Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Reactant: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of (E,E)-farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: B.O1CCCC1.[C:7]1([CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[OH-].[Na+]>>[NH2:23][CH2:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][CH:14]([CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16]1
Reactant: N#CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in THF, 5.5 ml, 5.5 mmol, 3.5 equiv) was added under argon to neat 3-(4-diphenylmethylpiperidin-1-yl)propionitrile (480 mg, 1.58 mmol, 1.00 equiv). The mixture was stirred at reflux for 5 hours and then cooled to 0° C. Aqueous HCl (6N, 6 mL) was added cautiously, and stirring was continued at room temperature overnight, then at 42° C. for 1.5 hours. The solution was basified to pH 10-11 by addition of 6N aqueous NaOH and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3 -MeOH-NH3 (2.0M in MeOH) to give 420 mg (86%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.N#N.[Li]CCCC.[CH:27]([C:29]1[N:30]=[C:31]2[C:36]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:35][CH:34]=[N:33][N:32]2[C:43]=1[C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=O>C1COCC1>[O:40]1[CH2:39][CH2:38][N:37]([C:36]2[C:31]3[N:32]([C:43]([C:44]4[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=4)=[C:29](/[CH:27]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:30]=3)[N:33]=[CH:34][CH:35]=2)[CH2:42][CH2:41]1
Reactant: COC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CCOP(=O)(Cc1ccc2c(n1)CCCC2)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C

Procedure:
A solution of compound 58b (0.70 g, 2.5 mmol) in THF (15 mL) was purged with N2. n-BuLi (2.5 M in hexane, 1.1 mL, 2.8 mmol) was added dropwise with stirring at rt and allowed to stir for 1 h. To the mixture was added compound 58c (0.70 g, 1.9 mmol). The resulting mixture was stirred overnight at rt, and quenched with saturated NH4Cl solution (100 mL). The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 58d as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H29N5O3: 496.2 (M+H). Found: 496.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].N.[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Temperature: 24 °C
Reaction time: 26 h

Procedure:
Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (396.6 g, 1.37 mol) and ethanol (4 L), and concentrated aqueous ammonia (530 mL), in a two gallon autoclave. Add Raney nickel (410 g). Heat to 24° C. and charge with 205 psi of hydrogen. After 26 hours, vent the reactor and purge with nitrogen. Filter the reaction mixture through a celite pad and rinse the solids with ethanol (1.5 L). Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C(OC)(OC)OC.O=[C:40]1[CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH:42]1[CH2:43][CH:40]([N:11]2[CH2:10][CH2:9][CH:8]([C:7]3[C:2]([Cl:1])=[C:3]([NH:16][C:17]4[N:22]=[C:21]([NH:23][CH:24]5[CH2:25][CH2:26]5)[C:20]5=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]5[N:18]=4)[CH:4]=[C:5]([C:14]#[N:15])[CH:6]=3)[CH2:13][CH2:12]2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CNC3)CC2)c1
Reaction time: 0.02 h

Procedure:
To a suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 208) (60 mg, 0.138 mmol) in a mixture solvent of methanol (0.7 ml)/CH2CL2 (0.7 ml) was added trimethyl orthoformate (0.7 mL, 6.33 mmol), (The suspension converted to a clear solution within 1 min.), tert-butyl 3-oxoazetidine-1-carboxylate (237 mg, 1.383 mmol), and acetic acid (0.032 mL, 0.553 mmol). The mixture was stirred at Rt for 40 min and then sodium cyanoborohydride (87 mg, 1.383 mmol) was added and stirred at RT for overnight. The reaction mixture was partitioned between EtOAc and diluted aq. NaHCO3, The aqueous layer was extracted with EtOAc, the combined organic layer was washed with brine and concentrated. The crude intermediate was purified by prep HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml permin, 20-100% B, over 20 min). The HPLC fractions containing the intermediate were applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 46 mg intermediate as a white solid which was dissolved in DCM (2 ml) and TFA (1 ml) was added. The resulting mixture was stirred at RT for 0.5 hour. Removal of the solvent and the residue was taken in MeOH/DCM and applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left the product (39 mg) as a white solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8]4[CH2:18][CH2:17][C:16](=[O:19])[C:9]=4[CH:10]=[CH:11][C:12]=3[NH:13][C:14]=2[CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)([CH3:26])=[O:25]>ClCCl>[C:24]([C:4]1[C:3]([O:2][CH3:1])=[CH:15][C:14]2[NH:13][C:12]3[CH:11]=[CH:10][C:9]4[C:16](=[O:19])[CH2:17][CH2:18][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:25])[CH3:26]
Reactant: COc1ccc2c(c1)[nH]c1ccc3c(c12)CCC3=O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2[nH]c3ccc4c(c3c2cc1C(C)=O)CCC4=O
Temperature: 0 °C
Yield: 80 %

