Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[CH:9][S:8][CH:7]=1)=[O:5])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([N+:12]([O-:14])=[O:13])[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cscc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Bromo-thiophene-3-carboxylic acid ethyl ester (97.6 g, 0.415 mol) was added over 10 min via pipette to 18.0 M sulfuric acid (660 mL) at 0° C. After stirring 5 min at 0° C., fuming nitric acid (18 mL) dissolved in 18.0 M sulfuric acid (130 mL) was added via addition funnel over 30 min. After the addition was completed, the reaction mixture was stirred for 5 min at 0° C., and then was poured onto ice (3.5 kg). The resulting precipitate was collected by filtration and was washed sequentially with water (300 mL), 10% aqueous sodium bicarbonate solution (400 mL) and water (300 mL). The brown/yellow solid thus obtained was dried in a vacuum oven overnight at 40° C. to afford the crude product, 4-bromo-5-nitro-thiophene-3-carboxylic acid ethyl ester (97.9 g, 0.350 mol, 84%). This material was further purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% hexanes in dichloromethane) in 20 g portions prior to use in the next step (recovery=80-90%). 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (3H, t, J=7.0 Hz), 4.30 (4H, q, J=7.0 Hz), 8.68 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[N:38]([CH:41]([CH3:43])[CH3:42])=[C:39]=[O:40].CC(=O)OCC.CCCCCC>CO.CC(=O)OCC>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:39]([NH:38][CH:41]([CH3:43])[CH3:42])=[O:40])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 64.6 %

Procedure:
The reaction mixture of aniline 46 (200 mg, 0.379 mmol) and 2-isocyanatopropane (64.5 mg, 0.758 mmol) was heated to 100° C. for 15 min in a microwave reactor. The reaction mixture was loaded directly into Biotage (Silicycle, HR, 12 g column, 50-100% EA/Hexane, then MeOH/EA, 0-20%). The collected fractions afforded the desired product 314 (150 mg, 0.245 mmol, 64.6% yield) as a white solid. MS: 613(MH)+, very weak signal.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:30]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)N=C=O
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and i-propyl isocyanate in a manner analogous to the procedure described in Example 7.
Reaction SMILES: FC1[CH:3]=[C:4]([CH:29]=CC=1OC)[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][C@@H:8]1[CH3:28])=[O:6].[F:34][C:35]1C=C(C=CC=1OC)C(Cl)=O.O1C=CC=C1C(Cl)=O.[C:54](Cl)(=[O:57])[CH2:55][CH3:56].C(Cl)(=O)C>>[F:34][CH2:35][O:57][C:54]1[CH:29]=[C:4]([CH:3]=[CH:56][CH:55]=1)[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([N:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][C@@H:8]1[CH3:28])=[O:6]
Reactant: CCC(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC)c(F)c2)c2ccccc21
Reactant: COc1ccc(C(=O)Cl)cc1F
Agent: O=C(Cl)c1ccco1
Solvent: CC(=O)Cl
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(OCF)c2)c2ccccc21

