Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH:9]=1>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:11]([C:14](=[O:17])[C:15]([CH3:1])=[CH:16][N:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: -4 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
To a 3-necked, 100 mL round-bottom flask was added DMF (26 mL) which was then cooled to −4° C. To the reaction was slowly added oxalyl chloride (2.8 g, 1.93 mL, 22.1 mmol) dropwise. Once the addition was complete, the reaction was warmed to room temperature. To the above mixture was added 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (1.3 g, 4.42 mmol) in DMF (10 mL). The reaction mixture was heated to 130° C. After 2 hr, HPLC showed a 35:65 product to SM ratio. The reaction was heated overnight at 130° C. HPLC the next day showed a 1:1 mixture of product to SM. The reaction mixture was poured over ice. Once the ice melted, the solids were filtered off. The recovery of solids was low so the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated. The crude (˜900 mg) was purified by flash chromatography (silica gel, 80 g, 0-40% ethyl acetate in hexanes). The starting material of 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (694 mg 53.4%) was recovered as a yellow oil. The desired product 7-chloro-1-(2-chloro-phenyl)-3-methyl-1H-quinolin-4-one (200 mg, 14.9%) of 7-chloro-1-(2-chloro-phenyl)-3-methyl-1H-quinolin-4-one was obtained as a red solid. 1H NMR (DMSO-d6) δ ppm (d, J=8.7 Hz, 1H) 7.97 (d, J=0.6 Hz, 1H) 7.82 (dd, J=7.8, 1.7 Hz, 1H) 7.76 (dd, J=7.5, 2.0 Hz, 1H) 7.56-7.73 (m, 2H) 7.40 (dd, J=8.6, 1.9 Hz, 1H) 6.63 (d, J=1.8 Hz, 1H) 1.98 (s, 3H). MS calcd. for C16H11Cl2NO [(M+H)+] 305.0, obsd. 304.0.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2OS(C(F)(F)F)(=O)=O>C(Cl)(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 1-(3-Phenyl-allyl)-piperidin-4-ylamine (4) (1.01 g,4.65 mmol) and diisopropylethylamine (1.63 mL, 9.3 mmol) in 10 mL CHCl3 was added a solution of compound 3 (1.1 g, 5.6 mmol) in 10 mL CHCl3. The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water and brine and dried with MgSO4. The yellow residue was triturated with a small volume of dichloromethane and filtered. The final product was converted to the HCl salt by addition of 4.0N HCl in dioxane to a suspension of the compound in dichloromethane. The solvent was removed by evaporation and the residue triturated with methanol to give the title compound (780 mg, 39%). 1H NMR (300 MHz, MeOD-d4) δ 1.92-2.22 (2H, m), 2.35-2.45 (2H, bd, J=11.8 Hz), 3.15-3.35 (2H, m), 3.65-3.75 (2H, bd, j=12.3), 3.85-4.0 (1H, m), 3.90-4.00 (2H, d, J=6.9 Hz), 5.46 (1H, s), 6.32-6.43 (1H, p, J=7.7 Hz), 6.92-6.98 (1H, d, J=16.2 Hz), 7.31-7.41 (4H, m), 7.52-7.54 (2H, m), 7.58-7.62 (1H, dd, J=2.0, 8.8 Hz), 8.148 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:23][C:24]2[CH:25]=[C:26]([NH:31][C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[CH:35]=3)=[O:33])[CH:27]=[CH:28][C:29]=2[CH3:30])=[O:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine4-carboxamide to give N-{3-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methylphenyl}-2-morpholinopyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 2.15 (s, 2H), 2.22 (s, 3H), 3.44 (m, 3H), 3.55 (t, 4H), 3.6 (m, 1H), 3.77 (t, 4H), 5.18 (m, 1H), 7.13 (d, 1H), 7.21 (m, 1H), 7.37 (m, 2H), 7.5 (t, 1H), 7.56 (s, 1H), 7.61 (d, 2H), 7.81 (d, 1H), 8.3 (d, 1H), 9.9 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 602.
