Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:15][CH:16]=2)=[N:9][N:8]=[N:7]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]5[N:9]=[N:8][N:7]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:6]=5)[CH:12]=4)=[CH:36][C:21]=3[C:22]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:26][CH:27]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(CC(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 37.6 %

Procedure:
1-bromo-2-methylpropane (23 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 38%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.63 Hz), 7.99-8.04 (2H, m), 7.87-7.94 (2H, m), 7.79-7.84 (1H, m), 7.73-7.78 (1H, m), 7.70 (1H, t, J=7.63 Hz), 7.41 (2H, t, J=8.70 Hz), 4.62 (2H, d, J=7.32 Hz), 2.87 (3H, d, J=4.27 Hz), 2.31-2.39 (1H, m), 0.95 (6H, d, J=6.71 Hz). LC-MS retention time: 2.09 min; m/z (MH+): 470. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=16.08 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.89 min, purity=99%.
Reaction SMILES: [OH-].[K+].[C:3](O)(=O)[CH2:4][C:5]([CH2:10][C:11]([OH:13])=O)([C:7]([OH:9])=[O:8])O.[CH3:16]N(C)C=O>>[C@@H:4]12[O:13][C@@H:11]([CH:16]=[CH:3]1)[CH2:10][C@@H:5]2[C:7]([OH:9])=[O:8]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)[C@H]1C[C@@H]2C=C[C@H]1O2
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 1 mmol of (1R,2R)-2-(naphthalene-2-sulphonyl)cyclohexyl ester (exo)-(1R,2S,4R)-7-oxabicyclo[2.2.1]-hept-5-ene-2-carboxylate in 5 ml of N,N-dimethylformamide is mixed with 2 mmol of potassium hydroxide and stirred at 60° C. for 17 hours. The reaction mixture is cooled to room temperature and, after addition of 1M citric acid solution, extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with cold water and cold brine, dried with sodium sulphate and evaporated at room temperature. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([O:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH2:3]1>CCO.[Pd]>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C@H:4]1[CH2:5][C@@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:7]([O:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C@@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of (+/−)-tert-butyl (1R,5S,6S)-5-methyl-6-(2-(methylsulfonyl)ethoxy)-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in degassed EtOH (0.17 M) was added Pd/C (0.3 equiv.). The mixture was purged with H2, and allowed to stir under H2 overnight at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate in 55% yield. LC/MS (m/z)=428.2 (MH+), Rt=0.59 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (d, J=6.85 Hz, 3 H), 1.46 (s, 9 H), 1.72-1.88 (m, 2 H), 2.62 (tt, J=12.23, 3.30 Hz, 1 H), 3.08 (s, 3 H), 3.21 (d, J=14.62 Hz, 1 H), 3.35-3.47 (m, 1 H), 3.58 (br. s., 1 H), 3.64 (br. s., 2 H), 3.70-3.86 (m, 1 H), 3.94-4.10 (m, 1 H), 4.10-4.22 (m, 1 H), 5.43 (d, J=9.00 Hz, 1 H), 6.89 (d, J=5.04 Hz, 1 H), 7.98 (d, J=4.99 Hz, 1 H), 8.03 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([Cl:31])=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a suspension of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (1.477 g, 5.0 mmol; Example 1C) in dichloromethane (20 mL) was added catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane, 3.75 mL, 7.5 mmol). After stirring for 60 minutes, the reaction was concentrated, dried under high vacuum overnight. The resulting material was taken for further reactions without additional purification.
Reaction SMILES: C(OC([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33]([OH:35])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[CH3:36][N:37](C)[CH2:38]CCN=C=NCC.Cl.CNC>ClCCl.C(OCC)(=O)C>[OH:19][C@H:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][NH:8][CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33]([N:37]([CH3:38])[CH3:36])=[O:35])[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (200 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (122 mg) and 1-hydroxyenzotriazole hydrate (66 mg) in dichloromethane (20 ml) was added dimethylamine hydrochloride (38.4 mg), and the mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel and treated with 4N hydrogen chloride in ethyl acetate to afford 2-[8-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N,N-dimethylacetamide (100 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>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.COCCOC>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 80 °C