Procedure:
(±)-Cis-N-[1-(3-fluoro-4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was made following general procedure A substituting 3-fluoro-4-methoxybenzoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[O:41][N:40]=[C:39]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45](O)=[O:46])[CH:38]=1.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[O:41][N:40]=[C:39]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45]([NH:60][O:59][CH:54]2[CH2:55][CH2:56][CH2:57][CH2:58][O:53]2)=[O:46])[CH:38]=1
Reactant: NOC1CCCCO1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)no2)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)no2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
N,N-Dimethy-4-aminopyridine (0.04 g, 0.3 mmol, 0.2 equiv), N-ethyl-N-isopropylpropan-2-amine (0.97 mL, 5.8 mmol, 4.5 equiv), T3P® (50% w/w solution in ethyl acetate, 3.0 mL, 4.96 mmol, 4.0 equiv), and (2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.46 g, 1.24 mmol, 1.0 equiv) were allowed to stir at room temperature for 30 min. A solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.16 g, 1.3 mmol, 1.2 equiv) in ethyl acetate (15 mL) was added, and the reaction was allowed to stir overnight (18 h) at room temperature. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25 g silica gel column, 0-100% gradient ethyl acetate in hexanes) to provide (2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.60 g, 10%). MS (LCMS) m/z 469.1 (M−1).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]([C:8]2[C:7]([F:6])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccnc1
Reactant: O=Cc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OC(c1cccc(F)c1)c1ncccc1F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, a solution of 9.75 g of diazabicyclo[2.2.0]octane in 150 mL of dehydrated diethyl ether was cooled to −40° C., added with 56 mL of 1.56 M n-butyllithium in hexane, and stirred at −20° C. for 1 hour. The solution was cooled to-60° C., added dropwise with 6.9 mL of 3-fluoropyridine, stirred at −60° C. for 1 hour, and added with 9.2 mL of 3-fluorobenzaldehyde. After stirring for 1 hour, aqueous ammonium chloride and ethyl acetate were successively added, and the mixture was recovered to room temperature. The organic layer was extracted, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:4), to give 12.6 g of the title compound as colorless needle crystals.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][C@H:17]1[CH2:22][C@@H:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>C1COCC1>[CH3:16][C@H:17]1[CH2:22][C@@H:21]([CH3:23])[CH2:20][C:19](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:18]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: C[C@@H]1CC(=O)C[C@H](C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CC(=C2SCCCS2)C[C@H](C)C1
Temperature: -78 °C
Yield: 92 %

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (30.1 g, 0.16 mol) in THF (250 mL) at 0° C. under an argon atmosphere was added a solution of n-butyl lithium (2.5 M in hexanes, 64 mL, 0.16 mol) and the mixture was cooled to −78° C. A solution of cis-3,5-dimethyl cyclohexanone (10 g, 0.079 mol) in THF (30 mL) was added over 10 min. After 3.5 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL). The aqueous phase was extracted with EtOAc (100 mL×4) and the combined organic layers were dried (MgSO4) and were evaporated. The reaction by-products were removed by vacuum distillation to yield the desired product (16.6 g, 92%). MH+229
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH:15]([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:10][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)=[C:15]([CH3:28])[N:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)C(C)Br)cc1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(C)c(-c3ccc(C(=O)OC)cc3)o2)cc1

Procedure:
α-(p-Carbomethylbenzamido)-p-carbomethoxypropiophenone, obtained by reacting p-carbomethoxybenzamide with α-bromo-p-carbomethoxypropiophenone, was refluxed with phosphorus oxychloride in toluene to yield dimethyl-4,4'-(4-methyloxazol-2,5-diyl)dibenzoate, G. The VIII was obtained in a similar manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN1CCNCC1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](C(=O)NCc3nccnc3Cl)CC2)CC1

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (40.7 mmol, 10.9 g) in dichloromethane (145 ml) and acetic acid (1.450 ml) at room temperature was added 1-methylpiperazine (52.9 mmol, 5.87 ml, 5.30 g) and sodium cyanoborohydride (81 mmol, 5.12 g). After 16 hours at room temperature dichloromethane and an aqueous saturated sodium hydrogencarbonate solution (15 mL) were added and the organic layer was separated. This organic layer was washed with brine. The aqueous layers were washed with dichloromethane twice and the combined organic extracts dried (sodium sulfate). Concentration in vacuo gave the crude product (mixture of cis and trans), which was purified using column chromatography (silica gel; dichloromethane/methanol gradient (0 to 20% methanol) to afford the cis isomer (275 mg), the trans isomer (2.5 g) and a mixture of cis and trans isomers (5.5 g).
Reaction SMILES: CN(C[N:5]([CH3:7])C)C.[O:8]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl[CH2:27]Cl>C(Cl)(=O)C.[Cl-].[Na+].O>[C:7]([CH2:27][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:5]
Reactant: CN(C)CN(C)C
Reactant: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: ClCCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: O
Product: N#CCc1c[nH]c2ccc(Oc3ccccc3)cc12
Reaction time: 0.17 h

