Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>[Pd].CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCNCC1C
Yield: 100 %

Procedure:
A mixture of 21 parts of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off the filtrate was evaporated. The residue was distilled twice, yielding 23 parts (100%) of ethyl 2-methyl-1-piperazinecarboxylate; bp. 95°-98° C. at 66.5 Pa (int. 37).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:20][NH:19][C:18]1[CH:17]=[CH:16][C:15]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:14][CH:13]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc(O)cc2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(O)cc32)cc1
Yield: 30 %

Procedure:
The title compound was prepared from 5-hydroxy-1H-indole-2,3-dione (Ijaz, et al., Indian Journal of Chemistry 1994, 33B, 288-9) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 30% yield: 1H NMR (DMSO-d6): δ6.79 (dd, J=2.2, 8.3 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 7.25 (s, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 9.20 (s, 1H), 10.80 (s, 1H), 12.82 (s, 1H); APCI−MS m/z 331 (M−H)−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an oven-dried 500-mL 3-neck flask purged with nitrogen was added oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125 mL), and the solution was cooled to −78° C. A solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was added dropwise from a constant-pressure addition funnel over a 20-minute period. A solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane (50 mL) was added dropwise from a constant-pressure addition funnel over a 20-minute period, and then the reaction mixture was stirred at −78° C. for 30 minutes. Triethylamine (32.6 mL, 234 mmol) was added dropwise via syringe over a 5-minute period and the thick white mixture was stirred in an ice-water bath for 30 minutes. The reaction was quenched with 10% (w/v) aq. citric acid (30 mL). The mixture was partitioned in a separatory funnel between Et2O (550 mL) and 10% (w/v) aq citric acid. The layers were separated, and the organic phase was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow oil (9.4 g), which was used directly in the next reaction.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O.[NH2:13][NH2:14]>C(O)CCC>[N:5]1([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCOCC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)CN1CCOCC1
Yield: 68 %

Procedure:
As described for example 112a, morpholin-4-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 1 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.40 (m, 4H), 2.90 (s, 2H), 3.57 (m, 4H), 4.24 (s, 2H), 8.91 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.N1C=CC=CC=1.[S:21](Cl)(Cl)=[O:22].[CH2:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O1CCCC1>[CH3:1][N:2]([S:21]([O:31][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:22])[C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCO
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCOS(=O)N(C)C(=O)Oc1cccc(C(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 3-isopropylphenyl methylcarbamate (3.8 g, 0.02 mol) in 20 ml anhydrous tetrahydrofuran was added 2.0 g pyridine (0.025 mol) and 2.5 g thionyl chloride (0.021 mol). The mixture was stirred for 12 hours at room temperature. Pyridine (2 g, 0.025 mol) was added and followed by 2.5 g of 1-hexanol (0.025 mol) added dropwise. Workup and purification according to procedure described for other derivatives yielded 6.5 g of the desired product (95% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClC1C=CC=CC=1Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[C:13](=[O:15])[C:5]3[C:6](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
In a 25 mL round bottomed flask, 3-nitrophthalic acid (1 g, 4.7 mmol) was suspended in 1,2-dichlorobenzene (3 mL). To this was added 4-tert-butylaniline (3 mL, 18.8 mmol). The reaction was heated to 150° C., resulting in a blood red solution. The reaction was held at 150° C. for 2.5 h, then poured into a 125 mL Erlenmeyer flask. Precipitation began to occur and 50 mL of Et2O was added to the flask. The suspension was stirred for 15 h and filtered. The filtered cake was washed copiously with Et2O and dried in vacuo at 30° C. for 4 h to afford a white brittle powder. No further purification was performed on this compound. MS (ES+): 325.1(M+H)+. Calc'd for C18H16N2O4-324.33.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-]>CO.CCOCC>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:30])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)O)cn2)ccc(C(C)=O)c1O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CCCc1c(OCCCSc2ccc(C(=O)OC)cn2)ccc(C(C)=O)c1O
Temperature: 0 °C

