Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[Cu][C:17]#[N:18]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:17]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15])#[N:18]
Reactant: N#C[Cu]
Reactant: COc1cc(Br)c2c(c1OC)C(=O)CC2
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C#N)c2c(c1OC)C(=O)CC2
Reaction time: 5.75 h

Procedure:
A mixture of 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone [Can. J. Chem. 57, 1603 (1979)] and 2.5 g (28 mmol) of copper(I) cyanide in 7 ml of DMF is stirred for 5.75 hours at 170°. The reaction mixture is then cooled to 100° and then 70 ml of toluene and a solution of 9.7 g (36 mmol) of iron(III) chloride hexahydrate in 15.6 ml of water and 3.5 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is then stirred for 30 minutes at 80°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is distilled at 150°-160°/0.1 mbar in a bulb tube still and corresponds to starting compound (a), m.p. 150°; IR (CH2Cl2): 2220, 1710 cm-1 ; 1H-NMR (CDCl3): δ=7.33 (s,1H); 4.12 (s,3H); 3.90 (s,3H); 3.19 (m,2H); 2.76 (m,2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.ClC1C=CC(C2C(C(F)(F)F)=[N:26][N:27]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)C=2)=CC=1.ClC1C=CC(C2C=C(C(F)(F)F)N(C3C=CC(S(N)(=O)=O)=CC=3)N=2)=CC=1>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:27]([C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[N:26]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-n2cc(-c3ccc(Cl)cc3)c(C(F)(F)F)n2)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Agent: NS(=O)(=O)c1ccc(-n2nc(-c3ccc(Cl)cc3)cc2C(F)(F)F)cc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4-Sulphonamidophenylhydrazine hydrochloride (982 mg, 4.4 mmol 1,1-equivalent) was added to a stirred solution of 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione from Step 1 (1.00 g, 4.0 mmol) in ethanol 150 mL). The reaction was heated to reflux and stirred for 20 hours. (HPLC area percent showed a 96:3 ratio of 4-[4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer (4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a light brown solid which was recrystallized from ethyl acetate and iso-octane to give the pyrazole (1.28 g, 80%, mp 143-145° C.). HPLC showed that the purified material was a 99.5:0.5 mixture of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer. 1H NMR (CDCl3/CD3OD 10/1) d 5.2 (s, 2H), 6.8 (s, 1H), 7.16 (d, j=8.5 Hz, 2H), 7.35 (d, j=8.5 Hz, 2H), 7.44 (d, j=8.66, 2H), 7.91 (d, j=8.66, 2H.); 13C NMR (CDCl3/CD3OD 10/1) d 106.42 (d, j=0.03 Hz), 121.0 (q, j=276 Hz), 125.5, 126.9, 127.3, 129.2, 130.1, 135.7, 141.5, 143.0, 143.9 (q, j=37 Hz), 144.0; 19F NMR (CDCl3/CD3OD 10/1) d −62.9. EI GC-MS M+=401.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[C:8]([C:11]3[S:12][C:13]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[CH:9]=[CH:10][C:2]1=2.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][C:42](=O)[O:43]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][C:42]([N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[S:12][C:13]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)=[CH:7][C:3]1=2)=[O:43]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)NCCO3)sc1N(C)CCOc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)sc1N(C)CCOc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 310.1 %

Procedure:
To ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20B) (0.150 g, 0.34 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (0.349 g, 0.11 mmol) was added acetonitrile (10 mL). The reaction mixture was allowed to heat to 85° C. and stirred for 8 hours. Then the reaction mixture was allowed to heat at 70° C. and stirred overnight. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. To the concentrate was added EtOAc and water and filtered. The layers of the filtrate were separated and extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.21 g (quantitative) ethyl 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20C): LC/MS (APCI): m/z 616.3 (M+H).
Reaction SMILES: C([N:8]([CH2:30][C@H:31]([OH:41])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1>[Pd]>[OH:41][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Agent: [Pd]
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Reaction time: 6 h
Yield: 94.6 %

Procedure:
5% Pd/C (8 g, 50% wet) was added to a solution of 3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide (16 g) in IMS and the mixture was stirred under hydrogen for 6 h. The resulting suspension was filtered through a plug of Celite which was then washed with IMS (160 ml). The combined washings were concentrated under reduced pressure to give the title compound (12.8 g) as an oil, LC RT=3.51 min, δ (CD3OD) 7.64 (1H, s), 7.61 (1H, m), 7.33 (2H, m), 7.20 (1H, s), 7.01 (1H, dd, J 2.2, 8.2 Hz), 6.65 (1H, d, J 8.2 Hz), 4.61 (1H, m), 4.54 (2H, s), 3.33 (4H, m), 2.72 (2H, m) 2.63 (2H, m), 2.57 (2H, m) 1.62 (2H, m), 1.46 (6H, m), 1.27 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:25]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)=[O:11])=[O:5].[OH-].[Li+]>O.C1COCC1>[CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:25]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=[O:11])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(NC(=O)c3ccccc3C)cc(NC(=O)c3ccccc3C)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 12.6 %