Procedure:
To a cooled (ice bath) solution of bis (dimethylamino)methane (0.34 g) in dichloromethane (25 ml), acetyl chloride was added dropwise over 5 minutes. After stirring for 10 minutes, 5-phenoxyindole (0.51 g) was added and stirring continued for a further one hour at room temperature. The mixture was basified with aqueous 2N sodium hydroxide, brine (50 ml) added and the organic phase separated washed with water (2×50 ml), dried (MgSO4) and the solvent removed at reduced pressure. The residue was dissolved in dimethylformamide (25 ml) and potassium cyanide (0.62 g) and iodomethane (0.61 g) added. After stirring for 48 hours, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with water (4×50 ml), dried (MgSO4) and solvent removed at reduced pressure to give 3-cyanomethyl-5-phenoxyindole (0.57 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].Cl[CH2:14][O:15][CH3:16].C(N(CC)CC)C.O.[O:25]1[CH2:29]CC[CH2:26]1>>[CH3:14][O:15][CH2:16][O:12][C:7]1[CH:6]=[C:5]([CH:11]=[CH:10][C:8]=1[O:9][CH2:26][O:25][CH3:29])[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: C1CCOC1
Reactant: COCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C(=O)CCl)cc1OCOC
Yield: 78 %

Procedure:
4-(Chloroacetyl)catechol (4.1 g, 22 mmol), chloromethylmethylether (3.7 ml, 44 mmol) and triethylamine (12 ml) in tetrahydrofuran (50 ml) were stirred together for 1 h, the mixture poured into water (80 ml) and extracted with diethyl ether (80 ml×2). The organic extract was washed consecutively with 2N aqueous sodium hydroxide (50 ml×2) and water (50 ml), dried (MgSO4), and solvent evaporated to give 4.7 g (78%) of the title compound as a pale brown solid. (The crude product was used in the next step without further purification.)
Reaction SMILES: [N:1]#N.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.N.O1CCOCC1>>[C:7]([C:6]1[CH:10]=[C:11]([CH:12]=[C:4]([Cl:3])[CH:5]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[NH2:1]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Reactant: N#N
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc(C(N)=O)c1

Procedure:
Steps N2 and N3. A mixture of 3-chloro-5-(methoxycarbonyl)benzoic acid (2 g, 9.3 mmol) and thionyl chloride (8 mL) was refluxed for 2 hours. After the excess thionyl chloride was removed under vacuum, the residue was treated with a 0.5M solution of ammonia in 1,4-dioxane (40 mL, 20 mmol) overnight. The solvent was removed under vacuum and methyl 3-carbamoyl-5-chlorobenzoate was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4]C=1.C1C(=O)N([Cl:28])C(=O)C1.CCOC(C)=O.[C:35]([Cl:39])(Cl)(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:5]([Cl:28])=[CH:4][C:35]=1[Cl:39]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)n2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(Cl)cc2Cl)CC1
Temperature: 40 °C
Yield: 26.5 %

Procedure:
A mixture of tert-butyl 4-(6-aminopyridin-2-yl)piperazine-1-carboxylate (320 mg, 1.150 mmol) and NCS (307 mg, 2.299 mmol) in Carbon tetrachloride (10 mL)/CH2Cl2 (5.00 mL) was refluxed at 40° C. for 2 h. Purification on silicon gel column with DCM, then 2% EtOAc in DCM gave tert-butyl 4-(6-amino-3,5-dichloropyridin-2-yl)piperazine-1-carboxylate (110 mg, 0.305 mmol, 26.5% yield). 1H-NMR (CDCl3, 500 MHz): δ 7.39 (1H, s), 4.71 (2H, s), 3.53 (4H, m), 3.21 (4H, m), 1.47 (9H, s).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17](I)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]([C:27]1[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:29][CH:28]=1)#[CH:26].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.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>[Br:1][C:2]1[S:3][C:4]([C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:26]#[C:25][C:27]3[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:28]=3)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[O:24])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c([N+](=O)[O-])c2)sc1Br

