Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].O1C=C[CH:37]=[C:36]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH:36]=[CH2:37])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3cc(F)ccc3C(CCCC)(CCCC)C1=O)N2
Temperature: 50 °C
Yield: 523.6 %

Procedure:
A solution of the compound of Example 20B (120 mg, 0.20 mmol), tri-(2-furyl)phosphine (5 mg, 0.020 mmol), tris-(dibenzylideneacetone)palladium (0) (9 mg, 0.010 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 min, during which time the solution changed from a deep maroon color to pale green. The solution was treated with vinyltributylstannane (118 □L, 0.403 mmol) followed by warming at 50° C. for 1.5 h. The solution was cooled, diluted with ethyl acetate and stirred for 1 h with 1 M KF solution. The mixture was filtered through Celite® and the layers separated. The organic layer was washed with saturated NaCl solution and dried over Na2SO4. Concentration in vacuo afforded an oil which was purified by flash chromatography eluting with ethyl acetate in hexane. These procedures afforded the title compound (52 mg, 52%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 0.59 (m, 2 H) 0.73 (m, 6 H) 0.89 (m, 2 H) 1.15 (m, 4 H) 1.88 (m, 2 H) 2.31 (m, 2 H) 5.41 (d, J=11.03 Hz, 1 H) 5.85 (d, J=17.65 Hz, 1 H) 6.74 (dd, J=17.47, 10.85 Hz, 1 H) 7.30 (m, 2 H) 7.43 (m, 2 H) 7.68 (m, 1 H) 7.94 (m, 2 H) 16.80 (s, 1 H).
Reaction SMILES: [Br:1]C(Cl)(Cl)C(Cl)(Cl)Br.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=O)=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([Br:1])[CH:26]2[CH2:28][CH2:27]2)=[CH:19][N:18]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(Nc1ccc(F)nc1)C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(N=C(Br)C2CC2)cn1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1,2-dibromotetrachloroethane (7.23 g, 0.022 mol) in 1,2-dichloroethane (50 ml) and triethylamine (4.49 g, 0.044 mol) was added to a stirred suspension of N-(2-fluoro-5-pyridyl)-cyclopropane carboxamide (2.0 g, 0.011 mol) - see Example 2 stage 1 and triphenylphosphine (5.83 g, 0.022 mol) in 1,2-dichloroethane (25 ml) at -10° C. under nitrogen at such a rate so that the temperature did not rise above -10° C. After complete addition (11/4 hours) the reaction mixture was allowed to warm up to room temperature and any triphenyl phosphine oxide was removed by filtration. Further quantities of triphenylphosphine oxide were removed by trituration of the residue with hexane. The filtrate was evaporated to give N-(2-fluoro-5-pyridyl)-cyclopropylmethanimidoyl bromide (2.54 g, 95%) as a yellow crystalline solid which was used in the next stage without further purification or characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[OH:15].N1C=CN=C1.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.6 %

Procedure:
To a solution of 224 (1.25 g, 6 mmol) in DCM (50 ml) was added imidazole (1.73 g, 25.4 mmol) and triisopropylsilyl chloride (2.71 ml, 12.7 mmol). The reaction mixture was stirred at rt for 22 h. Water (30 ml) and Chloroform (30 ml) were added. The layers separated and the aqueous layer extracted with chloroform (3×30 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography eluting with EtOAc:MeOH:TEA; 10:1:01 afforded the title compound (1.78 g, 81%) as colourless oil. 1H NMR (270 MHz; CDCl3) 1.06 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14 (6H, s, 2×CH3), 1.14-1.28 (3H, m, 3×CH), 2.51 (2H, s, CH2), 3.74 (3H, s, OCH3), 3.89 (2H, s, CH2), 6.46 (1H, s, CH), 6.51 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 12.95 (CH3), 18.03 (CH3), 27.76 (CH), 41.17 (CH2), 43.97 (CH2), 48.78 (C(CH3)2), 55.56 (OCH3), 112.96 (CH), 117.39 (CH), 126.24 (C), 126.92 (C), 143.58 (C), 149.34 (C). LC/MS (ES+) tr=2.65 min, m/z 364.36 (M++H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:8](C(O)=O)=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[N:12]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:14][C:10]1[N:9]=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([NH2:6])=[N:12][C:11]=1[Cl:13]
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(Cl)c(Cl)nc1C(=O)O
Agent: O=S(=O)(O)O
Product: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To 450 ml concentrated sulfuric acid cooled to 10° is added 50.0 g (0.2 m) 3-amino-5,6-dichloropyrazine carboxylic acid. To this solution cooled to 0°-5°, is added a cold solution of 15 ml fuming sulfuric acid in 15 ml fuming nitric acid dropwise over 15 minutes. The reaction mixture is stirred at 0°-5° for 2 hours and then at ambient temperature for 2 hours. The reaction mixture is then poured onto ice and the yellow solid is collected. This solid is taken up in ethyl acetate, washed twice with saturated sodium carbonate solution and then the solution is filtered through a pad of silica gel. The resulting solution is evaporated in vacuo to afford 35 g of 5,6-dichloro-3-nitropyrazinamine, m.p. 169°-170° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:12])=[N:5][C:6]([NH2:11])=[N:7][C:8]=1[S:9][CH3:10])[CH3:2].Br[CH2:14][C:15](=O)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CCOCC>[CH2:1]([C:3]1[C:8]([S:9][CH3:10])=[N:7][C:6]2[N:5]([CH:14]=[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[N:11]=2)[C:4]=1[CH3:12])[CH3:2]
Reactant: CCc1c(C)nc(N)nc1SC
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: CCOCC
Product: CCc1c(SC)nc2nc(C(=O)c3ccccc3)cn2c1C
Reaction time: 48 h
Yield: 54.4 %

