Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[OH:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([NH:36][O:37][CH3:38])=[O:35])=[CH:32][C:31]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:42][O:41][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:30]=1[O:29][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1)[C:34]([NH:36][O:37][CH3:38])=[O:35]
Reactant: CONC(=O)c1ccc(O)c(OC)c1
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CONC(=O)c1ccc(Oc2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)c(OC)c1
Temperature: 65 °C

Procedure:
A suspension of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.15 g, 0.35 mmol), 4-hydroxy-N,3-dimethoxybenzamide (0.102 g, 0.52 mmol) and potassium carbonate (0.52 mmol) in acetonitrile (3 ml) were heated to reflux (65° C.) for 2 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with dichloromethane (50 ml) and washed with brine. Evaporation of the organic layer furnished a crude material, which was purified by column chromatography; elution with 2% MeOH in dichloromethane furnished the required compound. 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.79 (s, 3H), 7.16-7.20 (m, 2H), 7.37 (d, 1H), 7.41-7.45 (m, 5H), 7.53 (s, 1H), 7.62-7.63 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H). 11.9 (s, 1H); MS m/z: 593 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18](N(OC)C)=[O:19])=[N:10]2)=[C:4]([F:24])[CH:3]=1.[CH3:25][Mg+].[Br-]>C1COCC1>[C:18]([C:11]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[CH:14][N:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=2[F:24])[N:10]=1)(=[O:19])[CH3:25]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 1-(4-bromo-2,5-difluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (5.0 g, 12 mmol) in THF (100 mL) was added dropwise to MeMgBr (1.0 M in THF, 50 mL, 50 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with 1 M HCl aqueous solution (70 mL) at −78° C. The mixture warmed up to room temperature and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound (3.6 g, 80% yield) as a yellow solid: NMR (300 MHz, DMSO-d6): δ ppm 2.50 (3H, s), 3.80 (3H, s), 8.03 (1H, dd, J=8.9, 6.6 Hz), 8.17 (1H, dd, J=10.0, 6.2 Hz), 8.52 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 360 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:2]
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CC(=O)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 38.1 g (0.52 mol) of diethylamine in 80 mL of toluene and cooled in an ice bath to 0° C. add dropwise a solution of 65.0 g (0.26 mol) of 2-bromoacetonaphthone in 300 mL of toluene. Stir the reaction mixture overnight. Monitor the progress of the reaction by thin-layer chromatography on silica gel (ethyl acetate:hexane, 1:1). Extract the reaction mixture with 3×150 mL of 3N HCl. Adjust the pH of the combined aqueous layers to pH=10 with 50% sodium hydroxide then extract with 3×150 mL of methylene chloride. Combine the extracts and dry over sodium sulfate. Remove the solvent in vacuo, and chromatograph the resultant oil on 2200 g of silica gel, eluting initially with methylene chloride and later with ethyl acetate. Combine the fractions containing product and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br-].[CH2:12]1COC[CH2:13]1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:13]=[CH:12][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CCOC1
Agent: [Br-]
Product: Clc1nccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to −78° C. Vinylmagnisium bromide (1.0 M in THF, 100 mL) was added dropwise under N2. The mixture was stirred at −78° C. for 1 hr, followed by −20° C. for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20% in H2O) and extracted with EtOAc (3×150 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7-chloro-1H-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37%). 1H-NMR (DMSO-d6) δ: 6.63 (d, 1H, J=3.2 Hz, Ar—H), 7.58 (d, 1H, J=5.6 Hz, Ar—H), 7.66 (d, 1H, J=2.8 Hz, Ar—H), 7.90 (d, 1H, J=5.2 Hz, Ar—H). MS (ESI+) m/z 153.0260 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[CH3:17]O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A 500-mL, three-necked, round bottom flask was eqipped with a teflon-coated stirring bar, soxlet extractor and condensor with drying tube at the top. The flask was charged with 10.0 g (66.6 mmol) of 4-formylbenzoic acid, about 320 mL of absolute CH3OH and 0.1 mL of concentrated H2SO4. The soxlet extractor was filled with 3 Å molecular sieve. After the solution was boiled for 48 hours, it was allowed to cool to room temperature and then was concentrated to a volume of about 50 mL, diluted with an equal amount of water, and extracted (ether 4×70 mL). The combined organic layers were washed with saturated NaHCO3 solution (5×50 mL), 0.1 NHCl (10×40 mL), H2O (2×50 mL), and saturated NaCl solution (2×50 mL). The resulting organic solution was finally dried (MgSO4, 2 h) and filtered and concentrated in vacuo. The white solid obtained was recrystallized (hexane) to give 6.3 grams (57.6%) of ester 33 mp 59.5°-60° C. [literature reports 59°-60° C.; see J. M. Landesberg, M. A. Slam, and M. Mandel J. Org. Chem., 46, 5025 (1981)]; IR (KBr) 1680-1740 cm-1 (C=O); 1H NMR (DCCl3) δ4.00 (s, 3H, OCH3), 7.80=8.32 (m, 4H, Ar-H), 10.10 (s, 1H, CHO); 13C NMR (DCCl3)ppm 52.6 [OCH3 ], Ar-C [129.6, 130.4, 135.2, 139.2], 166.0 [CO2CH3 ], 191.7 [CHO]; mass spectral data for C9H8O3 : m/e (M+): 164.0473. Found: 164.0472. ##STR19##
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[N:12]=[C:13]2[N:18]([CH:19]=1)[CH2:17][CH2:16][C@H:15]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=1)[O:14]2)([O-:10])=[O:9].[CH:34]([O:36][CH2:37][CH2:38]Cl)=[O:35].Cl>C(Cl)Cl>[CH2:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:15]3[O:14][C:13]4=[N:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][N:18]4[CH2:17][CH2:16]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1)=[O:35])[CH3:38]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Reactant: O=COCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reaction time: 14 h

