Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(CC(OC)=O)#N.C(Br)C(C1C=CC=CC=1)=O.[O-]S(C(F)(F)[F:39])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>C(#N)C>[Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([F:39])[C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Agent: COC(=O)CC#N
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(Cl)[nH]c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=O)[CH2:11]Cl.[BH4-].[Na+]>O1CCOCC1>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[NH:1][CH:11]=[CH:10]2
Reactant: Nc1cc(F)c(Cl)cc1C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1cc2[nH]ccc2cc1Cl
Yield: 52.5 %

Procedure:
382 mg (1.72 mmol) of 1-(2-amino-5-chloro-4-fluoro-phenyl)-2-chloro-ethanone as a 3:1 mixture of regioisomers were dissolved in 9.5 ml 90% aqueous dioxane and 72 mg (1.89 mmol) of sodium borohydride were added in portions. The reaction mixture was heated to reflux for 1 h, additional 72 mg (1.89 mmol) of sodium borohydride were added and the reaction mixture was heated to reflux over night. The solvent was evaporated, the residue dissolved in DCM. The organic layer was washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (25 g silica gel; heptane/DCM 4:1) to yield 153 mg (52%) 5-chloro-6-fluoro-1H-indole as light yellow crystals as a 3:1 mixture of regioisomers (predominantly the wanted one). 1H NMR (CDCl3, 300 MHz): δ 8.16 (br, 1H), 7.62 (d, 1H), 7.20 (s, 1H), 7.13 (d, 1H), 6.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28](=[NH:31])[NH:29][NH2:30])=[N:19]1>C(O)C>[F:14][C:15]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28]2[N:29]=[N:30][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:31]=2)=[N:19]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: Cc1ncc2c(C(=N)NN)nn(Cc3cccc(F)c3F)c2n1
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3nc(C)ncc23)nc1O
Yield: 27 %

Procedure:
374 mg (1.985 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 8 ml of ethanol and heated to reflux. Subsequently, 420 mg (1.324 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 8 ml of ethanol were added and the mixture was heated to reflux overnight. Another 299 mg (1.588 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate dissolved in 3 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered and purified directly by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→100:0). 163 mg of the target compound were obtained (purity 89%; 24% of theory).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]([CH:22]1[CH:26]([C@H:27]([CH3:30])[CH2:28]I)[CH2:25][N:24]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:23]1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:18][O:19][C:20]([C@:22]12[CH2:28][CH:27]([CH3:30])[CH:26]1[CH2:25][N:24]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23]2)=[O:21]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A 0.5 M solution of potassium hexamethyldisilazide in toluene (33 mL, 16.5 mmol) was added dropwise to a solution of 4-[(S)-2-iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (6.4 g, 14.8 mmol) in anhydrous tetrahydrofuran (100 mL) in an argon atmosphere at −78° C. After completion of dropwise addition, the mixture was stirred at the same temperature for 30 minutes. An ammonium chloride solution was added, and the mixture was heated to room temperature. After extraction with ethyl acetate, drying over magnesium sulfate, and filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to give 3.5 g (78%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CS(O[CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[N:17]([CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: COc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccn(CCN=[N+]=[N-])c1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
3-methoxypyridine-2-one (0.40 g, 3.20 mmol), 156a (0.79 g, 4.80 mmol), and K2CO3 (1.32 g, 9.60 mmol) stirred overnight in THF at reflux temperature. Reaction mixture was cooled down to room temperature. Reaction mixture was partitioned between CH2Cl2 (60 mL) and water (50 mL). Organic layer washed with water (2×35 mL), brine (1×30 mL). Organic layer dried on Na2SO4 and evaporated in vacuo. Crude product was purified by flash chromatography with stepwise gradient of CH2Cl2 and acetone (max 15%) to give 0.34 mg of 157a (55%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.77 (dd, J=6.9, 1.6 Hz, 1H), 6.48 (dd, J=7.5, 1.6 Hz, 1H), 5.96 (m, 1H), 3.91 (m, 2H), 3.62 (s, 3H), 3.52 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.39, 149.41, 128.61, 112.16, 104.37, 55.36, 49.00, 48.91. HRMS (EI) calcd for C8H10N4O2 [M]+ 194.0804. found 194.0816.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].C(=O)([O-])O.[Na+].[I-].[Na+].Cl[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>CN1CCCC1=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: OCCCCCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 88.8 %