Procedure:
A microwave vial was charged with 6-(cis-2-amino-3,3-difluorocyclohexylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (13.7 mg, 0.028 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.82 mg, 0.042 mmol) and bis(triphenylphosphine)palladium chloride (3.97 mg, 5.65 μmol) and placed under an inert environment. DME (283 μL) was added to the mixture and the resulting yellow slurry was degassed for 5 min. Sodium carbonate was added (56.5 μL, 0.113 mmol) and the slurry degassed for an additional 3 min. The vessel was capped and the mixture was heated at 80° C. for 4 h, cooled to ambient temperature, diluted with EtOAc (5 mL), and washed with water (3 mL) and brine (3 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to give the title compound as a dark brown residue which was used in the next step without further purification (21 mg). [M+H] calc'd for C26H29F3N6O3, 531; found, 531.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:27]2[CH:28]=[CH:29][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:25][C:26]2=[O:30])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Reactant: O=c1cc(-c2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccnc(-n2ccc(-c3ccccc3)cc2=O)c1
Temperature: 130 °C
Yield: 28.8 %

Procedure:
A degassed mixture of N-benzyl-2-chloroisonicotinamide (0.25 g, 1.01 mmol), 4-phenylpyridin-2(1H)-one (0.17 g, 0.91 mmol), potassium carbonate (0.20 g, 1.44 mmol), 8-hydroxyquiniline (0.02 g, 0.14 mmol) and copper(I) iodide (0.03 g, 0.14 mmol) in N,N-dimethylformamide (3.0 mL) was heated at 130° C. for 18 hours. The resulting solution was cooled to ambient temperature, quenched with ammonium hydroxide solution (10 mL) and extracted with ethyl acetate (2×25 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give N-benzyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)isonicotinamide as a colorless solid (0.10 g, 25%): mp 162-163° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.43 (t, J=5.1 Hz, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.24, (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.89 (d, J=5.1 Hz, 1H), 7.79-7.76 (m, 2H), 7.54-7.45 (m, 3H), 7.36-7.18 (m, 5H), 6.82 (s, 1H), 6.76 (d, J=7.3 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 164.2, 161.6, 152.7, 152.0, 150.2, 143.6, 139.4, 137.4, 136.6, 130.5, 129.6, 128.8, 127.9, 127.4, 127.3, 121.6, 119.9, 116.8, 105.6, 43.3; MS (ES+) m/z 382.6 (M+1).
Reaction SMILES: [N:1]1[C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][N:4]=[C:3]2[NH:16][CH:17]=[CH:18][C:2]=12.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C>[Br:26][C:18]1[C:2]2[C:3](=[N:4][CH:5]=[C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:1]=2)[NH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cnc2[nH]cc(Br)c2n1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
tert-Butyl (5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (2.45 g, 9.87 mmol) in DMF (50 mL) was treated with NBS (1.76 g, 9.87 mmol) at P. After about 15 min the solvents were removed under reduced pressure then the material was suspended in water (25 mL). The slurry was stirred for about 30 min then the solids were collected by filtration and dried to a constant weight under vacuum at about 70° C. to give tert-butyl (7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (3.15 g, 98%): LC/MS (Table 2, Method b) Rt=1.99 min; MS m/z 327 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O.[Cu]I>[CH3:14][C:3]1[C:2]([C:16]([F:21])([F:20])[F:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1cc(Br)c(C)cc1OC
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC
Temperature: 170 °C

Procedure:
To a mixture of methyl 5-bromo-4-methyl-2-(methyloxy)benzoate (may be prepared as described in Description 43; 2.5 g, 9.65 mmol) in N,N-dimethylformamide (40 ml) was added copper (I) iodide (4.04 g, 21.23 mmol) and potassium trifluoroacetate (2.94 g, 19.30 mmol). Toluene (10 ml) was added and the mixture heated in Dean Stark apparatus at 170° C. for 45 minutes. The toluene was removed via the Dean Stark trap and the resulting mixture was heated for 18 hours at 170° C. The mixture was diluted with water (10 ml) and ethyl acetate (20 ml) and the solid was removed using Celite. The filtrate was taken and the organic layer separated, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 50% Cyclohexane/diethyl ether) to yield the title compound as a white solid. 1.76 g.
Reaction SMILES: [C:1]([CH2:6][C:7]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18]>C(OC(=O)C)(=O)C>[C:1]([C:6](=[CH:15][O:16][CH2:17][CH3:18])[C:7]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)NC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)NC(=O)OCC)C(=O)OCC

