Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C@H:4]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[CH2:3]1.[Cl:33][CH2:34][C:35](Cl)=[O:36].CCN(C(C)C)C(C)C>CC#N>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:10][C:8]([C@@H:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][C:35](=[O:36])[CH2:34][Cl:33])[CH2:3][C@H:4]2[C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)=[O:9])=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Reaction time: 1.5 h

Procedure:
To the product from Example 54 (120 mg, 0.24 mmol) in MeCN (4 mL) was added chloroacetyl chloride (24 mg, 0.3 mmol). The reaction was aged for 90 min at rt and DIEA (45 μL, 0.24 mmol) was added. After 15 min, another portion of chloroacetyl chloride (12 mg, 0.15 mmol) was added, along with DIEA (45 μL, 0.24 mmol). The reaction was concentrated, diluted with CHCl3 and washed with Na2CO3/brine 1:1. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound. HPLC/MS: 575.1/577.0 (M+1); Rt=3.36 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1.O.C(=O)([O-])O.[Na+]>C(#N)C.CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.25 g (corresponding to 10.0 mmol) of 2-amino-5-methoxypyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 90° C. for 3.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The recovered precipitates were washed with acetonitrile, and dried under reduced pressure to obtain crude crystals. The resulting crude crystals were suspended in a mixed solution of 40 mL of water and 40 mL of methanol. The suspension was supplemented with about 20 mL of a saturated sodium hydrogencarbonate solution, and sonicated for 5 minutes by an ultrasonic washing machine. The precipitates were filtered and recovered from the resulting mixture, washed with water, and dried under reduced pressure, to obtain 1.96 g (corresponding to 8.16 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 1, Step 5).
Reaction SMILES: C(Br)(Br)Br.[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15](OC)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21].C[Al](C)C>>[NH:21]1[CH2:20][CH2:19][N:22]=[C:15]1[C:7]1[N:6]([CH3:5])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: COC(=O)c1cc2ccccc2n1C
Reactant: NCCN
Agent: C[Al](C)C
Solvent: BrC(Br)Br
Product: Cn1c(C2=NCCN2)cc2ccccc21

Procedure:
A stirred suspension of methyl 1H-indole-2-carboxylate (5.0 g), dimethyl sulphate (9 ml) and potassium carbonate (10.4 g) in dry acetone (200 ml) was heated under reflux for 24 h. After cooling to room temperature 5% ammonia solution (50 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried and the solvent evaporated to give methyl 1-methyl-1H-indole-2-carboxylate (5.4 g) as a white solid; IR (CHBr3) max 1695 cm-1. The ester was treated with ethylenediamine and trimethylaluminium as described in Example 1(a). Purification via column chromatography on silica eluting with 5% v/v methanolic ammonia in dichloromethane gave 2-(2-imidazolin-2-yl)-1-methyl-1H-indole as a white solid. The hydrochloride salt was prepared as in Example 3 and that recrystallised from ethanol/diethyl ether; mp 290°-295° C. (decomp) (Literature mp 260°-280° C. (decomp) D. J. Hlasta, D. Luttinger, M. H. Perrone, M. J. Silbernagel, S. J. Ward and D. R. Haubrich, J. Med. Chem. 1967, 30, 1555).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]1.[C:14](=[O:16])=[O:15]>C1COCC1>[O:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]1[C:14]([OH:16])=[O:15]
Reactant: O=C=O
Reactant: O=C(O)c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccoc1C(=O)O
Temperature: -78 °C

Procedure:
n-Butyllithium (2.5M in hexanes, 196 mL, 491 mmol) was introduced into a dry 3 L 3-necked flask fitted with an addition funnel, argon inlet, and mechanical stirrer. The mixture was diluted with dry THF (500 mL), and cooled to −78° C. 3-furoic acid (25 g, 223 mmol) was added as solution in THF (500 mL) dropwise. The mixture was stirred for 1.5 h, at which point dry carbon dioxide was bubbled through the reaction mixture for 1 h. After warming gradually to −10° C., the resultant thick white slurry was treated with aqueous HCl (2 N, 446 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to afford crude furan-2,3-dicarboxylic acid as an orange solid (44 g) which was used without further purification. 1H NMR (300 MHz, d6-acetone) δ 7.06 (d, J=1.7, 1), 7.97 (d, J=1.7, 1), 10.7 (bs, 2H); TLC (CHCl3/MeOH/H2O 6:4:1) Rf=0.56.
Reaction SMILES: C([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:13])[CH2:6][CH2:5]1)=O.[ClH:14].C(O)C>>[ClH:14].[O:13]=[C:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:4]([NH2:3])[CH2:5][CH2:6]1
Reactant: O=CNC1CCC(=O)c2sccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2sccc21

