Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[N:31]1[NH:32][N:33]=[N:34][C:35]=1[C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[N:34]1[NH:33][N:32]=[N:31][C:35]=1[C:36]1[CH:37]=[C:38]([NH:39][C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1
Reactant: Nc1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) in pyridine (10 mL) were added 3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (55.7 mg, 0.243 mmol) and T3P® (EA solvate) (220 mg, 0.346 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The reaction was quenched with ice-water. The mixture was concentrated to give crude product, which was purified by TLC to give N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (75 mg, 0.104 mmol, 42.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.62 (d, J=4.4 Hz, 2H), 8.04 (d, J=1.5 Hz, 1H), 7.94 (s, 1H), 7.61 (dd, J=6.1, 7.8 Hz, 2H), 7.38 (d, J=8.6 Hz, 3H), 6.92-6.85 (m, 3H), 5.35 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 3.77 (s, 2H), 3.38-3.33 (m, 3H), 1.30-1.18 (m, 3H). ES-LCMS m/z 623 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][Li]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([CH3:17])([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: [Li]C
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCCc2nc3ccccc3c(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of dry tetrahydrofuran was suspended 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one at ice temperature and 78 ml (4 eq) of 1.2M CH3Li solution in ether was added thereto at such a rate as to avoid bubbling. The reaction mixture was stirred overnight as it warmed to ambient temperature. The next day 20 ml more of the CH3Li solution was added to drive the reaction to a completion. After 0.5 hour the reaction was quenched with excess water and 4.97 g of the preciptitate was collected and air dried. The product was recrystallized from MeOH/toluene. The yield was 2.06 g (38%) of granules, melting point 250° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C#CCO
Product: OCC#Cc1ccc(-c2ccccc2)cc1

Procedure:
In a manner described in Example 18 above, propargyl alcohol was reacted with 4-bromobiphenyl to give the title compound as white crystals: NMR (CDCl3) δ 4.53 (d, J=4.74, 2H), 7.38 (d, J=7.17, 1H), 7.42-7.60 (m, 8H). MS m/z 208 (M+ calcd. for C15H12O=208.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([OH:23])=O)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:16]1[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)O
Reactant: NCCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)NCCO

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 from (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 33 Step 2) using ethanolamine instead of ammonium chloride.
Reaction SMILES: S(Cl)(Cl)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O:15][C:16]([C:18]1[CH:22]=[C:21]([Cl:23])[S:20][CH:19]=1)=O)C.C(OC(C1C=C(Cl)SC=1Cl)=O)C.ClC1SC=C(C(O)=O)C=1.ClC1SC(Cl)=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O.C(#[N:63])C>C(O)C.O1CCCC1.[OH-].[Na+].C1(C)C=CC=CC=1.CN(C)C=O>[Cl:23][C:21]1[S:20][CH:19]=[C:18]([C:16]([NH2:63])=[O:15])[CH:22]=1
Reactant: CC#N
Reactant: CCOC(=O)c1csc(Cl)c1
Agent: CCOC(=O)c1cc(Cl)sc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(Cl)sc1Cl
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1csc(Cl)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
3-Thiophenecarboxyalic acid ethyl ester (1.98 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.5 ml) was added under ice-cooling. The mixture was stirred at 10° C. for 30 minutes, and then 10% aqueous sodium thiosulfate (100 ml) was added. The resulting mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid ethyl ester and 2,5-dichloro-3-thiophenecarboxylic acid ethyl ester. This mixture was dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (15 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The resulting mixture was stirred at room temperature, and then washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid and 2,5-dichloro-3-thiophenecarboxylic acid (1.7 g). This mixture was suspended in toluene (15 ml), and oxalyl chloride (1.56 ml) was added dropwise. Further, N,N-dimethylformamide (1 drop) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduce pressure, and the concentrate was dissolved in ethyl acetate (10 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (16 ml) and ethyl acetate (70 ml) with stirring under ice- cooling. The resulting mixture was stirred at room temperature for 10 minutes, and the organic layer was collected. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-3-thiophenecarboxamide (0.76 g).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[CH:31]=[N:30]1.FC1C=C(C=CC=1)CN1C2C(=CC(N)=CC=2)C=N1.N1C=CC=CC=1CCl>CC#N.C(Cl)Cl>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([NH:38][C:34]1[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=1)[N:29]([CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[N:30]=[CH:31]3)=[N:3][CH:4]=[N:5]2
Reactant: COCCOCc1ccn2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Agent: ClCc1ccccn1
Agent: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: COCCOCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A suspension of 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (24 mg, 0.099 mmole), NaHCO3 (42 mg, 5 equiv) and 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine (22 mg, 1 equiv, prepared in the same manner as 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine but using 2-picolyl chloride) in dry CH3CN (1 mL) was left stirring at RT for 1 hr. The reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 1% MeOH) afforded the product as and oil (4.8 mg, 11%). 1H NMR (CDCl3) δ 3.26 (s, 3H), 3.76 (m, 4H), 4.90 (s, 2H), 5.75 (s, 2H), 6.56 (d, 1H, J=3 Hz), 6.83 (d, 1H, J=5 Hz), 7.18 (m, 1H), 7.40 (d, 1H, J=5 Hz), 7.49 (d, 1H, J=2 Hz), 7.56 (m, 2H), 7.96 (s, 1H), 8.07 (s, 1H), 8.22 (d, 1H, J=1 Hz), 8.59 (m, 1H), 9.65 (s, 1H); MS: 429 (M+H)+; HPLC Ret Time: 1.30 min (YMC ODS-A C18 S7, 3.0×50 mm, 2 min gradient (starting with 0% solvent B and ending with 70% solvent B), 5 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:23]>>[BrH:23].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CNCC2c1ccc(OC)c(OC)c1
Agent: Br
Product: COc1ccc2c(c1)CNCC2c1ccc(O)c(O)c1