Reaction SMILES: C([N:8]1[CH2:16][C:15](=[N:17][O:18][CH3:19])[C:10]2([CH2:13][N:12]([CH3:14])[CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][O:18][N:17]=[C:15]1[C:10]2([CH2:11][N:12]([CH3:14])[CH2:13]2)[CH2:9][NH:8][CH2:16]1
Reactant: [H][H]
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C)C2
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C)C2
Yield: 87.9 %

Procedure:
340 mg of 6-benzyl-8-(methoxyimino)-2-methyl-2,6-diazaspiro[3,4]octane was dissolved in 10 ml of methanol and thereto 300 mg of 10% Pd-C was added. The resulting mixture was stirred for 2 hours at 50° C. under the pressure of hydrogen, filtered and concentrated under the reduced pressure to give 195 mg of the titled compound (yield: 85.2%).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(Cl)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (342 mg, 0.87 mmol) is coupled to 1-bromo-4-chlorobenzene (200 mg, 1.05 mmol) using Method B to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[Na].O>C(O)CCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Na]
Solvent: O
Solvent: CCCCO
Product: O=C(O)C1CNc2ccccc21
Yield: 86 %

Procedure:
A stirred suspension of 1H-indole-3-carboxylic acid (20.8 g, 0.129 mol) in 1-butanol (600 cm3) under nitrogen was heated under gentle reflux. Sodium (39.3 g, 1.71 mol) was added in small pieces over 3.5 h. After heating under reflux for a further 1.25 h the mixture was cooled and water (250 cm3) was added carefully. The resulting mixture was concentrated almost to dryness and the residue was acidified by the careful addition of 2M hydrochloric acid (900 cm3) with cooling. The aqueous mixture was washed with dichloromethane (2×300 cm3) and then was neutralised by the addition of 5%, aqueous sodium bicarbonate solution (ca. 450 cm3). The solution was evaporated to dryness under reduced pressure and the solid residue was triturated with dichloromethane-methanol (9:1, 400 cm3 then 3×200 cm3) to dissolve the product. The sodium chloride was filtered off and the filtrate was evaporated to afford a gum (18.1 g), which was dissolved in dichloromethane-methanol (9:1, 200 cm3). This mixture was evaporated to low volume before diethyl ether was added, then the solvent was evaporated to leave a froth. This was triturated with diethyl ether (150 cm3), filtered off and dried at 30° C. under vacuum to give the title compound (15.9 g, 76%): positive ion ESI (M+H)+ 164.5.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7](=[O:24])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][C@@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]1=[O:23])([CH3:5])([CH3:4])[CH3:3].C(OC([NH:35][CH2:36][C:37](O)=[O:38])=O)C1C=CC=CC=1.C(P(=O)(OCC)OCC)#N.Cl.O1CCOCC1>CO.[C].[Pd].C(N(CC)CC)C.CN(C)C=O>[ClH:1].[C:2]([O:6][C:7](=[O:24])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:37](=[O:38])[CH2:36][NH2:35])[C@@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]1=[O:23])([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)CN
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a mixture of 3.7 g of (S)-2-oxopiperazine-1,3-diacetic acid di-t-butyl ester hydrochloride, 3.3 g of N-benzyloxycarbonyl glycine and 10 ml of dimethylformamide were added dropwise, while stirring at 0° C., 3.1 g of diethyl cyanophosphonate then 3.2 g of triethylamine in the course of 10 minutes. The mixture was stirred for one hour at the same temperature then for 3 hours at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate and concentrated to give a crude product. The crude product was dissolved in 30 ml of methanol, to which were added 1 g of 10% palladium-carbon and 1.8 ml of 4N HCl-dioxane solution. The mixture was stirred for one hour at room temperature under hydrogen. The catalyst was removed, and the reaction mixture was concentrated under reduced pressure to afford 2.6 g of the title compound as a colorless oily product. This product was processed with ether to give colorless powder.
Reaction SMILES: C(Br)(Br)(Br)Br.[C:6]([O:10][C:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([OH:24])[C:17]([C:25]2[CH:29]=[CH:28][O:27][C:26]=2[CH2:30]O)=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]2[C:17]([C:25]3[CH:29]=[CH:28][O:27][C:26]=3[CH2:30][O:24]2)=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1O
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OCc1occc1-2
Reaction time: 1 h
Yield: 28.9 %

Procedure:
Carbon tetrabromide (2.66 g) was added to a solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)-benzoate (Intermediate 17, 2.65 g) and triphenyl phosphine (2.1 g) in DCM (40 mL) and the resultant solution was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and DMF (60 mL) and cesium carbonate (5.59 g) were added to the residue. The resultant mixture was stirred for 1 hour, then partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 7-[bis-(tert-butoxycarbonyl)amino]-4H-furo[2,3-c]-chromene-6-carboxylate (0.735 g) as a gum which crystallised on standing.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=3)[C:16](=[S:32])[NH:15][C:14]=2[N:33]=1)(C(C)(C)C)(C)C.[F-].[CH2:35]([N+](CCCC)(CCCC)CCCC)[CH2:36]CC.O>O1CCCC1>[CH2:35]([S:32][C:16]1[N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:24][CH:25]=2)[C:18](=[O:19])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[N:33][C:14]=2[N:15]=1)[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1nc2nc(CO)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (498 mg) was suspended in tetrahydrofuran (15 ml), a tetrahydrofuran solution (1M, 3 ml) of tetrabutylammonium fluoride was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (15 ml), iodoethane (0.24 ml) and 1M aqueous sodium hydrogen carbonate solution (1 ml) were added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1M hydrochloric acid and water, and the precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (373 mg) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]([C:20]2([CH2:35][NH:36]C(=O)OC(C)(C)C)[CH2:25][CH2:24][N:23]([C:26]3[C:27]4[CH:34]=[CH:33][NH:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH2:22][CH2:21]2)=[O:19])[CH3:16])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:36][CH2:35][C:20]1([C:18]([NH:17][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH3:16])=[O:19])[CH2:21][CH2:22][N:23]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:24][CH2:25]1