Procedure:
In the manner described in Example 36, N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is hydrolyzed with 2 N hydrochloric acid/ethanol to afford 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride, melting point 230° C. to 232° C. (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1.[CH2:23]([O:27]C=C)[CH2:24]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1)(=[O:27])[CH3:24]
Reactant: COC(=O)c1ccc2c(Br)nn(CC(=O)OC(C)(C)C)c2c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of methyl 3-bromo-1-(2-tert-butoxy-2-oxoethyl)-1H-indazole-6-carboxylate (1.00 g, 2.71 mmol), n-butyl vinylether (1.75 mL, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) and triethylamine (0.45 mL, 3.25 mmol) in dry CH3CN (10 mL) was heated at 100° C. under microwave irradiation for 7 h. Then, the mixture was further heated at 120° C. for 5 h under microwave irradiation. The solvent was evaporated, and the residue was then treated with 4N HCl/dioxane with stirring at RT for 16 h. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the pure fractions the title compound. MS (LC-MS): 333 [M+H]+, 355 [M+Na]; tR (HPLC conditions k): 3.83 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25](OC)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CSC>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Solvent: CSC
Product: Cl
Product: OCCc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Yield: 159.5 %

Procedure:
Following general procedure E2, methyl 2-(3-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.080 g, 0.20 mmol) was reacted with BH3.DMS (2.0 M, 0.30 mL, 0.60 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.064 g, 80%) as a light yellow solid. MW=401.33. 1H NMR (DMSO-d6, 500 MHz) δ 14.08 (s, 1H), 9.81 (s, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.76-7.68 (m, 1H), 7.67-7.63 (m, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.30-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.20-7.16 (m, 1H), 7.09 (s, 1H), 3.65 (t, J=6.5 Hz, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.77 (t, J=6.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:10]2)=[N:4][CH:5]=[CH:6][C:7]=1I.[Cl:26][C:27]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:29]2[CH:35]=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:26][C:27]1[C:28]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:9]3[CH:14]=[CH:13][C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:10]3)[C:2]=2[F:1])=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: COc1ccc(COc2cn(-c3nccc(I)c3F)ccc2=O)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)c(Cl)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3nccc(-c4c(Cl)cnc5[nH]ccc45)c3F)ccc2=O)cc1
Temperature: 135 °C

Procedure:
To a room temperature solution of 132 mg (0.292 mmol) 3′-fluoro-4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one in 2 mL THF in a 5 mL microwave vial (Biotage) were added 253 mg (0.584 mmol) 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, 1 mL 1.0 M cesium carbonate (1.0 mmol), and 23.8 mg (0.029 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The vial was sealed and the reaction mixture was heated at 135° C. under microwave irradiation for 15 minutes, then cooled. The organic layer was separated, washed with 1 mL water, dried over Na2SO4, filtered, stirred over Quadrapure TU resin (Aldrich), concentrated in vacuo, and used without further purification.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([O:21]C)=[O:20])[CH2:15]1>O1CCOCC1.C(#N)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([OH:21])=[O:20])[CH2:15]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(C/C=C/c2cc(F)ccc2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(C/C=C/c4cc(F)ccc4F)C3)c2c1
Yield: 48.6 %

