Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]1[C:24]2[CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][C:34]=3[CH:35]=[O:36])[CH:27]=[CH:28][C:23]=2[O:22][C:21]1=[O:37].[F:38][C:39]([Si](C)(C)C)([F:41])[F:40]>C1COCC1.C(OCC)(=O)C.O>[CH3:19][N:20]1[C:24]2[CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][C:34]=3[CH:35]([OH:36])[C:39]([F:41])([F:40])[F:38])[CH:27]=[CH:28][C:23]=2[O:22][C:21]1=[O:37]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C(O)C(F)(F)F)cc21

Procedure:
A solution of TBAF in THF (1M, 0.02 mL, 0.02 mmol) was added dropwise to a mixture of 3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-4-carbaldehyde (54 mg, 0.21 mmol) and (trifluoromethyl)trimethyl silane (0.2 mL, 0.42 mmol) in THF (0.8 mL) at 5° C. under nitrogen. After 5 min at this temperature, TBAF (1M in THF, 1 mL, 1 mmol) was added. The resulting solution was diluted with ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2O4. After concentration, the residue was purified by PTLC (10% MeOH in DCM, v/v) gave 3-Methyl-5-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-3H-benzooxazol-2-one. (13 mg, 19%); ESI-MS m/z: 325 [M+1]+, Retention time 1.53 min; 1H-NMR (MeOD, 400 MHz) δ 8.65 (1H, d, 5.6 Hz), 8.50 (1H, s), 7.79 (1H, d, J=5.6 Hz), 7.39 (1H, d, J=8.0 Hz), 7.17 (1H d, J=1.6 Hz), 7.12 (1H, dd, J=8.0, 1.6 Hz), 5.16 (1H, q, J=6.8 Hz), 3.43 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24](=[O:27])[NH:25][CH3:26])[CH2:22][CH2:21][N:20]3[CH2:28][CH2:29][N:30]([CH2:38][C:39]3[CH:47]=[CH:46][C:42]4[O:43][CH2:44][O:45][C:41]=4[CH:40]=3)C(=O)OC(C)(C)C)[CH:16]=[C:15]([CH3:48])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.O.[OH-].[NH4+]>C(Cl)Cl>[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24]([NH:25][CH3:26])=[O:27])[CH2:22][CH2:21][N:20]3[CH2:28][CH2:29][NH:30][CH2:38][C:39]3[CH:47]=[CH:46][C:42]4[O:43][CH2:44][O:45][C:41]=4[CH:40]=3)[CH:16]=[C:15]([CH3:48])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNC(=O)C1CCN(CCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1CCN(CCNCc2ccc3c(c2)OCO3)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
2,2,2-Trifluoroacetic acid (5.00 mL, 67.3 mmol) was added dropwise over 5 minutes to a 0° C. solution of tert-butyl 2-(2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidin-1-yl)ethyl(benzo[d][1,3]dioxol-5-ylmethyl)carbamate (100 mg, 0.18 mmol) in CH2Cl2 (5 mL). The reaction mixture was warmed to rt over 30 minutes then water (20 mL) was added. The solution was brought to pH=9 with ammonium hydroxide (100 mL), extracted with CH2Cl2 (3×10 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford 50 mg (61%) of 2-(2-(1 H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-1-(2-(benzo[d][1,3]dioxol-5-ylmethylamino)ethyl)-N-methylpyrrolidine-3-carboxamide as yellow oil. [M−H]+ 462.00.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:30])[NH:7][C:8]2[CH:29]=[CH:28][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]3[CH3:27])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:31]>>[ClH:31].[CH:1]1([NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]3[CH3:27])=[O:13])=[CH:28][CH:29]=2)=[O:30])[CH2:2][CH2:3][CH2:4]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(NC(=O)NC2CCC2)cc1
Agent: Cl
Product: C[C@H]1CNCCN1C(=O)c1ccc(NC(=O)NC2CCC2)cc1

Procedure:
tert-Butyl 4-(4-(3-cyclobutylureido)benzoyl)-3-methylpiperazine-1-carboxylate (0.20 g, 0.48 mmol) was treated with an ethanolic solution of hydrochloric acid (2 mL, 14.5 wt % hydrochloric acid in ethanol). The resultant mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, azeotroped with dichloromethane (×2) and dried under vacuum to afford the title compound (0.152 g) as a white foamy solid. MS (ESI) m/z 317.0 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]([Sn](CCCC)(CCCC)CCCC)=[CH2:10]>C1(C)C=CC=CC=1>[CH:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH2:10]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1cc(Br)cs1
Solvent: Cc1ccccc1
Product: C=Cc1csc(C=O)c1