Procedure:
357.70 g (1.686 Mol) of 3,5-dinitrobenzoic acid are suspended in 750 ml of 1-methyl-2-pyrrolidone. The suspension is stirred up to 50° C. 386.36 g (4.599 Mol) of sodium hydrogen carbonate are added and the mixture was heated up to 90° C. 22.50 g (0.150 Mol) of sodium iodide and 204.0 ml (1.533 Mol) of 6-chlorohexanol are added to the reaction mixture which is heated to 100° C. for 1 h. After 1 h of reaction, the reaction is complete and the orange suspension is thrown on 2 l of ice and 1 l of water. The product is filtrated, washed water and dried at 50° C. under vacuum for 24 h to give 425.0 g (91%) of 6-hydroxyhexyl 3,5-dinitrobenzoate as a rose powder.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 32 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and acetyl chloride as starting material, 17.5 mg (32%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 7.95 (2H), 7.92 (s, 1H), 7.48 (d, 1H), 7.43-7.36 (m, 5H), 6.56 (s, 1H), 5.60 (s, 2H), 4.75-4.69 (m, 1H), 4.47 (s, 2H), 3.98-3.92 (m, 1H), 3.54-3.46 (m, 1H), 3.31-3.28 (m, 1H), 2.80-2.72 (m, 1H), 2.24-2.20 (m, 2H), 2.10 (s, 3H), 1.75-1.64 (m, 2H); LC-MS m/z [M+H]+ 483.2, RT 3.02 min.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43]([OH:45])=O)=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:46][CH:47]([S:49]([NH2:52])(=[O:51])=[O:50])[CH3:48].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43](=[O:45])[NH:52][S:49]([CH:47]([CH3:48])[CH3:46])(=[O:51])=[O:50])=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: CC(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
1,1′-Carbonyldiimidazole (262 mg, 1.62 mmol) was added to a slurry of 13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (603 mg, 1.36 mmol) in THF (3 mL). The reaction mixture was heated at 60° C. for 1.5 h, cooled to rt, treated with propane-2-sulfonamide (200 mg, 1.62 mmol), stirred 10 min and then treated with the dropwise addition of a solution of DBU (0.27 mL, 1.8 mmol) in THF (0.75 mL). The reaction mixture was stirred at rt overnight, diluted with EtOAc (15 mL) and washed with H2O (˜5 mL), 1N HCl (aq.) (2×10 mL) and brine (˜5 mL). The combined aqueous layers were extracted with EtOAc (15 mL) and the organic layer was washed with 1N HCl (aq.) (˜10 mL). The combined organic layers were washed with brine (˜5 mL), dried (MgSO4), filtered and concentrated. The residue was stirred with Et2O (˜15 mL) for 2 h and the solids were collected by filtration, rinsed with Et2O and dried to yield methyl 13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (640 mg, 1.2 mmol, 85%) as a bright yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.12-2.13 (m, 10H), 1.47 (d, J=7.0 Hz, 6H), 2.73-2.86 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 4.06-4.26 (m, 1H), 4.09 (septet, J=7.0 Hz, 1H), 5.51-5.71 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.4, 2.6 Hz, 1H), 7.44 (dd, J=8.4, 1.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H), 8.57 (s, 1H). LCMS: m/e 551 (M+H)+, ret time 3.87 min, column B, 4 minute gradient.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[H-].[Na+].CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([C:4]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C(=O)N3CCOCC3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 16 h