Procedure:
Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, chloroethyl formate (0.11 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was then added to the reaction mixture, followed by extraction with methylene chloride. After washing the organic layer with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from acetone-water to afford the title compound as a pale yellow powder (0.36 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)CCl
Temperature: 25 °C
Yield: 94.5 %

Procedure:
At −75° C., chloroacetyl chloride (11.3 g, 8.1 mL, 0.1 mol) was added slowly to a suspension of methyl-phenethyl-amine (13.5 g, 0.1 mol), triethylamine (15 mL) in dichloromethane (50 mL). The suspension was warmed to 25° C. over the course of 3 hours and the salt was removed by filtration. The organic phase was washed with HCl solution (1 N, 200 mL), dried with sodium sulfate. The solvent was evaporated in vacuo to give 2-chloro-N-methyl-N-phenethyl-acetamide (20 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.03 (s, 3H), 3.6 (m, 2H), 2.99 (s, 2H), 2.8 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12](O)=[O:13])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][OH:13])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Product: N#CCNC(=O)[C@@H]1CCC[C@H]1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
trans-2-{[(Cyanomethyl)amino]carbonyl}cyclopentanecarboxylic acid (860 mg, 4.38 mmol) was placed in a 50 mL round bottom flask. The flask was fitted with a rubber septum and then flushed with nitrogen. Tetrahydrofuran (9 mL) was added and the reaction mixture was cooled to −78° C. 4-Methylmorpholine (0.53 mL, 4.8 mmol) was added, followed by addition of isobutyl chloroformate (0.61 mL, 4.7 mmol). The reaction mixture was warmed to ambient temperature over 1.5 h and then recooled to −78° C. Sodium borohydride (0.28 g, 7.4 mmol) was added and then methanol (3.0 mL). The reaction mixture was stirred at −78° C. for 2 h and then quenched with saturated aqueous ammonium chloride (10 mL). The reaction mixture was warmed to ambient temperature and then poured into 100 mL saturated aqueous sodium chloride solution. The product was extracted into ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Toluene (5 mL) was added to the residue and the reaction mixture was stirred for 30 min. The solution was removed by decantation and the residue was dried under high vacuum to give trans-N-(cyanomethyl)-2-(hydroxymethyl)-cyclopentanecarboxamide as a colorless solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44]O)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44][Br:1])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a slurry of N-bromo succinimide (3.54 g, 19.9 mmol, 3 eq) in DCM (30 ml) was added a solution of triphenyl phosphine (4.87 g, 18.8 mmol, 2.8 eq) in DCM (15 ml). The solution was stirred for a further 5 minutes before addition of pyridine (644 μl, 7.96 mmol, 1.2 eq) and a solution of (S)-2-tert-butoxycarbonylamino-5-hydroxy-pentanoic-acid cyclopentyl ester (2.0 g, 6.64 mmol) in DCM (20 ml). The solution was stirred for 18 hours, concentrated in vacuo and the residual solvent azeotroped with toluene (3×30 ml). The residue was triturated with diethyl ether (30 ml) and ethyl acetate:heptane (1:9, 2×30 ml). The combined ether and ethyl acetate/heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide the title compound as a clear oil (1.34 g, 55% yield).
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].CC[N:17](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N.O1CCOCC1>CN(C=O)C>[CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C(=O)O)cnc1CC(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(C(N)=O)cnc1CC(C)C
Reaction time: 2 h