Procedure:
A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11.4 ml of vinyltributyltin, and 3.6 g of tetrakistriphenylphosphine palladium in 100 ml of toluene was heated at 110° C. for 4 hours under a sealed tube condition. The organic layer was extracted with ethyl acetate and washed with water. In addition, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.4 g of 4-vinylthiophene-2-carbaldehyde as a brown liquid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][NH:24][CH:25]1[CH:33]=[CH:32][CH2:31][CH:30]2[CH:26]1[CH2:27][NH:28][CH2:29]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH3:23][NH:24][CH:25]1[CH:33]=[CH:32][CH2:31][CH:30]2[CH:26]1[CH2:27][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH:17]=[CH2:18])[C:10]=1[F:16])[CH2:29]2
Reactant: CNC1C=CCC2CNCC21
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(F)c(N2CC3CC=CC(NC)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 76.1 %

Procedure:
0.46 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.34 g of 4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindole and 0.18 g of DABCO are refluxed for 2 hours in a mixture of 3 ml of acetonitrile and 1.5 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 20 ml of water, and the product is filtered off with suction, washed with water and dried. 0.5 g of 7-(4-methylamino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1.N>>[O:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([NH2:3])[CH2:5][CH2:6]1
Reactant: CON=C1CCOc2ccccc21
Agent: CON=C1CCOc2ccc(C)cc21
Agent: N
Product: NC1CCOc2ccccc21

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 16A for the product of Example 7A. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (dd, J 1.0 and 7.5 Hz, 1H), 7. 05 (m, 1H), 6.81 (m, 1H), 6.70 (dd, J 1.0 and 7.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.83 (t, J 6.0 Hz, 1H), 2.03-1.66 (m, 4H). MS (DCI/NH3) m/e 150 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH2:17]([SH:20])[CH2:18][CH3:19].[H-].[Na+]>>[CH2:17]([S:20][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[CH2:18][CH3:19]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Product: CCCSc1nc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 40.9 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (243 mg, 0.966 mmol) was reacted with propanthiol (229 mg, 3.01 mmol) and sodium hydride (145 mg, 3.62 mmol) to afford title compound (115 mg) after purification by column chromatography (Hex EtOAc=2/3).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].[Li].[H-]>O>[C:2]1([CH:1]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][NH:21][CH2:18][CH2:19][NH:20]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Li]
Solvent: O
Product: c1ccc(C2NCCNCc3ccccc32)cc1

Procedure:
Add 40 g. of the condensation product of o-benzoylbenzoic acid and ethylenediamine in small portions to a suspension of 15 g. of lithium aliminum hydride in 1500 ml. of anhydrous either with stirring. Reflux with stirring for 16 hours. Cool and add water carefully to decompose excess hydride. Separate the ether layer, dry over magnesium sulfate, and remove the solvent under reduced pressure to obtain 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, m.p. 125° C. To prepare the dihydrochloride, dissolve the base in anhydrous ether and saturate with dry hydrogen chloride. Separate the precipitated solid, and recrystallize from ethanol to obtain 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine dihydrochloride, m.p. 297° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].C12C[CH:33]([C:35](=[O:39])[CH2:36]OC)CC1CNC2>C(O)(C)C>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH:14]12[CH2:13][CH:12]([C:16](=[O:19])[CH2:17][O:39][CH:35]([CH3:36])[CH3:33])[CH2:11][CH:10]1[CH2:9][NH:8][CH2:15]2
Reactant: COCC(=O)C1CC2CNCC2C1
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCC(=O)C1CC2CNCC2C1

Procedure:
1-(3-Azabicyclo[3.3.0]oct-7-yl)-2-isopropoxy-1-ethanone trifluoroacetate was prepared from 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.087 g, 0.27 mmol) and isopropanol, according to the procedure described above for the preparation of 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-methoxy-1-ethanone trifluoroacetate, to give a mixture of cis and trans isomers (1H NMR (CD3OD, 300 MHz): δ 4.21 and 4.20 (s, 2H), 3.64 (heptet, J=6.1 Hz) 1H), 3.54-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.98-2.90 (m, 4H), 2.37-2.22 and 2.06-1.99 (m, 2H), 1.82-1.75 and 1.65-1.54 (m, 2H), 1.18 (d, J=6.1 Hz, 6H); MS (m/z): 212 (M+1)). This material exhibited Ki values at rat and human α4β2 of 427 nM and 261 nM respectively and did not pass HTS for α7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]2[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:38]2[CH:37]=[N:36][N:35]([CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:39]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound. LCMS: 519.00 (M+1)+; HPLC: 97.07% (@ 254 nm) (Rt; 4.925; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.76 (t, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 5.89 (s, 1H), 5.34-5.31 (m, 1H), 4.39 (d, 2H, J=4.8 Hz), 4.30 (t, 2H, J=6.8 Hz), 3.54 (m, 4H), 2.76 (t, 2H, J=6.4 Hz), 2.42 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H, J=6.4 Hz).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24]C(C6C=CC(OC)=CC=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CC(O)=O.C1COCC1>O>[C@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@H:23]([OH:24])[C@H:22]([CH2:27][OH:26])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.2 %