Procedure:
14.2 cm3 of a 5 N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 1.25 g (2.336 mmol) of methyl (±)-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in solution in 25 cm3 of dioxane. After stirring under reflux for 16 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 cm3 of acetonitrile. After stirring for 0.5 hour at a temperature in the region of 0° C., the orange solid in suspension is filtered, rinsed with twice 7 cm3 of acetonitrile and then dissolved in 55 cm3 of water. The aqueous phase is then acidified with 1 N hydrochloric acid to a pH value in the region of 6–7 and then extracted with twice 20 cm3 of dichloromethane. The organic phases are combined, washed with twice 10 cm3 of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.55 g of (±)-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid, in the form of a yellow solid melting at 77° C.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:18]#N)([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.[OH-:21].[K+].C(O)C[OH:25]>O>[C:18]([C:7]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1)([OH:25])=[O:21]
Reactant: COc1ccc(C2(C#N)CCC3(CC2)OCCO3)cc1
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C2(C(=O)O)CCC(=O)CC2)cc1
Yield: 83.1 %

Procedure:
A mixture of 27.98 g. (0.103 mole) of 4-cyano-4-(4-methoxyphenyl)cyclohexanone ethylene ketal (prepared in Example 21) and 28 g. of potassium hydroxide in 280 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer is covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness and the solid remaining is recrystallized from a mixture of methylene chloride and Skellysolve B to give 22.35 g. (83.1% yield) of 4-carboxy-4-(4-methoxyphenyl)cyclohexanone, ethylene ketal, having a melting point of 154° to 155.5°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([OH:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:24](I)([CH3:26])[CH3:25].CC([O-])(C)C.[K+].CCOC(C)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)I
Reactant: Nc1nc(-c2ccccc2)c(-c2ccc(=O)[nH]c2)nc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (283 mg) was dissolved in DMF (10 ml). To the solution were added i-PrI (172 mg) and t-BuOK (114 mg). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=96:4, v/v) to give isopropyl 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate as yellow crystal (64 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([C:28]#[C:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:25]([C:41]([F:44])([F:43])[F:42])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.C(N(CC)CC)C.CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:25]([C:41]([F:44])([F:42])[F:43])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude methyl 2-(2-((2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (I77) in DMF (10 mL) and triethylamine (1 mL) was added 20% Pd(OH)2 (0.92 g) and the resulting suspension was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through celite and the filter cake washed with EtOAc (3×75 mL). The combined filtrates were evaporated to dryness to give a brown solid, which was suspended in MeOH (25 mL) and then sonicated. The resulting suspension was filtered to give the title compound (I78) (211 mg, 29%) as a tan solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.29-7.15 (m, 4H), 6.96-6.78 (m, 3H), 3.76 (s, 2H), 3.64-3.49 (m, 5H), 3.38 (s, 2H), 3.11-3.00 (m, 2H), 3.00-2.91 (m, 2H), 2.68 (t, J=12.0 Hz, 2H), 1.80 (d, J=10.7 Hz, 2H), 1.48 (ddd, J=15.0, 12.2, 3.5 Hz, 2H), 1.39 (s, 9H). LCMS Method C: rt 5.87 min; m/z 614 [M+H]+.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:25][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C(CC=C(C)CCC=C(C)COC1CCCCO1)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 150 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl 2-acetyl-5,9-dimethyl-10-(2-tetrahydropyranyl)oxy-4,8-decadienate (370 mg, 1.05 mmol) in methylsulfoxide (2 ml) were added sodium chloride (180 mg, 3.08 mmol)and water (0.1 ml), and the mixture was stirred at 150° C. After four hours, the reaction mixture was allowed to cool to room temperature, and water (15 ml) was added thereto. The product was extracted with ether (20 m1×2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(2-tetrahydropyranyl)oxy-5,9-undecadien-2-one (70%).
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:6]([Cl:26])=[N:7][C:8]2[C:13]([C:14]=1[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:12][CH:11]=[CH:10][CH:9]=2>C(O)C>[NH2:1][C:2]1[N:15]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([Cl:26])[C:5]=2[N:4]=1
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)c(Cl)nc2ccccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
Cyanogen bromide (4.6 g, 44 mmol) was added to a solution of tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (13.46 g, 39.96 mmol) in ethanol (140 mL), and the reaction was heated at reflux overnight. An analysis by LC/MS indicated the presence of starting material, and additional cyanogen bromide (1.25 g, 12.0 mmol) was added. The reaction was heated at reflux for an additional two hours, and the reaction was still incomplete. Additional cyanogen bromide (1.25 g, 12.0 mmol) was added, and the reaction was heated at reflux for two hours and allowed to cool to room temperature. Most of the solvent was removed under reduced pressure, and aqueous sodium hydroxide (700 mL of 2 N) was added. The mixture was stirred for 30 minutes, and the aqueous portion was decanted away. Ethyl acetate (500 mL) was added, and the mixture was stirred for 20 minutes. The ethyl acetate was then decanted away, and the residue was filtered. The filter cake was washed several times with diethyl ether (1 L total), and the resulting solid was stirred vigorously with diethyl ether (500 mL). The solid was collected by filtration and dried under vacuum overnight to provide 7.02 g of tert-butyl 2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate as a reddish-brown solid.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C[O:14][C:15]([C:17]1[CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH:22]=1)=O>ClCCl>[C:26]([O:25][C:23]([N:19]1[CH2:18][C:17]([C:15](=[O:14])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[Br:5])=[CH:22][CH2:21][CH2:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1Br
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2ccccc2Br)C1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
Trimethylaluminium (2M in heptane, 3 ml) was added dropwise to a solution of 2-bromoaniline (860 mg) in dichloromethane (15 ml). After gas evolution ceased, 5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Chem. Commun. 1999, 1757-1758, 1.2 g) dissolved in dichloromethane (10 ml) was added and the resulting mixture was refluxed for 5 hrs. The solution was cooled to 0° C., quenched by careful addition of saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 85:15) to afford 5-(2-bromo-phenylcarbamoyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g), which was characterised by its mass and NMR spectra.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=O)[CH2:2][C:3](C)=O.Cl.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:1]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)[N:19]=[CH:3][CH:2]=1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1ccnn1-c1ccc(Br)cc1
Yield: 34.9 %

