Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>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].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][CH:42]=[N:43]6)=[CH:38][CH:37]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 100 °C
Yield: 91 %

Procedure:
Argon was bubbled through a suspension of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetamide (4.61 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (5.76 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.138 mmol), and 2.0 M aqueous potassium carbonate (18.44 mmol) in 1,4-dioxane (36.9 mL) for 10 minutes then the reaction was heated at 100° C. for 2 hours. The reaction was cooled, treated with silica powder (˜10 g) then evaporated under reduced pressure to dryness. Purification of the residue on silica gel by flash chromatography (ethyl acetate, then 10% methanol/ethyl acetate) followed by combination of the product fractions and concentration to a residue that was taken into dichloromethane, filtered through celite, and concentrated in vacuo afforded the title product racemate (2.27 g, 91% yield) as a light tan solid. MS(ES)+ m/e 489.5 [M+H]+. Chiral resolution of the racemate by chiral HPLC (Chromegachiral CC4, methanol) gave the title product as a light yellow foam (1.0 g, 45%). This solid was triturated with hot 3,3-dimethyl-2-butanone (10 mL) with ultrasonification for 5 minutes. The suspension was cooled to room temperature and the solids were filtered then vacuum dried to afford the title compound as an off white solid in 100% ee (770 mg, 34%). MS(ES)+ m/e 489.4 [M+H]+. αD=+43 deg (c=0.2, methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:24][CH:23]=1)[CH3:28]
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and diethylamine there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid diethylamide of melting point 111°-112° C.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[N+:20]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-:22])=[O:21]
Reactant: NCCCCCNC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Yield: 84.3 %

Procedure:
Triethylamine (1 eq.) was added to a suspension of 4-chloro-3-nitroquinoline hydrochloride (13 g, 53 mmol) in chloroform. A suspension of N-(5-aminopentyl)benzamide (11 g, 53 mmol) in chloroform was added and the reaction mixture was heated to reflux. Progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under vacuum. The residue was diluted with toluene, heated to reflux and then filtered while still hot. The filtrate was allowed to cool. The resulting precipitate was isolated by filtration to provide 16.9 g of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide as a yellow solid, m.p. 130-132° C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 9.02 (broad s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.43 (t, J=6.0 Hz, 1H), 7.89 (dd, J=8.0, 1.2 Hz, 1H), 7.83 (dt, J=8.0, 1.2 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.57 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.63 (q, J=6.0 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.55 (quintet, J=7.0 Hz, 2H), 1.39 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K]>CN(C)C=O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[C:11]([NH:13][C:14]2[CH:32]=[CH:31][C:17]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.00 g), potassium phthalimide (2.02 g) and dimethylformamide (100 ml) is stirred at 100° C. for 5 hours. The reaction mixture is filtered and the filtrate is distilled off. The resulting residue is extracted with ethyl acetate and the organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-phthalimidohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.06 g) as white powder, m.p. 145°-146.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[O:17])=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>FC(F)(F)C(O)=O>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([NH:15][C:13]2[S:14][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:33])[F:32])[CH:5]=3)=[CH:11][N:12]=2)=[O:17])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)Nc2ncc(-c3cccc(OC(F)(F)F)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)Nc2ncc(-c3cccc(OC(F)(F)F)c3)s2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 1-[({-5-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}amino)carbonyl]-4-piperidinylcarbamate 19-14 (0.016 g, 0.033 mmol) was dissolved in trifluoroacetic acid and stirred at room temperature until deblocking was complete. The trifluoroacetic acid was then removed under reduced pressure and the titled product 19-15 was isolated via lyophilization. Hi-Res MS: calc: 387.1097 found: 387.1092. 1H-NMR (DMSO): 7.94 ppm (s, 1H); 7.56 ppm (m, 3H); 7.26 ppm (d, 1H); 4.23 ppm (s, 2H); 3.27 ppm (s, 1H); 2.92 ppm (t, 2H); 1.91 ppm (d, 2H); 1.41 ppm (q, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[N:3]1.[Li+].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.IC.O>C1COCC1>[CH3:14][CH:9]1[CH2:10][CH2:11][N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc(N2CCCC2=O)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCN(c2ccn(C)n2)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (1.5 g) in THF (60 mL) was added 1.3 M LHMDS THF solution (7.3 mL) at −78° C., and the mixture was stirred at −78° C. for 1 hr. Iodomethane (0.60 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (927 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([C:34]([O:36][CH3:37])=[O:35])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)Cl
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nccc(N(C(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)OC)c1Cl
Temperature: 25 °C
Yield: 28.3 %