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinic acid (200 mg, 0.871 mmol) and DIPEA (450 mg, 3.48 mmol) in DMF (9 mL), PyBOP (498 mg, 0.958 mmol) is added at 0° C. The mixture is stirred for 15 min before 0.5 M NH3 in dioxane (6.1 mL, 3.05 mmol) is added. Stirring is continued for 2 h at rt. The mixture is concentrated to give crude 6-isobutyl-5-methyl-nicotinamide; LC-MS: tR=0.55 min, [M+1]+=193.10. This material is dissolved in DCM (8 mL), and pyridine (430 mg, 4.43 mmol) followed by trifluoroacetic anhydride (1.25 g, 5.94 mmol) is added dropwise at 0° C. The mixture is stirred at rt for 2 h before it is diluted with DCM. The mixture is washed with a 10% aq. citric acid solution followed by a sat. aq. Na2CO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 6-isobutyl-5-methyl-nicotinonitrile (126 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+1]+=175.17; 1H NMR (CDCl3): δ 0.98 (d, J=6.8 Hz, 6H), 2.20 (hept. J=7 Hz, 1H), 2.38 (s, 3H), 2.74 (d, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:9]([Cl:22])[CH:8]=1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[CH:8][C:9]=1[Cl:22])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1Cl
Reactant: CC(C)(C)CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Add butyllithium (11.7 mL, 18.65 mmol) to a solution of 4-bromo-N-(tert-butoxycarbonyl)-2-chloro-benzylamine (2.601 g, 8.11 mmol) in diethyl ether (86 mL) at −78° C. under nitrogen and stir for 2 h. Add 3,3-dimethylbutyraldehyde (1.868 g, 2.3 mL, 18.65 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.825 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH:15]2[CH2:19][F:20])[CH:28]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCNC(CF)C1
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])c(F)c3)CC2CF)c1
Temperature: 60 °C
Yield: 57.3 %

Procedure:
A stirred mixture of (3-fluoro-4-nitrophenyl)(3-(fluoromethyl)piperazin-1-yl)methanone (456 mg, 1.6 mmol), N-tert-butyl-3-(chloromethyl)benzamide (361 mg, 1.6 mmol), triethylamine (3.1 mmol, 341 mg) and sodium iodide (1.6 mmol, 240 mg) in acetonitrile (10 mL) was heated to 60° C. for several hours. The reaction was concentrated under reduced pressure. The residue was then dissolved in dichloromethane and extracted with water (×3). The organic phase was dried (sodium sulfate) and concentrated under vacuum. The crude material was purified using silica chromatography to give the title compound (435 mg). MS (ESI) m/z 475.7[M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:13])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[NH2:14][C:15]#N>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:13][C:15]#[N:14])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCCOC(=N)c1cncc(N)c1
Reactant: N#CN
Solvent: CC#N
Product: CCCOC(=NC#N)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.6 %