Procedure:
8-Methoxy-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one (82) (27.8 g, 110.8 mmol, 1 eq) was dissolved in dry dichloromethane (300 mL). Anhydrous AlCl3 (29.5 g, 221.5 mmol, 2 eq) was added in portions with stirring and cooling, followed by the dropwise addition of AcCl (24 mL, 332.4 mmol, 3 eq). The reaction mixture was stirred at about 5° C. for 24 h and poured into ice water (violent foaming should be avoided). The precipitated orange solid was filtered off, washed with water (10×100 mL), CH2Cl2 (3×50 mL), acetone (3×50 mL) to give 26 g (80%) of 9-acetyl-8-methoxy-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one (83).
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH3:15])[CH:5]=1.[CH2:16]([NH:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([NH:23][S:24]([C:27]1[CH:28]=[C:29]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[CH:5]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1cc(Br)c2ccccc2c1=O
Reactant: COc1ccc(B(O)O)cc1S(=O)(=O)NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: COc1ccc(-c2cn(C)c(=O)c3ccccc23)cc1S(=O)(=O)NCc1ccccc1
Reaction time: 0.05 h
Yield: 58.3 %

Procedure:
For about 3 min, N2 was bubbled through the mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (56 mg, 0.24 mmol), [3-(benzylsulfamoyl)-4-methoxyphenyl]boronic acid (83 mg, 0.26 mmol), aqueous 2M Na2CO3 (0.375 mL) and Pd(dppf)Cl2 (9 mg, 0.001 mmol) in dioxane (1.5 mL) which was then microwaved at 120° C. for 1 h and then filtered through a plug of anhydrous Na2SO4 using ethyl acetate to transfer and rinse. Silica gel chromatography, eluting with 0-60% EA in hexane over 6 min and continuing 60% isocratic EA gave the title compound (60 mg, 0.14 mmol) as a white solid in 58% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.57 (s, 3 H), 3.89 (s, 3H), 4.11 (d, J=6.32 Hz, 2H), 7.16-7.23 (m, 6H), 7.34 (d, J=8.08 Hz, 1H), 7.47 (s, 1H), 7.53-7.59 (m, 2H), 7.65 (d, J=2.27 Hz, 1H), 7.72-7.77 (m, 1H), 7.94 (t, J=6.32 Hz, 1H), 8.34 (d, J=7.33 Hz, 1H). LCMS (M+H)+ 435.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].COC1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:3]=[C:4]([O:29][CH3:30])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:28])=[CH:6][C:7]=2[F:8])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
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: COC1CCCC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(F)c(Cl)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.310 g, 0.627 mmol). (3-chloro-4-fluorophenyl)boronic acid (0.175 g, 1.003 mmol), Pd(Ph3P)4 (0.072 g, 0.063 mmol). The vial was sealed with a septum cap and flushed with Ar (g), then CPME (3.14 ml) and sodium carbonate 1.9 M (0.990 ml, 1.881 mmol) were added via syringe. The mixture was heated to 100° C. for 1 h and then partitioned between water (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (2×20 mL) and all the organic layers were combined, dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (40 g) using 90:10 Heptane: EtOAc to 100% EtOAc gradient to afford racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.325 g, 0.598 mmol, 95% yield) as a light-yellow film. Racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC using a Regis Whelk-0 (s,$) column and 50% MeOH in CO2. Peak 1 was (P)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and peak 2 was (M)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.49-11.82 (br s, 1H), 8.71 (d, J=1.55 Hz, 1H), 8.37 (d, J=1.87 Hz, 1H), 8.17-8.28 (m, 1H), 7.94 (d, J=5.88 Hz, 1H), 7.86 (dd, J=1.98, 8.92
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.S(=O)(=O)(O)O.[C:20]1(C)[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1CCl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Yield: 89 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 390 parts of benzene is added to a mixture of 135 parts of 85% strength by weight phosphoric acid, 270 parts of 85% strength by weight sulfuric acid and 10 parts of p-toluenesulfonic acid at from 75° to 80° C, whilst stirring thoroughly. After a further 4 hours at from 75° to 80° C the organic phase is separated off and 81 parts (89% of theory) of o-benzyltoluene (nD25 : 1.5739) are isolated by distillation at from 98° to 100° C at 0.2 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-])=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Solvent: ClCCl
Product: Clc1nccc2c(Br)cccc12