Procedure:
A solution of 2 (952 mg, 1.82 mmol), benzyl 4-ethynylbenzoate (472 mg, 2.00 mmol), Pd(PPh3)2Cl2 (128 mg, 0.18 mmol), K2CO3 (250 mg, 1.81 mmol), and Et3N (238 mg, 2.36 mmol) in DMF (4 mL) was stirred for 24 hours at room temperature. Water (5 mL) was added to the mixture and then extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 3 as a solid foam (600 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.11-8.06 (m, 3H), 7.87 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.47-7.34 (m, 5H), 5.38 (s, 3H), 4.19 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.86, 169.64, 165.88, 149.62, 142.04, 137.57, 136.41, 135.95, 135.92, 135.39, 133.02, 132.40, 131.08, 130.02, 129.93, 128.91, 128.66, 128.55, 126.69, 125.60, 124.44, 122.06, 99.57, 84.06, 67.32, 61.77, 35.25, and 14.42.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][NH:4][CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][N:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3
Reactant: O=c1cccc2n1C[C@@H]1CNC[C@H]2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1cccc2n1C[C@H]1C[C@@H]2CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a 25 ml round bottom flask was added 0.510 gm (2.68 mmol) cytisine in 10 ml of 1,2-dichloroethane. The above solution was treated with 0.272 ml (2.68 mmol) benzaldehyde, 153 μl acetic acid and 0.852 gm (4.02 mmol) sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 hours and was then partitioned between methylene chloride 1 N HCl (aq). The organic phase was washed with brine, dried and the solvent evaporated in vacuo to a solid. Chromatography on silica gel eluting with 1% methanol in methylene chloride afforded 434 mg (58%) of the title product which was used in the next step. 1H NMR (CDCl3, 250 MHz) δ7.28 (dd, 1H), 7.15 (m, 3H), 6.98 (m, 2H), 6.52 (d, 1H), 5.92 (d, 1H), 4.10 (d, 1H), 3.88 (dd, 1H), 3.40 (dd, 2H), 2.88 (m 3H), 2.39 (brs, 1H), 2.32 (dd, 2H), 1.82 (dd, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]2[CH2:21][NH:20][C:19](=[O:22])[N:18]2[CH3:23])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[H-].[Na+].[CH3:28][S:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)(=[O:31])=[O:30].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:39][CH:38]=3)[C:19](=[O:22])[N:18]2[CH3:23])=[CH:12][CH:13]=1)([CH3:24])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CNC(=O)N2C)cc1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(S(C)(=O)=O)cc3)C(=O)N2C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
A solution of 2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid ethyl ester (0.143 g, 0.408 mmol) in dry DMF (4 mL) was treated a 60% suspension of NaH (0.033 g, 0.825 mmol) and the resultant mixture was stirred at room temperature for 20 minutes under N2. The reaction mixture was cooled to 0° C. and then treated with p-methylsulfonylbenzyl chloride and then warmed to room temperature and stirred for 16 h. The reaction was acidified with aqueous 1 N HCl (4 mL), diluted with water and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by column chromatography using a gradient of 4:1 to 1:1 hexanes:acetone to afford 0.090 g (42%) 2-(4-{2-[1-(4-methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. Rf=0.40 (1:1 hexanes:acetone) MS (ES+) Calc'd for C26H35N2O7S (M+1) 518. Found m/z 518 (100%). 1H NMR.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]3)[CH:12]2[CH:20]=[N:21][OH:22])=[CH:7][CH:6]=1.C(OCC)(=O)C>CO.C(O)C>[CH3:3][O:22][N:21]=[CH:20][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]1[CH2:14][CH2:15]2
Reactant: CN1C2CCC1C(C=NO)C(c1ccc(F)cc1)C2
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CON=CC1C(c2ccc(F)cc2)CC2CCC1N2C

Procedure:
The carbaldehyde-oxime obtained above is converted to an alkyl oxime by treatment with a diazoalkane such as diazomethane. Thus 3-(4-fluoro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carbaldehyde oxime is dissolved in an appropriate alcohol such as methanol or ethanol or an organic solvent such as ethyl acetate and then this solution is cooled in an ice/water bath and then a solution of diazomethane. (excess 1.1-20 equivalents) is added. The reaction mixture should be stirred until the reaction is complete (TLC) and then the desired product isolated by solvent evaporation. The pure product is obtained by crystallization or flash column chromatography.