Reactant: C[C@H](NC(=O)C1(CNC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)C1(CN)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Trifluoroacetic acid (2 mL, 25.96 mmol) was added to (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (Intermediate 13) (0.257 g, 0.5 mmol) in DCM (20 mL) at 25° C. The resulting solution was stirred at 25° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 7N ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford (S)-4-(aminomethyl)-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.095 g, 46.0%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:6][N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.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]>[S:10]1[CH:11]=[CH:12][C:8]([C:7]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([CH:16]=[O:17])=[CH:19][CH:20]=3)=[N:3][C:4]3[N:5]([N:13]=[CH:14][CH:15]=3)[CH:6]=2)=[CH:9]1
Reactant: Clc1nc2ccnn2cc1-c1ccsc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccsc2)cc1
Temperature: 80 °C

Procedure:
To a mixture of 276 mg 5-chloro-6-thiophen-3-yl-pyrazolo[1,5-a]pyrimidine and 228 mg 4-formylphenylboronic acid in 13 ml 1,2-dimethoxyethane are added 1.8 ml of a 10% w/w sodium carbonate solution and 48 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The resulting mixture is heated to 80° C. under an inert gas atmosphere for 7 h. An additional portion of 228 mg 4-formylphenylboronic acid and 48 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) is added and the mixture is heated to 80° C. for 2 h. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and the solvent is evaporated. The solid residue is stirred in diethylether, filtered and dried to yield the desired product.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1.[C:36]([O:47][CH3:48])(=[O:46])[C:37]1[CH:45]=[CH:44][CH:43]=[C:39]([C:40]([O-])=[O:41])[CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:20][CH2:21][N:22]([C:40]([C:39]5[CH:38]=[C:37]([CH:45]=[CH:44][CH:43]=5)[C:36]([O:47][CH3:48])=[O:46])=[O:41])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: Cc1ccccc1C1(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A mixture of 2-methyl-1-(8-{2-[4-(2-methyl phenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole dihydrochloride (0.40 g, 0.84 mmol), monomethyl isophthalate (0.15 g, 0.84 mmol) and triethylamine (0.4 mL, 2.9 mmol) in dimethylformamide (3 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.35 g, 0.92 mmol) and stirred at rt for 1 h. The mixture was diluted with water and the resultant precipitate was collected, washed with water, dried and purified by chromatography on silica gel eluting with 1:33 methanol:dichloromethane to give methyl 3-{[4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl) piperidin-1-yl]carbonyl}benzoate as a glass (0.240 g, 47%). 1H NMR (400 MHz, CDCl3) δ 8.08 (m, 2H), 7.67 (m, 2H), 7.59 (m, 1H), 7.49 (t, 1H), 7.13-7.29 (m, 6H), 4.62 (m, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 3.56 (m, 2H), 3.26 (m, 2H), 2.54 (m, 5H), 2.36 (m, 4H), 1.95 (m, 10H), 1.64 (m, 4H). HRMS C38H44N4O3 m/z 605.3492 (M+H)Cal. 605.3497 (M+H)Obs..
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH2:36][CH3:37])([C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([CH2:33][CH3:34])([OH:32])[CH2:30][CH3:31])=[C:23]([CH3:35])[CH:22]=3)[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:38])=[CH:10][CH:11]=1)C.[OH-].[Na+].P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1>[CH2:19]([C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([CH2:5][C:4]([OH:39])=[O:3])=[CH:11][CH:10]=2)=[C:13]([CH3:38])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([CH2:30][CH3:31])([OH:32])[CH2:33][CH3:34])=[C:23]([CH3:35])[CH:22]=1)[CH2:36][CH3:37])[CH3:20]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)cn3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
[6-(4-{1-Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 81-(1); 24.6 mg, 0.047 mmol) was dissolved in methanol/tetrahydrofuran=1:1 (1 mL). A 1 N sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred at room temperature for one hour. A 30% sodium dihydrogenphosphate aqueous solution (0.3 mL) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (15 mg, 65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[N:9])[CH2:3][CH2:2]1.[OH-].[K+].[NH2:12][C:13]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:14]=1[CH:15]=O>CS(C)=O.O.[NH4+].[Cl-]>[Br:22][C:18]1[CH:17]=[C:14]2[C:13](=[CH:20][C:19]=1[F:21])[N:12]=[C:8]([NH2:9])[C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH:15]2
Reactant: N#CCN1CCOCC1
Reactant: Nc1cc(F)c(Br)cc1C=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc2cc(F)c(Br)cc2cc1N1CCOCC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine.