Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[C:16]1[CH:17]=[C:18]([N:23]2CC[NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:22][C:21]3[CH:20]=[C:19]4[C:18](=[CH:17][CH:16]=3)[NH:23][CH2:24][CH2:25][NH:26]4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Clc1ccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)cc1Cl

Procedure:
Example 7 was prepared according to Example 2 except that in Step A 1-(3,4-dichlorophenyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 139°-141° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>C(O)C.ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:18][NH2:19])=[O:14])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Reactant: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: NNC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Temperature: 80 °C

Procedure:
In a round bottom flask equipped with reflux condenser, a yellow solution of ethyl [(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetate (2.095 mmol) in ethanol (5 mL) was treated with hydrazine monohydrate (41.9 mmol). The resultant yellow solution was stirred at 80° C. (reflux) overnight. The reaction was cooled to room temperature and concentrated in vacuo. Ethanol (10 mL) was added and the reaction was concentrated to give a clear oil. The oil was dissolved in dichloromethane (white solution observed), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a clear oil (quantitative). MS(ES)+ m/e 212.1 [M+H]+, 423.2 [2M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: CN(C)CCCN(C)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN(C)CCCN(C)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-6-((3-(dimethylamino)propyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 88 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.555 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0093 mmol) and the mixture was subjected to MW irradiation at 125° C. (MW irradiation) for 30 min. Additional pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol), Na2CO3 (59 mg, 0.555 mmol) and Pd(PPh3)2Cl2 (6.5 mg, 0.0093 mmol) were added and the mixture stirred at 125° C. for further 30 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. LC-MS (Condition 6) tR=1.33 min, m/z=474.0 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H](NC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), L-alanine (1061 mg, 11.9 mmol) and NaOMe solution (18 mL, 9 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 4 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as an off-white solid. MS: (+) m/z 393.25 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[OH-].[Na+].[C:7]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>O>[CH3:1][C:2](=[C:8]1[CH2:9][CH2:10][CH2:11][C:7]1=[O:12])[CH3:4]
Reactant: O=C1CCCC1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)=C1CCCC1=O

Procedure:
A mixture of 190 ml of acetone and 36.0 g of sodium hydroxide in 600 ml of water was treated with 60.0 g of cyclopentanone under stirring. After stirring for about 12 hours at about room temperature, the mixture was neutralized with 36% acetic acid and extracted with three 60 ml portions of ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give a residue. The residue was distilled to obtain 62.6 g of 2-(1-methylethylidene) cyclopentanone as a colorless liquid. The boiling point of this intermediate compound was determined to be 85°-88° C. at a pressure of 10 mm Hg. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(1-methylethylidene) cyclopentanone hydrochloride. The melting point of the product was determined to be 173°-175° C.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH3:18])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:17]([CH:13]([C:14]([NH2:16])=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:31])=[O:5])=[CH:12][CH:11]=2)[CH3:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
One hundred milligrams (0.237 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid-tert.butyl ester in 5 ml of benzene were heated together with some crystals of p-toluene-sulfonic acid hydrate to reflux temperature for half a day. According to the thin layer chromatogram no starting product could be then detected; however, according to the Rf -value and mass spectrum the desired product was formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:34][CH3:35])=[C:19]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:34][CH3:35])=[C:19]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CN(CCc2cc(F)cc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylate (D82) (100 mg) in isopropanol (15 mL) and water (5 mL) stirred under nitrogen at room temperature was added 2 M NaOH (0.193 mL) in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E33) (21 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 2.90 (2H, t), 3.47 (2H, br. s.), 3.66 (4H, m), 4.28 (4H, m), 4.80 (1H, m), 7.26 (1H, d), 7.32 (1H, d), 7.73 (1H, dd), 7.90 (1H, dd), 8.01 (1H, d), 8.46 (1H, s), 10.12 (1H, br s), 13.13 (1H, br s). δF (DMSO-d6, 376 MHz): −117.4, −73.9. MS (ES): C25H26ClFN2O4S requires 504. found 505.2 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH3:10].NN1C=NN=C1.C(#N)C>C(#N)C>[Br-:7].[CH2:8]([N+:5]1[N:4]=[CH:3][N:2]([NH2:1])[CH:6]=1)[CH2:9][CH3:10]
Reactant: CCCBr
Reactant: Nn1cnnc1
Solvent: CC#N
Product: CCC[n+]1cn(N)cn1
Product: [Br-]
Yield: 97.5 %

Procedure:
10.005 g 118 mmoles of 4-amino-1,2,4-triazole was weighed out and transferred to a three necked 500 ml, round bottom flask and dissolved 200 ml of acetonitrile. The solution then was stirred vigorously with an overhead stirrer the flask equipped with a reflux condenser and placed in a hot oil bath (50° C.) and allowed to heat. In a graduated cylinder, 1-bromopropane 58.865 g, 478 mmoles, was weighed out and then was slowly added to the hot 4-amino-1,2,4-triazole/acetonitrile mixture. The reaction mixture was stirred with heating for 36 hours, being monitored by thin layer chromatography, at which time the 4-amino-1,2,4-triazole was consumed. The flask was then removed from the oil bath, cooled under nitrogen atmosphere. The reaction solution was transferred to a large round bottomed flask and the acetonitrile and excess n-propyl bromide rotary evaporated away. The resultant oil was transferred to a preweighed Schlenk flask, rinsing the large flask with three 10 ml aliquots of fresh acetonitrile. The flask was evacuated for 20 hours to yield a highly crystalline solid 23.9584 g, 115 mmoles of 1-n-propyl-4-amino-1,2,4-triazolium bromide. Melting point: 63° C.; DSC onset 145° C.,
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]3)[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:15]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.C(OCC)(=O)C.C(O)(=O)C>[OH-].[OH-].[Pd+2]>[F:26][C:22]1([F:25])[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]([NH:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:15]=[C:14]([CH:12]3[CH2:11][CH2:10][CH2:9][N:8]([CH3:1])[CH2:13]3)[CH:19]=2)[CH2:21]1
Reactant: FC1(F)CCN(c2cc(C3=CN(Cc4ccccc4)CCC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCCC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Reaction time: 48 h
Yield: 2.2 %

Procedure:
A suspension of 4-(1-benzyl-3,4-dihydro-2H-pyridin-5-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (250 mg, 0.4850 mmol) and palladium hydroxide on activated charcoal (85 mg, 0.25 equiv., 0.1212 mmol) in methanol (20 ml, 500 mmol) and ethyl acetate (20 ml, 204 mmol) was charged with H2 balloon. The reaction was kept stirring for 48 h, while LCMS indicated olefin was reduced. The catalyst was filtered off, and new portion of catalyst was refilled, followed by addition of acetic acid (0.556 mL, 20 equiv., 9.699 mmol). The reaction was stirred with H2 balloon overnight. LCMS showed both m/z 442 and 456. The catalyst was filtered off, and the solvent was evaporated to dryness. The residue was submitted for HPLC purification to yield 4.7 mg (4.4%) off-white powder. LCMS: m/z 442 (M+H).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:18][C:13]1[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: CC(C)c1ccc(NN)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(-n2nc(O)c3ccccc3c2=O)cc1
Temperature: 125 °C
Yield: 44.5 %

Procedure:
4-Isopropyl phenyl hydrazine hydrochloride (2.77 g, 14.6 mmol) was added in one portion to a stirred mixture of phthalic anhydride (2.0 g, 13 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was heated to 125° C. for 2 hours, and then allowed to cool to room temperature. The resultant suspension was poured into H2O (100 ml), NaHCO3 solution (1M) was added and the resulting solid was removed by filtration. The mother liquor was acidified with conc. HCl The resulting solid was collected by filtration and dried in vacuum to give the title compound (1.62 g, 45% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.80 (1H, s), 8.30 (1H, d), 7.92–8.01 (3H, m), 7.92 (2H, d), 7.35 (2H, d), 2.96 (1H, m), 1.25 (6H, d); MS (ESI+)=345.12 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18]O)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])(=O)(=O)C.[N-]=[N+:26]=[N-:27].[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]1[N:46]=[C:36]2[N:37]=[C:38](S(C)(=O)=O)[N:39]=[C:40]([NH2:41])[N:35]2N=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][NH:41][C:40]3[N:39]=[C:38]([NH2:37])[N:27]4[N:26]=[C:33]([C:29]5[O:28][CH:32]=[CH:31][CH:30]=5)[N:46]=[C:36]4[N:35]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CO)CC[C@@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](CNc3nc(N)n4nc(-c5ccco5)nc4n3)CC[C@@H]2C1

Procedure:
7-Hydroxymethyl-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (see subpart (a) above), was converted to the corresponding mesylate, azide and amine sequentially according to Example 6, subparts (b)-(d) above. The corresponding amine was coupled to 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine in accordance to Example 1 to afford trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as yellow oil. This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2cccs2)CC1
Yield: 91 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), thiophene-2-boronic acid (13 mg, 0.11 mmol), tetrakis (triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (23 mg, 91%), LC-MS (ESI) Rt 1.17 min, m/z 288 (100%, [M+H]+); m/z (ESI) C15H18N3OS requires 288.1165 found [M+H]+ 288.1163.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CN(C)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: CN(C)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
1200 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 432 mg of the product obtained in stage 1 above are added. 65 mg of the expected product are thus obtained.
Reaction SMILES: I[C:2]1[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][O:5][C:6]=1[CH3:7].C([Mg]Br)(C)C.[O:18]1COC[O:20][CH2:19]1.C(=O)=O>C1COCC1.O>[CH2:9]([O:8][C:3]1[C:2]([C:19]([OH:20])=[O:18])=[C:6]([CH3:7])[O:5][N:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: Cc1onc(OCC(C)C)c1I
Reactant: C1OCOCO1
Agent: CC(C)[Mg]Br
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(OCC(C)C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a stirred solution of 4-iodo-3-isobutoxy-5-methyl-isoxazole (669 mg, 2.38) in THF (10 mL) at −30° C. and under argon was added isopropylmagnesium bromide (1.49 mL of a 2.0 M solution in THF) dropwise. The reaction mixture was warmed to 0° C. and stirred for 1 h, then 1,3,5-trioxane (429 mg, 4.76 mmol) in THF (1 mL) was added and the reaction mixture warmed to 50° C. After 1.5 h to the reaction mixture was added further 1,3,5-trioxane (860 mg, 9.52 mmol) and the reaction mixture heated at 70° C. After 2 h the mixture was cooled to 0° C. and solid CO2 (˜10 g) added. After 1 h the reaction mixture was diluted with water (15 mL) then extracted with diethylether. The aqueous phase was acidified with HCl (1 N, 10 mL), then the resultant precipitate filtered off and washed with water (5 mL), then dried under vacuum (60° C.) to afford the title compound (152 mg, 32%) as a white solid. MS: m/e=198.4 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]4[CH:17]([N:5]([C:6]=23)[CH:4]=[C:3]1[C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]4.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[N+:21]([C:8]1[C:7]2[C:2](=[O:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4][N:5]3[C:6]=2[C:11]([CH:12]2[CH:17]3[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)C1CCCCC12
Temperature: 0 °C

Procedure:
6 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 35 ml of concentrated sulfuric acid and stirred while cooling with ice, followed by dropwise addition of a mixture of 4.3 ml of concentrated nitric acid having a specific gravity and 15 ml of the concentrated sulfuric acid. After completion of the addition, the resulting mixture was stirred for one hour at room temperature and poured into 200 g of ice to precipitate yellow crystals. Recrystallization from dimethylformamide-water gave 7 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 251°-253° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.O>[Si:31]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 16 h

Procedure:
24 g (81 mmol) of the compound from Example 21A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 7.2 g (106 mmol) of imidazole and 27 g (98 mmol) of tert-butyl(chloro)diphenylsilane are added. After 16 h, the mixture is diluted with 1.2 l of water and extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. For crystallization, tert-butyl methyl ether is added, and the resulting crystals are filtered off and dried under reduced pressure. This gives 30 g (67% of theory) of the desired product.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1>C1COCC1.Cl>[N:11]1([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1ncn(C2CCC3(CC2)OCCO3)n1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(n2cncn2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole (379 mg, 1.81 mmol) was dissolved in a 1:1 mixture of THF and 3N HCl aqueous solution (9 mL). The resulting mixture was stirred at 40° C. for 5 h. Most of the THF was removed under vacuum then the remaining mixture was neutralized using a 3N NaOH aqueous solution until a basic pH was reached. It was extracted with 3 portions of 10 mL of dichloromethane. The organic portions were combined, dried over anhydrous Na2SO4 and concentrated to afford 4-[1,2,4]triazol-1-yl-cyclohexanone as a white waxy solid (257 mg, 86%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCC1CO1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.1 %

Procedure:
Quinoline-6-carboxylic acid (1 g; 5.78 mmol) is dissolved in DMF (10 mL) at ambient temperature. Epichlorohydrin (0.4517 mL; 5.59 mmol) is added followed by mortar ground potassium carbonate (0.80 g; 5.79 mmol). The mixture is stirred at ambient temperature for 48 hours. Potassium iodide (96 mg; 0.58 mmol) is added and stirring is continued at ambient temperature for 24 hours. The mixture is heated to 60° C. and maintained for 72 hours. After cooling, the mixture is poured onto water (700 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts are washed successively with water (100 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo at 30 C. The residue is purified via silica gel chromatography with gradient elution (20%→67% ethyl acetate in hexanes) affording the desired product (270 mg) as a white solid. ESMS:MH+ 230.0 (base).