Procedure:
The compound of Example 1 (500 mg, 1.284 mmoles) was dissolved in a mixture of CH3OH (10 ml) and ether (10 ml) cooled to 0° C. Diazomethane was added until a slight yellow color persisted. The reaction mixture was concentrated to afford the title compound, m.p. 66°-68°.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)C#C.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14]>CCCCCC.O1CCCC1>[CH3:14][C@:13]12[CH2:12][CH2:11][C@H:5]3[C@@H:5]([CH2:11][CH2:12][C:13]4[C@@H:10]3[CH2:9][CH2:8][CH2:7][CH:14]=4)[C@@H:10]1[CH2:9][CH2:8][C@@H:7]2[OH:6]
Reactant: [Li]CCCC
Reactant: C#CCOC1CCCCO1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
As described under 3D, 460 mg of 7G is produced from 442 mg of 7F with 1.30 ml of 2-(2-propinyloxy)tetrahydro-2H-pyrane and 5.36 ml of a 15% solution of butyllithium in hexane in 70 ml of tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=C=O)[NH:7]OCC)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][NH:21][C:22](OCC)=O>>[CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH3:15])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][NH:21][CH3:22]
Reactant: CCONC(=C=O)c1ccc(C)cc1
Reactant: CCOC(=O)NCc1cccc(OC)c1
Product: CNCc1ccc(C)cc1
Product: CNCc1cccc(OC)c1

Procedure:
In a similar manner as above, 4-methyl-N-methylbenzylamine and 3-methoxy-N-methylbenzylamine were prepared, respectively, from 4-methyl-N-ethoxy-carbonylbenzylamine and 3-methoxy-N-ethoxycarbonylbenzylamine.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:25]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: COC(=O)CNCC(=O)OC
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The conversion of 3-(tetradecyloxy)benzoic acid to the acid chloride followed by treatment with dimethyl iminodiacetate as in Example 1 gave N-(2-methoxy-2-oxoethyl)-N-[3-(tetradecyloxy)benzoyl]glycine methyl ester, mp <23°. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:6]3[C:12]([O:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:6]3[C:12]([O:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(OC)c3c(N4CCNCC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.300 g, 0.608 mmol) was placed in DCM (5 mL). TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness to give the crude product 5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine (0.239 g, quant.), which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]([OH:12])[CH3:11].I[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]([O:12][CH3:14])[CH3:11]
Reactant: CI
Reactant: CC(O)c1ccncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)c1ccncc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
Sodium hydride (60% in mineral oil, 148 mg, 3.71 mmol) was added to a solution of 1-(3-bromopyridin-4-yl)ethanol (500 mg, 2.475 mmol) in DMF (12 mL) at 0° C. After 10 min, iodomethane (1.237 mL, 2.475 mmol) was added dropwise and the resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (ethyl acetate-heptane, v/v, 0-30%) to give 418 mg of the title compound. 1HNMR (CDCl3, 400.3 MHz) δ 1.42 (d, J=6.4 Hz, 3H), 3.30 (s, 3H), 4.64 (q. J=0.4 Hz, 1H), 7.58 (s, 1H), 8.56 (s, 1H), 8.70 9s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.CN(C)C(=O)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O>[SH:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
36.6 g of 5-amino-2-mercaptobenzimidazole and 17.1 g of pyridine were added to 250 ml of N,N-dimethylacetamide, and thereto was added dropwise 34.4 g of phenyl chloroformate at room temperature. After the resulting solution as such was stirred for 1.5 hours at room temperature, 1.5 liters of ice cooled water was added to deposit crystals, which were filtered off and recrystallized from acetonitrile, whereby 47.7 g of 2-mercapto-5-phenoxycarbonylaminobenzimidazole was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25](F)[CH:26]=1)[C:22]#[N:23]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH:26]=1)[C:22]#[N:23]
Reactant: COc1cc(O)c(Cl)c(F)c1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(F)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, 2-chloro-3-fluoro-5-methoxyphenol (50-2) (6.7 g, 37.9 mmol) was diluted in NMP (40 mL, 0.95 M). To this solution Cs2CO3 (24.73 g, 76 mmol) was added and the reaction was allowed to stir at room temperature for 5 minutes. Then, 3-chloro-5-fluorobenzonitrile (11.81 g, 76 mmol) was added to the reaction and it was then heated to 120° C. After 2 hours the reaction was cooled to room temperature and then diluted with EtOAc (40 mL). It was partitioned with water (20 mL) and then extracted with EtOAc (3×30 mL). The organic extracts were then washed with water (3×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-15% EtOAc/Hexanes) gave 3-chloro-5-(2-chloro-3-fluoro-5-methoxyphenoxy)-benzonitrile (50-4) (10.4 g, 88%).
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6](I)[CH:7]=1)#[N:2].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:6]2[CH:7]=[C:3]([C:1]#[N:2])[NH:4][CH:5]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: N#Cc1cc(I)c[nH]1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#Cc2cccc(Br)c2)c[nH]1
Yield: 99 %