Procedure:
To a solution of 5-bromoisoquinoline-N-oxide (4.56 g, 20.4 mmol) in 100 mL CH2Cl2, phosphorus oxychloride (4.17 ml, 44.8 mmol) was added and the mixture heated at 45 C for 4 h. The mixture was allowed to cool and evaporated. Water and ice were added alternating, portion-wise and CH2Cl2 was added to the mixture. The organic layer was made pH 14 with 1 M NaOH, and the organic layer washed with sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The solid was triturated with methanol and the title compound collected as a fluffy off-white solid (3.93 g). MS (ESI pos. ion) m/z: 242 (MH+). Calc'd exact mass for C9H5BrClN: 242.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:20]2)=[C:10]([F:31])[CH:9]=1)C>O1CCOCC1>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([OH:32])=[O:6])=[CH:9][C:10]=2[F:31])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(OCCCCN2CCN(CCC(C)(C)C)CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)CCN1CCN(CCCCOc2ccc(C(=O)O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Sodium hydroxide (0.5 g, 13.2 mmol) and water (5 ml) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid ethyl ester from Example E72.2 (1.35 g, 3.3 mmol) in dioxan (20 ml). The mixture was stirred for 1 h at room temperature then heated at 60° C. for 20 h. Solvents were concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% chloroform) to yield the title compound (0.85 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:19](N(CC)CC)[CH3:20].BrCC>C(#N)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CCN(CC)CC
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Solvent: CCBr
Solvent: CC#N
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme VI, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as herein defined above) is esterified by reaction with a compound of formula R5-Br (where R5 is as herein defined) to provide the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate of compound (2). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (2). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH2:9]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:9]
Reactant: N#Cc1ccccn1
Reactant: O
Product: NC(=O)c1ccccn1
Reaction time: 3 h
Yield: 82 %

Procedure:
261/2 Grams (0.205 moles) of 2-cyanopyridine, 35 grams of Dowex 1-X8 anion exchange resin (OH- form) and 175 ml. water are placed in a reaction flask fitted with a reflux condenser and magnetic stirrer. After stirring briefly to dissolve the nitrile, the mixture is heated to reflux. After 3 hours and 15 minutes, the resin is filtered off and washed with 100 ml. of boiling water. The combined filtrates are evaporated under reduced pressure, and the resulting solid dried under vacuum at 80°C. An amount of 25.6 grams of picolinamide is obtained, corresponding to an 82% yield based on 2-cyanopyridine. A small amount recrystallized from benzenehexane melts at 107.0°-108.5°C.
Reaction SMILES: C(N(CC)CC)C.[Si]([C:15]#[C:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2(O)[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[F:31])(C(C)(C)C)(C)C.CS(Cl)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.O>[C:16]([C:17]1[C:18]([F:31])=[CH:19][C:20]([C:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH:24]=2)=[CH:21][N:22]=1)#[CH:15]
Reactant: CC1CCC(O)(c2cnc(C#C[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.28 mL (2.00 mmol) of triethylamine was added to a solution of 348 mg (1.00 mmol) of 1-{6-[(tert-butyldimethylsilanyl)ethynyl]-5-fluoropyridin-3-yl}-4-methylcyclohexanol in 15 mL of DCM and then 0.15 mL (2.00 mmol) of methanesulfonic acid chloride was added dropwise while the mixture was cooled. The reaction was stirred for 2 hours at RT and then a further 0.15 mL (2.00 mmol) of methanesulfonic acid chloride were added and the mixture was stirred for 1 hour at RT. A further 0.58 mL (4.00 mmol) of triethylamine was added and the mixture was stirred for 1 hour at RT. The reaction mixture was combined with 50 mL of ice water. The organic phase was separated off, washed with water, and the solvent was removed in vacuo. The residue was dissolved in 25 mL of DCM and combined with 315 mg (1.00 mmol) of TBAF. The solution was stirred for 30 minutes at RT and then combined with water. The organic phase was separated off, washed several times with water, dried over magnesium sulfate, and the solvent was eliminated in vacuo. Yield: 130 mg (45% of theoretical; 75% content of product); C14H14FN (M=215.266); calc.: molpeak (M+H)+:216; found: molpeak (M+H)+:216.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][CH3:49])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][CH3:49])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: CNCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: Cl
Solvent: CO
Product: CNCCN1CCCc2ccc(CO[C@H]3CNCC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-[2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-methyl-amine as a yellow oil; MS: 574 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:34][CH:35]=1)=[O:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:31]=[C:30]([CH:28]=[O:29])[CH:35]=[N:34][CH:33]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(C=O)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 5-formylpyridine-3-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 241. NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m),7.38 (1H, s), 9.18 (2H, m), 9.37 (1H, s), 10.25 (1H, s). MS (ESI+): MH+ 503.17 (100%)