Procedure:
Methyl 6-{[3,5-di-(2-methylbenzoylamino)benzoyl]amino}-3-pyridinecarboxylate (130 mg 0.25 mM) was stirred at room temperature overnight with lithium hydroxide (52.5 mg 1.25 mM) in water (2 ml) and THF (10 ml). The mixture was then evaporated to remove the THF and acidified with 1.0N hydrochloric acid to pH=3. The precipitated solid was filtered, washed with water and vacuum dried at room temperature (70 mg 72.1%). Recrystallisation from ethyl acetate/methanol gave the title compound (16 mg 16.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH3:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Br-:22].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>CC(O)=O.Br>[NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH2:20][Br:22])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Reactant: [Br-]
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)CBr)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A solution of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)ethanone (510 mg, 1.627 mmol) in AcOH (2 mL) and HBr in AcOH (0.5 mL of 33% w/v, 2.039 mmol) was treated with pyridinium tribromide (544.5 mg, 1.708 mmol) and the mixture allowed to stir at ambient temperature for 2 hours. The reaction was poured into ether (50 mL), partitioned between EtOAc/water and extract with EtOAc (3×). The mixture was dried (MgSO4), filtered, evaporated down and the resultant residue was purified on silica gel by flash column chromatography (0-100% EtOAc/Petrol) to afford the title compound as a orange oil (68 mg, 11% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, 3H), 3.12 (q, 2H), 3.31 (m, 4H), 3.52 (m, 4H), 4.86 (s, 2H), 7.21 (s, 1H), 8.34 (s, 1H) ppm; MS (ES+) 393.91
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:25].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH3:25])[C:14](=[O:19])[O:15][C:16]([CH3:17])([CH3:18])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(Br)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.34 g, 0.99 mmol) in dry DMF (10 mL) was added under nitrogen at room temperature sodium hydride (80 mg, 2.0 mmol) in one portion. The mixture was stirred at ambient temperature for 30 minutes, treated with iodomethane (1 mL, excess), and stirred for 2 hours. To the reaction mixture was added a cold saturated ammonium chloride solution (30 mL) and the white precipitate obtained was collected on a filter, washed with the distilled water to afford the title compound as a white solid (0.31 g, 87%): mp 157-158° C. 1H-NMR (DMSO-d6) δ 7.83 (s, 1H), 7.76 (dd, 1H, J=8.5, 2.0 Hz), 7.67 (m, 2H), 7.53 (dt, 1H, J=8.3, 1.9 Hz), 7.18 (d, 1H, J=8.5 Hz), 3.33 (s, 3H), 1.67 (s, 6H); 19F-NMR (DMSO-d6) −111.01 (m, 1F); MS (APCI) m/z 364 ([M+H]+, 96%), 366 ([M+H]+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5](=[C:11]([CH3:13])[CH3:12])[O:6]2.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23]#[C:24][CH2:25]Cl>CN(C)C=O>[Cl:21][CH2:22][C:23]#[C:24][CH2:25][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5](=[C:11]([CH3:12])[CH3:13])[O:6]2
Reactant: ClCC#CCCl
Reactant: CC(C)=C1Oc2cccc(O)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=C1Oc2cccc(OCC#CCCl)c2C1=O
Temperature: 50 °C

Procedure:
A mixture of 5.0 g 4-hydroxy-2-isopropylidenecoumaran-3-one, 4.6 g potassium carbonate, 3.3 ml 1,4-dichloro-but-2-yne and 100 ml dimethylformamide is warmed to 50° C. for 3 hours, then evaporated, mixed with water and extracted with dichloromethane. After evaporation of the extract, the residue (9.2 g) is purified by silica gel chromatography (eluent isohexane/ethyl acetate 9:1) to give 2.2 g of the desired intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(Br)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromopyridine-2-carbaldehyde (1.60 g, 8.60 mmol, 1.07 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.1 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (45/55) to provide 2.70 g (94% yield) of tert-butyl 4-[(4-bromopyridin-2-yl)methyl]piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m/z): 356 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C[N:23]([CH:25]=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH2:25]([NH:23][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCC
Reaction time: 3.5 h
Yield: 35 %