Procedure:
N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70.0 mg, 0.145 mmol) was added to a solution of AcOH (0.742 mL, 13.0 mmol), THF (0.235 mL) and water (0.261 mL). The solution was stirred at rt for 4 days before being concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (27.6 mg, 52%). LC/MS: Rt=0.94 min, ES+ 365 (FA standard).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cccc(F)c3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound is prepared by hydrolysis of 9h using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16][C:17]([F:27])([F:26])C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([C:17]([F:27])([F:26])[F:16])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(C(F)(F)F)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 4-trifluoromethylbenzaldehyde instead 4-fluorobenzaldehyde. 1H-NMR (CDCl3): δ=3.93 (s, 3H); 4.55 (s, 1H); 7.52 (d, 2H); 7.66 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:23])[O:3]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32](C)C=O>ClCCl>[CH3:1][C:2]1([CH3:24])[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:32][CH3:31])=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:23])[O:3]1
Reactant: CN(C)C=O
Reactant: CON(Cc1ccc(C(=O)O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoic acid (0.150 g, 0.45 mmol) in dichloromethane (2 ml) was treated at 22° C. with oxalyl chloride (0.08 ml) and a trace (capillary) of N,N-dimethylformamide and the resulting mixture was stirred for 2 h. The solvent and excess reagent were evaporated in vacuo and the residue was dissolved in dichloromethane (2 ml). This solution was added dropwise to a cold (5° C.) solution of methylamine (0.5 mmol, 0.25 ml of a 2M solution in tetrahydrofuran) and pyridine (0.01 ml) in dichloromethane (2 ml). After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution ethyl acetate and acetonitrile, 0 to 5%) yielded 0.060 g (38% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.69 (6H, s, CH3), 2.77 (3H, d, J=4.5 Hz, NCH3), 3.72 (2H, s, OCH3), 4.85 (2H, s, NCH2), 6.18 (1H, s, CH), 7.35 (2H, d, J=8.2 Hz, aromatics), 7.79 (2H, d, J=8.2 Hz, aromatics), 8.41 (1H, broad q, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:32])([F:31])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([F:31])([F:32])[F:15])=[CH:20][CH:21]=2)[C:29]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)F)cc1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 48.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.971 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.0 g of 2-[4-(2,2,2-trifluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.825 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,2-trifluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Cl)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Product: COc1ccc(Nc2cnc3[nH]c4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
3-Chloro-5,7,8,9-tetrahydro-dipyrido[2,3-b;3′,4′-d]pyrrole-6-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), p-anisidine (48 mg, 0.39 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (12 mg, 0.03 mmol), and KOH (0.03 ml, 0.97 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 95° C. The crude mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 44 (16 mg, 13% yield) as a brown oil. LC-MS (M+H=395, obsd.=395).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH:24]1([N:29]2[CH2:32][CH2:31][CH:30]2[C:33]([O-])=[O:34])[CH2:28][CH2:27][CH2:26][CH2:25]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:33]([CH:30]2[CH2:31][CH2:32][N:29]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:34])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1CCN1C1CCCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCCC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-cyclopentylazetidine-2-carboxylate 201 carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-cyclopentylazetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 505.2 (100) [(M+H)]]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[F:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (500 mg, 1.107 mmol) in DCM (11 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine (266 mg, 1.107 mmol), HBTU (504 mg, 1.329 mmol), and TEA (0.386 mL, 2.77 mmol). This mixture was stirred at room temperature for 18 h before being purified by CombiFlash chromatography to afford 0.6767 g (96%) of the title compound. LC-MS m/z 637 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li:15])CCC>C(OCC)C.CCCCC>[CH3:1][C:2]1[CH:10]([Li:15])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Product: [Li]C1C(C)=Cc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 3 g (20 mmol) of 2-methylindene (C. F. Koelsch, P. R. Johnsen, J. Am. Chem. Soc. 65, 567, (1943)) in 50 ml of diethyl ether is cooled to -78° C. and admixed with 14.6 ml of a 1.58 molar solution of n-butyllithium in n-pentane. The solution is warmed to room temperature and the 2-methylindenyllithium formed is filtered off and dried under reduced pressure. The yield is 2.5 g (91.9% of theory).