Procedure:
The dimethylformamide was vigorously deoxygenated with nitrogen gas before use in this reaction. To a solution of 2-cyano-4-iodopyrrole (2.30 g, 10.52 mmol) in dimethylformamide was added dichloropalladium(II) bistriphenylphosphine (185 mg), copper(I) iodide (50 mg) and finally triethylamine (3.85 mL). After stirring ten minutes, 1-bromo-3-ethynyl-benzene (2.38 g, 13.15 mmol) was added. This mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 2% aqueous lithium chloride and 5% aqueous sodium chloride. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to afford 4-(3-bromo-phenylethynyl)-1H-pyrrole-2-carbonitrile as a yellow solid, 2.84 g, 99% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([CH2:20][CH:21]=[C:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3([CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:21][CH2:20][CH:14]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(CC=C1CCOCC1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCC2(CCOCC2)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of ethyl 2-{[(4-nitrophenyl)sulfonyl]amino}-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (164) (1.87 g, 4.7 mmol) in anhydrous chloroform (47 mL) was added trifluoromethanesulfonic acid (0.2 mL, 2.3 mmol) and the reaction stirred at room temperature under nitrogen for 4 h. The reaction was diluted with dichloromethane and washed with saturated NaHCO3 and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-70% hexanes/EtOAc to afford the title compound as a white solid (1.47 g, 79% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19-8.36 (m, 2H) 8.08 (d, J=8.8 Hz, 2H) 4.52 (dd, J=8.5, 2.1 Hz, 1H) 3.99-4.14 (m, 2 H) 3.87-3.99 (m, 2H) 3.21-3.49 (m, 2H) 2.58-2.78 (m, 2H) 2.10-2.30 (m, 2H) 1.89-2.06 (m, 2H) 1.77 (dd, J=13.0, 2.1 Hz, 1H) 1.35 (dd, J=12.9, 1.6 Hz, 1H) 1.22 (t, J=7.1 Hz, 3H). LC-MS ESI (M+H)+=399.47.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(O)CC>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(N)=O)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C(N)=O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-carbamoyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 200 mg, 0.430 mmol) in 6 mL of DCM was added 2 mL of TFA. After stirring at RT for 3 h, the mixture was treated with 20 mL of n-propanol and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4-6% MeOH/DCM) to afford 88.0 mg (61%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.41 (d, 1H, J=8.6 Hz), 8.03 (s, 1H), 7.81 (dd, 1H, J=8.6, 2.3 Hz), 7.74 (d, 1H, J=2.3 Hz), 5.89 (m, 1H), 2.20-2.38 (m, 4H), 1.71-1.95 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C18H17N5O2, 336.1 (M+H), found 336.1.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][Cl:31])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.O.C(C(C)=O)C(C)C>[ClH:31].[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:30][CH2:29][CH2:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)=[O:32])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cl
Product: O=C(CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 77 °C
Reaction time: 48 h