Procedure:
The propyl 5-amino-3-pyridinecarboximidate (110 mg, 0.6 mmol) was then dissolved in acetonitrile (1 ml), and an aqueous solution (2 ml) of NaH2PO4 ·2H2O(375 mg, 2.4 mmol), Na2HPO4 (85 mg, 0.6 mmol) and NH2CN (50 mg, 1.2 mmol) was added to the solution. The mixture was stirred at room temperature for 19 hours. After the completion of the reaction, the reaction mixture was extracted with chloroform (20 ml×3), and the chloroform layer was dried over- anhydrous sodium sulfate and concentrated under reduced pressure to give a crude oil of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg, yield 82%).
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>C1COCC1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of fluorenyllithium in 50 cm3 of THF was added at room temperature to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of THF. After stirring at room temperature for 2 hours, 60 cm3 of water were added. The resulting precipitated substance was filtered off with suction, washed with diethyl ether and dried at an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene (correct elemental analyses; 1H-NMR spectrum) were obtained.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[Na].[Cl:8][C:9]([Cl:13])([Cl:12])[C:10]#[N:11]>C(O)(=O)C>[NH2:11][C:10]1([C:9]([Cl:13])([Cl:12])[Cl:8])[O:6][CH2:1][CH:2]=[CH:3][CH2:4][O:5]1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: OC/C=C\CO
Agent: [Na]
Solvent: CC(=O)O
Product: NC1(C(Cl)(Cl)Cl)OCC=CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To cis-2-butene-1,4-diol (22.28 g, 252.9 mmole) there was added a catalytic amount of sodium followed by a slow addition at ~0° C. of trichloroacetonitrile (110 g, 3 equivalents). Upon completion of the trichloroacetonitrole addition, the solution was stirred at room temperature for 16 hours. The solution was acidified with 1 ml glacial acetic acid and stirred for 15 minutes. The resulting solution was distilled under reduced pressure (0.25 mm Hg) and several fractions were collected at different temperatures. The minor fraction (9.71 g) collected between 98°-110° was characterized as the cyclic title product. IR (KBr): 3430-3350, 3040, 2940-2920, 1607, 1110 and 825 cm-1. 1H NMR was consistent with the indicated structure.
Reaction SMILES: NCCC1N=CN([C:9](C2C=CC=CC=2)(C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=1.[C:28]1([C:34]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][NH:42][S:43]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])(=[O:45])=[O:44])[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Br)C1C=CC=CC=1>>[C:60]1([C:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][NH:42][S:43]([N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:45])=[O:44])[N:37]=[CH:36]2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
4-(2-Aminoethyl)-1-(triphenylmethyl)-imidazole (Example 17 step b) was converted to N-2-[1-(triphenylmethyl)imidazol-4-yl]ethyl-N'-tert-butoxycarbonyl-sulfamide according to the procedure of Example 12 step a. The subsequent alkylation with benzyl bromide was performed essentially as Example 12 step b and gave N-[2-(1-(triphenylmethyl)imidazol-4-yl)ethyl]-N'-tert-butoxycarbonyl-N'-phenylmethyl-sulfamide. The final deprotection was carried out in the manner of Example 17 step b and the title compound (Rf 0.21; 1:10:90 ammonia(880)/methanol/dichloromethane) was isolated as a colourless oil: 1H NMR (300 Hz, d6 -DMSO) 7.50(1H, s), 7.30(6H, m), 6.95(1H, t), 6.78(1H, s), 3.96(2H, s), 3.03(2H, dd), 2.65(2H, t). The maleate salt was prepared by lyophilysis of an equimolar solution of the product and maleic acid in water/dioxan. Found: C 48.05, H 5.10, N 13.87%; C16H2ON4O6S requires: C 48.48, H 5.09 N 14.13%.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1.[N:19]1([CH2:25][C:26]2[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=2)[O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:13]1([CH2:12][CH2:11][CH2:10][C:6]2[C:7](=[O:9])[NH:8][C:3]([NH:33][CH2:32][CH2:31][CH2:30][O:29][C:28]3[CH:34]=[CH:35][CH:36]=[C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:27]=3)=[N:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1ncc(CCCc2ccccc2)c(=O)[nH]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: O=c1[nH]c(NCCCOc2cccc(CN3CCCCC3)c2)ncc1CCCc1ccccc1
Yield: 19.6 %

Procedure:
A mixture of 2-(methylthio)-5-(3-phenylpropyl)-4(3H)-pyrimidinone (0.52 g) and 3-[3-[(1-piperidinyl)methyl]phenoxy]propanamine (1.056 g) was heated at 140° for 4 h. The residue was chromatographed (silica/methanol-ethyl acetate 1:1) and the oily product titrated with light petroleum (b.p. 60°-80°) to give the title compound (0.18 g), m.p. 104°-108°.