Procedure:
18.54 g (100 mmol) dodecylamine(laurylamine), 6.36 g (60 mmol) Na2CO3 and 50 mg tetrabutyl ammonium iodide (TBAI) were suspended in 100 ml anhydrous DMF in a 500 ml 3-neck flask having a reflux condenser and a dropping funnel. A solution of 16.4 ml (60 mmol) 1-bromo tetradecane in 100 ml anhydrous dioxane were added dropwise at 100° C. over a period of 110 minutes and the mixture was steered for another 3.5 hours at 100° C. (FIG. 6). The solution was filtered at a temperature as hot as possible. The crystalline solid which precipitated at 4° C. over night, was removed and was washed with a little of cold methanol. Subsequently, the solid was re-crystallised from 200 ml methanol. 9 g of colourless leaf-like crystals were obtained which are re-crystallised from 100 ml MtBE. The crystals which precipitated at −18° C., were sucked off from a cooled frit and washed with cold MtBE. 7.94 g (21 mmol) of a colourless crystalline solid were obtained, corresponding to a yield of 35%.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:17][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:20](O)=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1.[Cl-].[NH4+:24]>>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([NH2:24])=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: O=Cc1c(C(=O)O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylic acid (0.09 g) was reacted with ammonium chloride similar to as described in Example 2 to give 60 mg of 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH:10]([C:14]([NH2:16])=[O:15])[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:19](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:14]([C:10]1[N+:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:19][NH:13][C:11]=1[O-:12])(=[O:15])[NH2:16]
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)C(NCc1ccc([N+](=O)[O-])cc1)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 41.60 g of p-nitrobenzylamine in 660 ml of dry ethanol was added 49.34 g of α-bromomalonamide and 38.2 ml of triethylamine. After being stirred for two hours under refluxing, the reaction mixture was cooled to room temperature. And then separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 53.36 g of α-(4-nitrobenzyl)aminomalonamide. And a mixture of 50.45 g of α-(4-nitrobenzyl)aminomalonamide, 177.8 g of triethyl orthoformate and 0.76 g of p-toluenesulfonic acid monohydrate in 1.3 liters of dry ethanol was stirred for three hours under refluxing in an argon atmosphere. The reaction mixture was cooled on an ice-bath and separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 50.78 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[CH:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[OH:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:19]1
Reactant: OC1CCC2(CC1)CCC(C=Cc1ccoc1)CC2
Agent: [Pd]
Solvent: CCO
Product: OC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Reaction time: 2 h

Procedure:
A suspension of 2.65 g of (EZ) 9-hydroxy-3-(2-(3-furyl)vinyl)-spiro[5.5]undecane (I-ag, Ex. 31) in 50 ml of ethanol and 0.26 g of palladium on carbon (5%) was hydrogenated at room temperature and atmospheric pressure for 2 hrs, then was filtered and the filtrate evaporated to dryness to give 2.59 g of pure 9-hydroxy-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane (I-ap, Ex. 38) as white solid, mp 66°-69° C. TLC: Rf=0.42 (SiO2 plates, n-hexane/diethylether 60/40). 1H-NMR (300 MHz, CDCl3, ppm from TMS):7.35 (1H, m), 7.20 (1H, m), 6.25 (1H, m), 3.63 (1H, hept), 2.49 (2H, t), 1.95-0.95 (19H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][Cl:42])=[CH:13][N:12]([CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCCCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of {(R)-2-[5-amino-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (42 mg, 0.089 mmol) in dichloromethane (2 mL) were added triethylamine (25 μl, 0.178 mmol) and 4-chloro-butyryl chloride (11 μl, 0.097 mmol) in the order. The solution was stirred at room temperature for 2 hrs and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 2/1/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 78%). 1H NMR (300 MHz, CDCl3) δ 1.33 (9H, s), 2.17 (2H, p), 2.57 (2H, t), 3.63 (2H, t), 4.10 (1H, m), 4.34 (1H, t), 4.99-5.14 (3H, m), 5.47 (1H, d), 6.96 (2H, m), 7.24-7.39 (6H, m), 7.72 (1H, s), 8.65 (1H, s)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1.Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:42])[NH2:36])=[CH:31][CH:30]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC(C)(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
110 mg (283 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoic acid (racemate), 65.6 mg (339 μmol) of tert-butyl 4-aminobenzoate, 129 mg (339 μmol) of HATU and 148 μl (849 μmol) of N,N-diisopropylethylamine in 9 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 100 mg (62% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])[CH2:9][CH2:10]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COCCN1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
1-(2-Methoxy-ethyl)-piperidin-4-ylamine (2.01 g) and triethylamine (3.24 mL, 2.35 g) were added to 1,4-dioxane (60 mL). 4-Chloro-3-nitrobenzenesulfonamide (2.50 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the material purified by flash column chromatography on silica gel using 10% methanol in dichloromethane.