Procedure:
A stirred suspension of 4.5 g of 5-ethyl-4-methyl-6-methylthio-2-pyrimidinamine in 28 ml of ether was treated with 5.5 g of 3-bromo-1-phenylpropane-1,2-dione to obtain a yellow solution. After standing two days at room temperature, the crystallized pyrimidinium salt was filtered off, washed with ether and heated for one hour in refluxing ethanol. The solution was evaporated to dryness under reduced pressure and the residue was shaken with a mixture of chloroform and aqueous potassium carbonate. The organic layer was washed, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration of the residue with ethanol and filtration yielded 4.1 g (53% yield) of [6-ethyl-5-methyl-7-(methylthio)imidazo[1,2-a]pyrimidin-2-yl]phenylmethanone after recrystallization from methanol in the form of a buff solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11].O>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1F
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1F
Reaction time: 15 h

Procedure:
To a cold (-2°), stirred solution of 285 g. (2.26 mol) of 2-fluoroanisole in 1.1 L of acetic anhydride was added, dropwise, 114 mL of fuming nitric acid (sp. gr. 1.59) at such a rate that the reaction temperature remained between -2° and 0°. The reaction mixture was stirred for 5 hours at this temperature then poured into 4.0 L of water. The suspension was stirred for 1.5 hours, stored for 15 hours, then extracted with methylene chloride (2×1.0 L). The combined extracts were washed with water (2×500 mL), dried over anhydrous magnesium sulfate, then concentrated in vacuo (475 g.). Crystallization from ethanol gave 147.4 g. (38%) of material suitable for further transformation. Additional material (34.5 g.) was obtained from three scouting runs.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][O:9][C:8]=1[CH:7]=[CH:6]2.[CH:16]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=1)=[O:17].[Cl-].[NH4+].[CH2:44]1[CH2:48]OC[CH2:45]1>>[NH:21]1[CH:22]=[C:18]([C:16]([C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[C:12]2[CH:11]=[CH:10][O:9][C:8]=2[CH:7]=[CH:6]3)([OH:17])[CH:44]([CH3:48])[CH3:45])[N:19]=[CH:20]1
Reactant: Brc1ccc2c(ccc3occc32)c1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CC(C)C(O)(c1ccc2c(ccc3occc32)c1)c1c[nH]cn1
Temperature: 0 °C

Procedure:
Iodomethyl (0.05 mL) was added to mixture THF (5 mL) and magnesium (turnings, 0.719 g) with stirring. 7-bromonaphtho[2,1-b]furan (6.09 g) was added and the mixture was refluxed for 2 h. The resulting mixture was cooled to 0° C. and a solution of 4-formyl-1-trityl-1H-imidazole (4.71 g) in THF (40 mL) was added. The mixture was stirred at room temperature for 1 h and aq. ammonium chloride was added. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was chromatographed on silica gel (eluent; hexane:ethyl acetate=2:1→1:2) to give the titled compound (2.30 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([CH2:23][C:24]#[N:25])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC.C([O-])(=O)C.[NH4+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[C:23]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:24]#[N:25])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Solvent: CCC(=O)O
Product: COc1cc2c(cc1OC)C(C)(C)CC2=C(C#N)C(=O)C(C)(C)C
Temperature: 120 °C
Yield: 50 %