Procedure:
Ethyl acetoacetate (3.49 g, 0.02684 mol) and 4-bromophenylhydrazine hydrochloride (6.00 g, 0.02684 mol) were refluxed in acetic acid (50 mL) for 4 hours. The precipitate was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (7:93) as mobile phase to yield 1-(4-bromophenyl)-1H-5-pyrazolyl ethyl ether (2.63 g, 0.00936 mol) as an off-white solid.
Reaction SMILES: CC1(C)CCC[C@H]1[C:7]1[CH:8]=[C:9](C=[CH:15][C:16]=1O)[C:10]([O:12][CH3:13])=[O:11].[CH3:19][C:20]1(C)CCC[C@@H]1C1C=C(C=CC=1O)C(OC)=O.CC1(C)C(C2C=C(C=CC=2O)C(OC)=O)=CCC1.[CH2:55]1[CH2:59][O:58][CH2:57][CH2:56]1>>[CH:7]1([CH:8]([C:55]2[CH:59]=[CH:20][CH:19]=[C:57]([OH:58])[CH:56]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(O)c([C@H]2CCCC2(C)C)c1
Reactant: COC(=O)c1ccc(O)c([C@@H]2CCCC2(C)C)c1
Reactant: C1CCOC1
Agent: COC(=O)c1ccc(O)c(C2=CCCC2(C)C)c1
Product: COC(=O)CC(c1cccc(O)c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(R)-methyl 3-(2,2-dimethylcyclopentyl)-4-hydroxybenzoate (66.6AA) or (S)-methyl 3-(2,2-dimethylcyclopentyl)-4-hydroxybenzoate (66.6AB). A mixture of Rh(COD)2BF4 (Stern Chemical, 35138-22-8, 137.2 mg, 0.338 mmol) and (R)-1-[(S)-2-(R)-(ditertbutylphosphino)ferrocenyl]ethyl-bis-(3,5-bistrifluoromethylphenyl)phosphine (Solvias, SL-J210-1, 302 mg, 0.3718 mmol) was stirred in THF (300 mL) under N2 for 60 minutes and a dark red solution formed. To the resulting solution was added methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-hydroxybenzoate 66.6H (41.64 g, 168.98 mmol) and TEA (10 mol %, 2.35 mL, 16.9 mmol). The resulting solution was filled with H2 (200 psi) three times and stirred at room temperature/200 psi for 2 hours. The reaction mixture was then passed through a short plug of silica gel, eluting with 1:1 hexane/EtOAc, followed by concentration afforded the desired product as a white solid (98.9A % conversion, 99% yield (41.6 g), 99% ee).