Procedure:
640 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 13 ml of 48% aqueous hydrogen bromide, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and crystals which separated out were collected, affording 580 mg of 7-methoxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12](C)[CH2:11][C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OC(C1C=C(O)C2C=COC=2C=1)=O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:8]2[CH:11]=[CH:12][O:13][C:9]=2[CH:10]=1)=[O:4])[CH3:26]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)c1cc(O)c2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2ccoc2c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (180 mg, 1.03 mmol), Cs2CO3 (630 mg, 1.93 mmol), and 4-hydroxy-benzofuran-6-carboxylic acid ethyl ester (8a) (199 mg, 0.97 mmol). Purification by flash column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow oil (261 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H) 7.91 (s, 2 H) 7.74 (s, 1 H) 7.65 (s, 1 H) 7.13 (s, 2 H) 6.66 (s, 1 H) 4.41 (s, 2 H) 3.08 (s, 3 H) 1.42 (s, 3 H); LCMS for C18H16O6S m/z 383.00 (M+Na)+.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][CH:8]1[CH2:10][CH:9]1[C:11]([OH:13])=[O:12].CN(C=O)C.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1.C1COCC1>[C:1]([Cl:6])(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]([O:13][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:12]
Reactant: OCc1ccccc1
Reactant: CC1CC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2.0 M oxalyl chloride in dichloromethane solution is prepared by adding with stirring 98% oxalyl chloride (110.0 mL) to anhydrous dichloromethane (600.0 mL). The resulting solution of oxalyl chloride (1.20 mol) is added dropwise over 1 h to a stirring solution of 2-methylcyclopropanecarboxylic acid (commercially available product which is a cis-trans mixture, 120.0 g, 1.20 mol) in toluene (800.0 mL) containing DMF (0.6 mL, 7.8 mmol). The mixture is stirred 2 h at room temperature; then it is added dropwise to a solution of benzyl alcohol (114.0 mL, 1.10 mol), anhydrous THF (800.0 mL), and pyridine (194.0 mL, 2.41 mol) over 1.5 h. The mixture is stirred 1 h longer after addition, partitioned between ethyl acetate (2 L) and 10% aqueous potassium carbonate (2 L); and the organic phase is washed (10% aqueous potassium carbonate (2 L) and brine (2 L)), dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with 5% ethyl acetate in hexanes, provides the major product, racemic benzyl trans-2-methyl-cyclopropanecarboxylate as a clear, colorless liquid (193.8 g, 93%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]([NH2:24])=O)[CH:19]=[N:18]2)=[CH:13][CH:12]=1.S(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]#[N:24])[CH:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(N)=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C#N)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide obtained in Example 2-(2) (0.466 g) in N,N-dimethylformamide (5.0 mL), thionyl chloride (1.0 mL) was added dropwise under ice cooling and stirred at 0° C. for 30 minutes. The reaction mixture was adjusted to pH 8 by addition of water and saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1), and the resulting crystal was washed with hexane:diisopropyl ether (1:1) to give the titled compound (0.253 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: CN(C)C1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Dimethylamino-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and dimethyl-piperidin-4-yl-amine. MS calcd. for C29H30ClN5O2 [(M+H)+] 516.2, obsd 516.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)(=O)=O.[C-:20]#[N:21].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu]I.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>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:20]#[N:21])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: Cc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc2cccc(C#N)c2n1
Yield: 98.1 %