Procedure:
44 g (0.2 mol) of 5,6-dimethoxy-3,3-dimethyl-1-indanone, 25 g (0.2 mol) of pivaloylacetonitrile, 32 g of propionic acid and 17 g of ammonium acetate are mixed in 80 g of xylene and heated at 120° C. for 7 hours. After the system has been cooled to room temperature and the organic phase has been washed, the xylene is distilled off, and the crude product which remains is recrystallized in methanol. Yield: 50% theory; E1/1730 (λmax 373 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[H-].[Na+].Cl[CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:33][C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[C:21](=[O:25])[CH:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: N#Cc1cc(COc2cc[nH]c(=O)c2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cn1cc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)cc2=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
To a solution of 2-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyridinyl)oxy]methyl}benzonitrile (60 mg, 0.143 mmol) in N,N-dimethylformamide (2 mL) was added Sodium hydride (40 mg, 1.00 mmol) at rt in one portion. After stirring at rt for 10 min, 4-(chloromethyl)-1-methyl-1H-pyrazole (40 mg, 0.306 mmol) was added. The reaction mixture was heated at 60° C. in the microwave for 30 min, then quenched by addition of methanol, concentrated. Purification via Biotage-C18 system afforded the title product (13.6 mg) as a white solid. LC-MS (ESI): m/z 515 [M+H]+; 3.36 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23][C:24](=[CH:26][C:27](=[O:33])[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:25].C(O)(=O)C>CC(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[C:26]([C:27](=[O:33])[CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[C:24]([CH3:25])[NH:23][C:19]([CH3:20])=[C:18]2[C:16]#[N:17])=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2
Reactant: CC([O-])=CC#N
Reactant: CC(N)=CC(=O)CCC(C)C
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c3c(=O)cc(C)oc23)C(C(=O)CCC(C)C)=C(C)N1

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 75.3 mg (0.49 mmol) of 2-amino-7-methyloct-2-en-4-one and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The yellow crystals are filtered off with suction and purified further on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 75.2 mg (38.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2].[CH2:20](I)[CH2:21][CH2:22][CH3:23].N1C(C)=CC=CC=1C>>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)Nc1ccc(CCC(=O)O)cc1
Solvent: Cc1cccc(C)n1
Product: CCCCN(c1ccc(CCC(=O)O)cc1)[C@@H](C)C(=O)OCC
Temperature: 135 °C

Procedure:
N-(4-Carboxyethylphenyl)alanine ethyl ester (2.6 g, 0.01 mol), n-butyl iodide (1.8 g, 0.01 mol) and 2,6-lutidine (1.5 g, 0.04 g) were sealed in a glass tube. The contents of the tube were heated at 135° C. for 48 h. The tube was then cooled and the contents were partitioned between 200 mL ethyl acetate and 200 mL brine. The organic layer was separated, dried over anhyd. sodium sulfate and concentrated at reduced pressure. The resulting oil was charged onto a silica gel column, and eluted with heptane:THF (4:1). The desired ester was isolated as a light yellow oil (0.5 g, 16%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C(c2ccccc2)C1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A suspension of potassium tert-butoxide (1.25 g, 11.1 mmol) and methyltriphenylphosphonium bromide (3.86 g, 1.1 mmol) in tetrahydrofuran (100 mL) was stirred at 40° C. for 30 minutes. The mixture was then cooled to room temperature and a solution of tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (2.35 g, 8.5 mmol) in tetrahydrofuran (30 mL) was added slowly. The reaction mixture was stirred at 40° C. for 24 hours. The mixture was cooled to room temperature and quenched by the addition of water and diluted with ethyl acetate (250 mL), The organic layer was separated then washed with water, 10% aqueous citric acid and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica gel (hexane:ethyl acetate 95:5 to 9:1) provided tert-butyl 4-methylene-2-phenylpiperidine-1-carboxylate (2.24 g, 96%). 1H NMR (400 MHz, CDCl3): 7.31 (m, 4H), 7.21 (m, 1H), 5.48 (br d, 1H), 4.84 (dd, 2H), 4.07 (br dd, 1H), 2.85 (br, t, 1H), 2.78 (dtr, 1H), 2.64 (dd, 1H), 2.28 (dtr, 1H), 2.20 (br d, 1H), 1.42 (s, 9H). GC/MS (EI) for C17H23NO2: 273 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][OH:13].C([O-])(O)=O.[Na+]>>[OH:13][NH:12][C:1](=[NH:2])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=Cc1ccc(C(=N)NO)cc1