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3- (2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (30 mg) in THF (1 mL) at RT was added 0.25 mL of morpholine and NaH (20 mg of an 80% dispersion). After stirring for 16 hours, 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 75/25/1 CH2Cl2 /MeOH/NH4OH) gave 10 mg of a solid. 1H NMR (300 MHz, CD3OD) δ 7.62-7.52 (m, 2 H), 7.50-7.42 (m, 2H), 7.40 (s, 1H), 7.06 (s, 4H), 5.52 (s, 2H), 3.82-3.72 (m, 4H), 3.58-3.46 (m, 4H), 2.94 (q, 2H, J=7.5 Hz), 2.69 (s, 3H),1.30 (t, 3H, J=7.5 Hz)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In a nitrogen atmosphere, 20.00 g of 4-propylbromobenzene, 0.58 g of tetrakis-triphenylphosphine palladium, and 55 mL of an aqueous potassium carbonate solution (2 mol/L) were dissolved in 100 mL of ethanol, and the resultant solution was heated to 60° C. Then, a solution prepared by suspending 15.27 g of 4-methoxyphenylboronic acid in 60 mL of ethanol was added dropwise to the solution. After stirring at 60° C. for 2 hours, the mixture was allowed to cool to room temperature, and toluene was added to separate the mixture into layers. An aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with an organic layer. The resultant mixture was washed with saturated brine and dried by adding sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethanol to yield 21.60 g of 4-(4-propylphenyl)anisole.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[N:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].BrC1N=CC(N2CCN([CH:46]3[CH2:49][O:48][CH2:47]3)CC2)=CC=1>>[O:48]1[CH2:49][CH:46]([N:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:10]=[N:11][C:6]([Sn:5]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)[CH2:17][CH2:16]2)[CH2:47]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reactant: Brc1ccc(N2CCN(C3COC3)CC2)cn1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C3COC3)CC2)cn1

Procedure:
Following the procedure described for intermediate 7.14, starting from 1-(6-bromopyridin-3-yl)-4-(oxetan-3-yl)piperazine (1.78 g, 5.97 mmol), 1.78 g of 1-(oxetan-3-yl)-4-(6-(tributylstannyl)pyridin-3-yl)piperazine 7.16 was obtained. LCMS [M+H]+: 510.07.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 72 h
Yield: 67 %

Procedure:
Dibenzylamine (4.1 ml, 21.24 mmol, 1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (6.5 g, 21.24 mmol, 1 eq) and triethylamine (3.2 ml, 23.36 mmol, 1.1 eq) in toluene (100 ml), and refluxing was carried out for 72 h. Then the reaction solution was concentrated and the residue was taken up in dichloromethane (300 ml), washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% ethyl acetate in hexane), a yellow solid was obtained. Yield: 67% (5.8 g, 14.21 mmol).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][S:22]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)(=[O:24])=[O:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:18][P:16]([CH3:19])([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]5[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:28][CH2:29]5)[CH:34]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CS(=O)(=O)CCN1CCC(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CP(C)(=O)c1ccc(-c2cccn3nc(Nc4cccc(C5CCN(CCS(C)(=O)=O)CC5)c4)nc23)cc1

Procedure:
203 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-{3-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (75.0 mg, 0.245 mmol) and 3-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenylamine (78.0 mg, 0.276 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (21.0 mg, 0.0384 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as an off-white solid (0.078 g, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([C:39]3[CH:40]=[CH:41][S:37][CH:38]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(Cc1c[nH]c2c(-c3ccsc3)cccc12)NC(=O)OC(C)(C)C
Yield: 68.6 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (340 mg, 0.779 mmol) in dimethylformamide (5 mL) is added triethylamine (0.14 mL, 1.01 mmol), tetrakis(triphenylphosphine)-palladium (36 mg, 0.0312 mmol) and 3-thiopheneboronic acid (130 mg, 1.01 mmol). The mixture is refluxed for 22 hours, then cooled and diluted with brine and ethyl acetate. The organic phase is washed 7 times with brine. The organics are dried over anhydrous sodium sulfate, filtered and then evaporated in vacuo. The residue is purified using silica gel chromatography (hexane/20% ethyl acetate, hexane gradient elution) to give 198 mg of [1,1-dimethyl-2-(7-thiophen-3-yl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (69%). FDMS m/e=371 (M++1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12.CO>C(Cl)Cl.CO>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1ncnc2[nH]ncc12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: ClCCl
Solvent: CO
Product: OC(CNCCNc1ncnc2[nH]ncc12)COc1ccccc1
Reaction time: 5 h
Yield: 55 %

Procedure:
3.2 g. Phenyl glycidyl ether and 5.9 g. 4-(2-aminoethylamino)-pyrazolo[3,4-d]pyrimidine are stirred in 100 ml. methanol for 24 hours at ambient temperature and then for 5 hours at 80° C. Solid material (0.8 g.) is then filtered off with suction, the filtrate is evaporated and the yellowish oil obtained is dissolved in methylene chloride-methanol (9:1 v/v) and purified chromatographically in the manner described in Example 50. There is obtained 1.8 g. (26% of theory) of the desired product in the form of colorless crystals; m.p. 142°-144° C., after recrystallization from ethanol.