1.62-1.52 (m, 2 H). LCMS (ESI): m/z 483.9 [M+Na+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:20])[O:19][C:5]=2[CH:4]=1.Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][N:15]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:14][C:13]=3[C:18](=[O:20])[O:19][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Reactant: CC(=O)CCl
Product: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CC(C)=O)C3
Yield: 85.8 %

Procedure:
Prepared by the method described for Example 26 from 1,2,3,4-tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.52 g, 0.02 moles) and 1-chloro-2-propanone (3.5 g, 0.038 moles). Recrystallization from methanol gave the product (5.7 g), mp 222°-225° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH3:9][O:10][C:11]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:12]=1[CH2:13][N:14]1[C@H:17]([CH2:18][CH:19]=O)[C@H:16]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]1=[O:32]>O.CCO>[CH3:9][O:10][C:11]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:12]=1[CH2:13][N:14]1[C:15](=[O:32])[C@@H:16]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:17]1[CH2:18]/[CH:19]=[N:2]/[OH:3]
Reactant: NO
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CC=O)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C/C=N/O)c(OC)c1
Reaction time: 20 h

Procedure:
To a solution of hydroxylamine hydrochloride (160 mg, 2.25 mmol) and sodium bicarbonate (2.4 mL, 2.23 mmol) in water (6 mL) was added a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(2-oxoethyl)azetidin-3-yl)carbamate (886 mg, 2.15 mmol) in EtOH (200 μL) followed by an EtOH (200 μL) wash. After stirring for 20 h, the reaction mixture was partially concentrated in vacuo and partitioned between DCM and brine. The aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.76 min, m/z=428.1 (M+1). Method 2m_acidic.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:18][N:4]1[C:5]2[C:10](=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2)[CH:11]=[C:3]1[CH:2]=[O:1]
Reactant: COc1cc2c(cc(CO)n2C)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: COc1cc2c(cc(C=O)n2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxymethyl-1-methyl-4,5,6-trimethoxyindole (861 mg) was dissolved in benzene (50 mL), activated manganese dioxide (8.7 g) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[N:13]2[C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([NH2:24])[C:15]=3[N:25]=[C:12]2[CH2:11][N:10]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:9]1.Cl>FC(F)(F)C(O)=O.C(O)C.[Pt]=O>[OH2:27].[ClH:2].[ClH:2].[NH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[N:13]2[C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[N:17]=[C:16]([NH2:24])[C:15]=3[N:25]=[C:12]2[CH2:11][N:10]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:9]1
Reactant: CS(=O)(=O)N1Cc2nc3c(N)nc4ccccc4c3n2[C@@H](CCCN)C1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CS(=O)(=O)N1Cc2nc3c(N)nc4c(c3n2[C@@H](CCCN)C1)CCCC4
Reaction time: 48 h
Yield: 121.7 %

Procedure:
(11S)-11-(3-Aminopropyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride hydrate (1.30 g, 2.80 mmol) was dissolved in 10 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (635 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 2 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with ethanol and the combined filtrates were concentrated under reduced pressure. The resulting residue was concentrated with 2 N HCl in ethanol three times to give white solid. The white solid was treated with hot 2 N HCl in ethanol and the solution was allowed to cool, leaving a white solid. The solid was isolated by filtration and rinsed with ethanol and dried under vacuum at 80° C. to give (11S)-11-(3-aminopropyl)-9-(methylsulfonyl)-1,2,3,4,8,9,10,11-octahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride hydrate (800 mg) as an off-white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[C:7]2=[O:18])[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 86.5 %

Procedure:
To a solution of 99.3 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 158 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine, followed by heating under reflux for 8 hours. The reaction treatment and purification were conducted similarly as in Example 17 to obtain 109 mg of the desired compound (yield 87%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:12][C:11]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[Cl:41][C:42]1[CH:59]=[CH:58][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]=[O:57])=[CH:48]2)=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]([C:13]3[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:29])=[CH:2][CH:3]=4)(=[O:9])=[O:8])=[C:11]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:12]=3)[OH:57])=[CH:48]2)=[CH:58][CH:59]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Reaction time: 0.33 h
Yield: 26.6 %

Procedure:
To a stirred solution of 2-[5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine (0.15 g, 0.35 mmol) in dry THF (10 mL) was added 2.5 M n-BuLi solution in hexane (0.21 mL, 0.525 mmol) under N2 at −78° C. After 20 minutes at this temperature, a solution of N-4-chlorobenzylindole-3-carboxaldehyde (0.1 g, 0.37 mmol) in dry THF (3 mL) was then added through a cannula. Stirring was continued at this temperature for 1 hour. The reaction was then quenched with H2O (10 mL) at 0° C. The aqueous solution was extracted with dichloromethane (3×15 mL). Combined dichloromethane solution was washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude material was separated by silica gel chromatography (2:1 hexane/ethyl acetate to 2:1 ethyl acetate/hexane) to afford the desired intermediate [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as an oil (65 mg, 30%). 1H NMR (CDCl3) δ −0.05 (s, 9H), 0.70 (t, 2h, J=6), 2.55 (s, 3H), 3.2–3.35 (m, 2H), 4.02 (d, 1H, J=7), 5.2–5.4 (m, 2H), 5.41 (s,2H), 6.4 (d, 1H), 7.0–8.0 (m, 16 H), 8.8 (d, 1H J=5). ESMS calcd for (C37H39ClN4O4SSi): 698.6; found: 699.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Si:24]([O:31][CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:36]1[CH:37]=[C:33]([CH2:32][O:31][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[N:34]=[CH:35]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 136.7 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2-methanesulfonyloxyethyl)pyrrolidine (13.2 g) was reacted with 4-(t-butyldimethylsilyloxymethyl)imidazol (8.30 g) and potassium t-butoxide (4.39 g) in substantially the same manner as Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-{4-(t-butyldimethylsilyloxymethyl)-imidazol-1-yl}ethyl]-4-methanesulfonyloxypyrrolidine (23.7 g) as a brown paste.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH3:11][O:12][NH2:13].[C:14]1(=[O:21])[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C(O)(C)C>[CH3:11][O:12][N:13]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][C:14](=[O:21])[CH2:20]2
Reactant: O=C1C=CCCC=C1
Reactant: CON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CON1C2CCC1CC(=O)C2
Reaction time: 6 h
Yield: 20 %

Procedure:
N,N-Diisopropylethylamine (14.5 ml) was added dropwise to a stirred suspension of O-methylhydroxylamine hydrochloride (2.32 g) in isopropyl alcohol (25 ml). After 30 minutes cyclohepta-2,6-dienone (3.0 g) in isopropyl alcohol (5 ml) was added dropwise. After 24 hours N,N-diisopropylethylamine (4.9 ml) was added. After 6 hours the mixture was allowed to stand at room temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid (×3). The combined aqueous fractions were washed with diethyl ether (×3), neutralised with sodium hydroxide and extracted with diethyl ether (×3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (0.86 g).