Procedure:
To a solution of 2-methylquinolin-8-yl trifluoromethanesulfonate (3.0 g, 10.3 mmol) in acetonitrile (26 mL) was added sodium cyanide (1.0 g, 20.6 mmol). The solution was degassed under nitrogen for 10 minutes, followed by addition of copper (I) iodide (0.20 g, 1.03 mmol) and Pd(PPh3)4 (0.60 g, 0.52 mmol) under nitrogen. The mixture was heated at reflux for 2 hours. After cooling the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40 M; 20% ethyl acetate:hexanes) to afford 2-methylquinoline-8-carbonitrile (1.70 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>>[CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:19][CH:20]([OH:23])[CH2:21][O:22][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCCC2
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCCC2
Yield: 60 %

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl]propane-1,2-diol (9.6 g, 0.031 mol) with tert-butyldimethylsilyl chloride (4.86 g, 0.032 mol) and imidazole (2.51 g, 0.037 mol) generally according to the procedure described for Intermediate 3 afforded 7.93 g (61%) of (±)-1-[1-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf=0.63 (silica, ethyl acetate:hexanes 1:3); 1H NMR (DMSO-d6) δH 7.48 (d, 2H); 7.35 (m, 3H); 7.03 (d, 1H); 6.78 (d, 1H); 4.77 (q, 2H); 4.55 (d, 1H); 3.75 (m, 1H); 3.45 (m, 2H); 2.85 (dd, 1H); 2.69 (m, 4H), 2.51 (dd, 1H); 1.68 (m, 4H); 0.8 (s, 9H); 0.0 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:46](Cl)([CH3:49])(=[O:48])=[O:47]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By reacting tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148 (h)] with mesyl chloride according to a method known from the literature there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [MS: 707 (M+NH4)+ ] as a colourless solid. Further reaction with diethylamine in acetonitrile at 50° C. analogously to Example 34 gave tert-butyl (3RS,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-diethylaminomethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a brown foam; MS: 667 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52](Cl)(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1>C(#N)C>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4cccnc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0297 g, 0.0643 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.386 mmol) and 8-quinolinesulfonyl chloride (0.0440 g, 0.193 mmol) to obtain 4-(8-quinolinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0164 g, yield 39%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CC[C@H](O)C5)c34)cc2C)cn1
Yield: 15 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-3-pyrrolidinol to give the title compound in 15% yield; N Spectrum: 1.50-1.55 (m, 1H), 1.91-1.96 (m, 1H), 2.19 (s, 3H), 2.41-2.44 (m, 1H), 2.44 (s, 3H), 2.55 (dd, 1H), 2.68 (dd, 1H), 2.82-2.90 (m, 3H), 4.17 (br s, 1H), 4.41 (t, 2H), 4.70 (br s, 1H), 6.95 (d, 1H), 7.17-7.25 (m, 2H), 7.62-7.65 (m, 2H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([O:20]C(=O)C(C)(C)C)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C1(C)C=CC=CC=1>CCOC(C)=O>[N:32]1([CH2:2][C:3]2[C:8]3[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[N:10][O:11][C:7]=3[C:6]([OH:20])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: CCOC(=O)c1nc(CBr)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Reactant: c1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Cn2cccn2)c2c(-c3ccc(OC)cc3)noc2c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
Ethyl 4-(bromomethyl)-3-(4-methoxyphenyl)-7-(pivaloyloxy)isoxazolo[4,5-c]pyridine-6-carboxylate (34 mg, 0.069 mmol) and pyrazole (9.4 mg, 0.138 mmol) were added to 1 mL of toluene, and the mixture was stirred at room temperature for 48 h. An additional equiv. of pyrazole was added, and the mixture was stirred at room temperature for 16 h and then at 45° C. for 16 h. The mixture was diluted with EtOAc (20 mL) and washed with 1M hydrochloric acid. The organic layer was dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 19 mg of the title compound. MS: (+) m/z 395.29 (M+1).