Procedure:
4-Cyanostyrene is transformed to the corresponding hydroxyamidine according to literature procedures using hydroxylamine hydrochloride and NaHCO3 as base (e.g. E. Meyer, A. C. Joussef, H. Gallardo, Synthesis 2003, 899-905); LC-MS: tR=0.55 min; [M+H]+=163.04; 1H NMR (D4-methanol): δ 4.86 (s br, 3H), 5.30 (d, J=11.0 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].Cl[CH2:7][P:8](=[O:11])([OH:10])[OH:9].[OH-].[Na+]>O>[P:8]([CH2:7][NH:1][CH2:2][C:3]([OH:5])=[O:4])([OH:11])([OH:10])=[O:9]
Reactant: O=P(O)(O)CCl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 25 °C

Procedure:
A mixture of about 50 parts of glycine, 92 parts of chloromethylphosphonic acid, 150 parts of 50% aqueous sodium hydroxide and 100 parts water was introduced into a suitable reaction vessel and maintained at reflux temperature while an additional 50 parts of 50% aqueous sodium hydroxide was added. The pH of the reaction mixture was maintained between 10 and 12 by the rate of addition of the sodium hydroxide. After all of the caustic solution had been added, the reaction mixture was refluxed for an additional 20 hours, cooled to room temperature and filtered. About 160 ml. of concentrated hydrochloric acid were then added and the mixture filtered to provide a clear solution which slowly deposited N-phosphonomethylglycine. This material had a melting point of 230° C. with decomposition.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1C(O)=O)=O.Br[C:17](=[CH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C(OC(=O)C)(=O)C.O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:8]2[C:9]([CH2:13][CH2:14][CH2:15]2)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cccs1
Reactant: CCOC(=O)C(Br)=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccncc2)c(-c2cccs2)n2c1CCC2

Procedure:
N-(2-Thienylcarbonyl)proline (4.69 g, 21 mmol) is dissolved in acetic anhydride (15 ml) at 60° C. (15 min), ethyl 2-bromo-3-(4-pyridyl)propenoate (6.40 g, 25 mmol) is added to the clear solution and the mixture is heated at 90° C. for 16 h, whereupon a tlc sample (Al2O3-ethyl acetate/THF 9:1) no longer indicates starting material. The cooled reaction mixture is treated with ethyl acetate (120 ml) and intensively stirred with saturated Na2CO3 solution (80 ml) for 15 min and diluted with water (50 ml). The ethyl acetate phase is separated off, the water phase is extracted with a further 3 portions of ethyl acetate (150 ml), and these organic phases are combined, washed with saturated Na2CO3 soln (50 ml) and, after drying (K2CO3 sicc.), concentrated in vacuo. 8 g are obtained as a residue, which is dissolved in a little ethyl acetate and purified by cc (Al2O3-ethyl acetate/n-hexane 2:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (26.000 g, 137 mmol) in THF (30 mL) was cooled to −30° C. and morpholine (17.88 mL, 205 mmol) was slowly added. After 5 min, triethylamine (57.2 mL, 410 mmol) was slowly added. Following addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 30 min, the mixture was filtered through a fine-fritted funnel and the filtrate was concentrated to give an orange oil. The crude material was purified by chromatography through a Thompson Instruments pre-packed silica gel (330 gram) column eluting with a gradient of 0% to 100% EtOAc in hexane over 50 min to give 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol, 58.7% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.79 (td, J=8.07, 2.45 Hz, 1H); 6.90 (dd, J=8.31, 2.84 Hz, 1H); 3.67-3.72 (m, 4H); 3.49 (s, 2H); 2.39-2.48 (m, 4H). m/z (ESI, +ve ion) 197.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[CH3:34]OC([Si](C)(C)C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.FC(F)(F)C(O)=O>>[CH:13]([N:12]([CH2:24][CH3:25])[CH:11]([CH3:10])[CH3:28])([CH3:14])[CH3:34].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: CC=C(CC)C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C1COCCN1
Solvent: O=C(O)C(F)(F)F
Product: CC=C(CC)C1N(CCCN2CCOCC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 57 %

Procedure:
In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 83a (0.3 g, 0.47 mmol) was reacted with morpholine (12 mL), trifluoroacetic acid (5 mL) and then N,N-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.15 g, 57%).