Procedure:
A mixture of 125.5 g (0.5 mole) of 4-diphenylmethyl-piperidine, 110 g (0.55 mole) of 4'-fluoro-4-chlorobutyrophenone, 110 g (0.8 mole) of potassium carbonate, a small amount of potassium iodide and 600 ml of methyl isobutyl ketone was refluxed and stirred for 21/2 days, then filtered. The filtrate was concentrated under reduced pressure. The remaining residue was dissolved in ether and treated with ethereal HCl. A gummy residue formed which was dissolved in ethyl acetate with a small amount of water and heated on a steam bath to a vapor temperature of 77°C then cooled. The resulting precipitate was washed with ether and recrystallized from ethyl acetate, toluene and isopropyl alcohol to give the desired product, M.P. 194°-195.5°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:14][CH2:13][CH2:12][Br:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 56.7 %

Procedure:
To a solution of 3-nitrophenol (0.0689 g, 0.495 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.500 mL, 3.05 mmol) followed by Cs2CO3 (0.244 g, 0.748 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0730 g, 56.6%). EI-MS Rt (2.20 min).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[N:23][OH:24])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].ClN1[C:34](=[O:35])[CH2:33][CH2:32]C1=O.C(O)C#C.CCN(CC)CC>CN(C=O)C>[OH:35][CH2:34][C:33]1[O:24][N:23]=[C:22]([C:17]23[CH2:20][CH2:21][C:14]([C:7]4[NH:8][C:9]5[N:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[N:3]([CH2:26][CH2:27][CH3:28])[C:4](=[O:25])[C:5]=5[N:6]=4)([CH2:19][CH2:18]2)[CH2:15][CH2:16]3)[CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1c(=O)c2nc(C34CCC(C=NO)(CC3)CC4)[nH]c2n(CCC)c1=O
Agent: C#CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2nc(C34CCC(c5cc(CO)on5)(CC3)CC4)[nH]c2n(CCC)c1=O
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbaldehyde oxime (87 mg, 0.22 mmol) and N-chloro succinimide (1.2 eq, 0.27 mmol, 36 mg) in DMF (6 ml) was heated in an oil bath at 60° C. for 1.5 h. The reaction flask was removed from the bath and allowed to cool to rt and propargyl alcohol (2.0 eq, 0.44 mmol, 25 mg) was added. The flask was returned to the oil bath, Et3N (2.0 eq, 0.44 mmol, 44 mg) was added over a period of 15 minutes and the resulting mixture was heated at 60° C. for 3.5 h. The cool reaction mixture was evaporated in vacuo to afford a solid residue that was purified by radial chromatography (2 mm plate) using a gradient of 2-10% MeOH in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 31 mg (26%) of a white solid. MS: 442 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:9]=[N:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[N:6]=1)(=O)C.CO.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[N:6]=[C:5]([OH:4])[CH:9]=[N:8]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Oc1cnn(-c2ccc(Br)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Oc1cnn(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2-(4-bromophenyl)-2H-1,2,3-triazol-4-yl acetate (520 mg, 1.84 mmol) was treated with methanol (10 ml) and water (10 ml) followed by 1,4-dioxane (5 ml). The resulting solution was treated with lithium hydroxide (265 mg, 11.1 mmol). The reaction mixture was stirred at RT for 36 hours. 1N HCl (40 ml) was added to the reaction mixture and the product was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over potassium carbonate, filtered, and concentrated. The crude material was purified by chromatography on silica gel (4:1 heptane:EtOAc 1:4 heptane:EtOAc) to furnish a light tan solid (440 mg, 98% TY). MS (LC/MS) m/z 240.21 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (s, 1H) 7.58 (d, J=8.98 Hz, 2H) 7.78 (d, J=8.98 Hz, 2H).