Procedure:
Following the procedure of Example 1, N-(2-carbethoxyacetyl)urethane is reacted with triethyl orthoformate in acetic anhydride to give α-carbethoxy-β-ethoxy-N-ethoxycarbonylacrylamide. This is reacted with 2,4,6-trichlorophenylhydrazine, giving α-carbethoxy-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide which is cyclized to yield 5-carbethoxy-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10](O)([CH3:12])[CH3:11].[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1c(C)cccc1C(C)(C)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(C)c1OC
Reaction time: 3 h
Yield: 41.6 %

Procedure:
71.37 g (395.96 mmol) of 2-(2-methoxy-3-methylphenyl)-propan-2-ol and 149 g (791.92 mmol) of 2-trimethylsilanyloxyacrylic acid ethyl ester are introduced into 1.1 l of dichloromethane. At −78° C., 44.8 ml (379.91 mmol) of tin tetrachloride is added in drops, and the batch is then stirred for three hours at this low temperature. 1.4 l of semiconcentrated potassium carbonate solution is added in drops, and the reaction mixture is thus brought to room temperature. The batch is filtered, and the filtrate is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried on sodium sulfate, and the solvent is spun off. The residue is chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). The residue is chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). 45.81 g (41.6%) of the desired compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([OH:24])=O.[N:28]1([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([N:31]1[CH2:30][CH2:29][N:28]([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH2:33][CH2:32]1)=[O:24]
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 9 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3-Chloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (51 mg) in 9% yield as colorless oil. MS m/e=565.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:27]I.CCOC(C)=O>C1COCC1>[I:27][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: II
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 29, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (1M, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes: EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes: EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39](=[O:40])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 4-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (30 mg, 0.07 mmol) in dichloromethane (1 mL) were added triethylamine (13 uL, 0.09 mmol) and ethyl chloroformate (9 uL, 0.09 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. After concentration it was purified by chromatography affording the title compound (20 mg, 57%) as a colorless foam. MS m/e: 496.4 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:22]([CH:24]1[CH2:26][CH:25]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=O>CN1C(=O)CCC1>[CH2:30]([O:29][C:27]([CH:25]1[CH2:26][CH:24]1[C:22]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]([N:11]3[CH2:17][C:16]4([CH3:19])[CH2:18][CH:12]3[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]4)=[O:10])=[CH:3][C:2]=2[N:1]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1CC1C=O
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)c(N)c2)C1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CC1c1nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
To a solution of (3,4-diaminophenyl)-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)methanone (500 mg, 1.74 mmol) in dry NMP (25 mL) at room temperature under an inert atmosphere of nitrogen was added approx. 500 mg of molecular sieve 4 Å followed by ethyl 2-formyl-1-cyclopropanecarboxylate (0.51 mL, 3.86 mmol). The mixture was stirred for 16 hrs at 50° C. The reaction was quenched by the addition of water (100 mL) followed by extraction with diethyl ether (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried in vacuo at 50° C. affording 60 mg (8%) of the title compound as a solid. MS-ESI m/z 410; 1H NMR (400 MHz, CDCl3) δ 0.88-1.06 (m, 6H), 1.07-1.20 (m, 4H), 1.25 (t, 3H), 1.27-1.34 (m) and 1.49-1.66 (m, 3H), 1.36-1.48 (m, 2H), 1.72-1.84 (m, 2H), 2.36-2.48 (m, 1H), 2.66-2.76 (m, 1H), 3.18-3.27 (m, 1H), 3.30 (d) and 3.65 (d, 1H), 4.00-4.06 (m) and 4.57-4.65 (m, 1H), 4.14 (q, 2H), 7.18-7.30 (m, 2H), 7.57 (d, 1H), 10.37 (br s, 1H).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([O-:18])=[O:17]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]([CH3:24])([N+:16]([O-:18])=[O:17])[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[CH:10]=2)[NH:7][CH:6]=1
Reactant: COC(=O)C(C)[N+](=O)[O-]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(Cc1c[nH]c2ccc(OC)cc12)[N+](=O)[O-]
Yield: 38.3 %

Procedure:
A solution of commercially available 5-methoxy gramine (6.24 g) and commercially available methyl 2-nitro-propionate (4.07 g) in a mixture of toluene (50 ml) and N,N-dimethylformamide (2 ml) is refluxed for one day while bubbling argon through the reaction mixture. The solvent is evaporated, the residue is taken up in dichloromethane (300 ml), is washed subsequently with 2 M aqueous HCl, 2 M aqueous NaOH, and water, is dried and concentrated. Column chromatography of the residue (toluene-acetone, 98:2→95:5) gives the title compound (3.42 g, 38%). M.p. 109-110° C. (from ethyl acetate-light petroleum).