Procedure:
0.87 g (2.0 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of tetrahydrofuran, and the solution was stirred at room temperature. Then, 0.058 g (2.4 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 2 ml of a tetrahydrofuran solution containing 0.38 g (4.0 mmol) of methyl chloroformate was dropwise added thereto at a temperature of from -5° to 0° C, and the mixture was stirred for 30 minutes at a temperature of from -5° to 0° C. and for 12 hours at room temperature. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then purified by high performance liquid chromatography to obtain 0.28 g of the desired product as a white powder (melting point: 62° to 64° C.)
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[C:29]([F:32])([F:31])[F:30])[C:21]3=[O:33])[CH2:16][CH2:17][S:18][CH3:19])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:29]([F:32])([F:30])[F:31])[C:21]2=[O:33])[CH2:16][CH2:17][S:18][CH3:19])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CSCC[C@@H](C(=O)Nc1cnc([C@H]2COC(C)(C)O2)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: CSCC[C@@H](C(=O)Nc1cnc([C@H](O)CO)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of (S)—N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide (26 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was treated with a 1N aqueous hydrochloric acid solution (1 mL) and stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove the tetrahydrofuran and the remaining material was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo to afford (S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide (20 mg, 85%) as a pale yellow gum: HR-ES(+) m/e calcd for C20H21N4O4SF3 [M+H]+ 471.1309, observed 471.1306; 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.16 (s, 1H), 8.44 (d, J=1.28 Hz, 1H), 8.02 (t, J=7.46 Hz, 2H), 7.71-7.81 (m, 1H), 5.55 (d, J=4.90 Hz, 1H), 5.18 (dd, J=5.01, 9.48 Hz, 1H), 4.93-5.02 (m, 1H), 4.77-4.87 (m, 1H), 4.72 (t, J=5.86 Hz, 1H), 4.58-4.66 (m, 1H), 3.61-3.71 (m, 1H), 3.55 (td, J=5.86, 11.29 Hz, 1H), 2.48-2.65 (m, 3H), 2.22-2.38 (m, 1H), 2.09 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=[O:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]2[CH2:20][O:19]2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Oc1ccc(Br)c(F)c1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1c(Br)ccc(OCC2CO2)c1F
Yield: 71 %

Procedure:
A solution of the crude 4-bromo-2,3-difluorophenol (0.40 g) [prepared using published procedure, WO0121606] and (2R)-glycidyl 3-nitrobenzenesulfonate (0.49 g) in dry acetone (19 mL) was treated with potassium carbonate (0.79 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chomatogaphed (20% ethyl acetate/hexanes) to yield the desired product (0.33 g) in 71% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.23-7.19 (m, 1H), 6.74-6.71 (m, 1H), 4.35-4.32 (m, 1H), 4.03-3.99 (m, 1H), 3.38-3.35 (m, 1H), 2.93-2.92 (m, 1H), 2.77-2.76 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]2[C:12]([C:13]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][C:15](=[O:22])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:27](OCC)(=O)C>[Pd]>[C:23]([C:13]1[C:12]2[C:17](=[C:18]([CH2:19][CH2:20][CH3:21])[C:9]([OH:8])=[CH:10][CH:11]=2)[O:16][C:15](=[O:22])[C:14]=1[CH3:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(C(C)(C)C)cc(=O)oc12
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCc1c(O)ccc2c(C(C)(C)C)c(C)c(=O)oc12
Reaction time: 6 h

Procedure:
A solution of 7-benzyloxy-4-tert-butyl-8-propylcoumarin (718 mg) in ethyl acetate (25 mL) was treated with 10% palladium (107 mg) on carbon. The mixture was shaken under a hydrogen atmosphere (40 psi) for six hours. The mixture was filtered through Celite and concentrated to get the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH3:42])[CH2:20][CH2:21][C@:22]3([O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH2:27][C@H:26]4[CH2:28][CH2:29][C@@H:23]3[CH:24]=[C:25]4[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(C)(C)C>C1COCC1>[OH:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH3:42])[CH2:20][CH2:21][C@:22]3([O:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH2:27][C@H:26]4[CH2:28][CH2:29][C@@H:23]3[CH:24]=[C:25]4[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3cccc(O[Si](C)(C)C(C)(C)C)c3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3cccc(O)c3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Reaction time: 0.75 h
Yield: 56 %

Procedure:
To a solution of 287 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-[2-({3-[7-(tert.-butyl-dimethyl-silanyloxy)-1H-benzoimidazol-2-yl]-propyl}-methyl-amino)-ethyl]-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester in 6 mL THF were added 73 mg of NEt3 trihydrofluoride. After stirring for 45 min the reaction was quenched by addition of sat. aq. NaHCO3. The mixture was extracted with EtOAc and the organic phase was dried over MgSO4. Concentration in vacuo and purification by CC with EtOAc-MeOH (2:1) yielded 131 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(7-hydroxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.S(Cl)(Cl)=O.[N:24]12[C:46](=[O:47])[CH2:45][NH:44][CH2:43][C:42](=[O:48])[N:33]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)[CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:44]1[CH2:45][C:46](=[O:47])[N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][N:33]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[C:42](=[O:48])[CH2:43]1)=[O:19]
Reactant: O=C1CNCC(=O)N2CCOCCOCCN1CCOCCOCC2
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C1CN(C(=O)CCCCCCCCCCCCCCCBr)CC(=O)N2CCOCCOCCN1CCOCCOCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a round bottom flask, 0.99 g (3 mmol) of 16-bromohexadecanoic acid was dissolved in 15 mL (15 mmol) of thionyl chloride. The solution was heated at reflux for 30 minutes. Thionyl chloride was removed under reduced pressure, at 40° C. The residue was dissolved in 30 mL of dichloromethane. To this solution, 1.11 g (3.1 mmol) of 4,7,13,16-tetraoxa-1,10,21-triaza-bicyclo[8.8.5]tricosane-19,23-dione and 1.4 mL (7.7 mmol) of DIPEA were added. The mixture was stirred at room temperature for 1 day. DIPEA and solvent were removed from the solution by evaporation of the solvent mixture under reduced pressure, and the residue was redissolved in 100 mL of dichloromethane. The solution was washed three times with 100 mL of 2 N HCl, once with 100 mL of water, and finally dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the product was finally purified by column chromatography (CH2Cl2:CH3OH 20:1) to afford a yellow oil. Yield: 0.96 g (72%). Rf:0.32 (CH2Cl2:CH3OH 20:1), 1H-NMR (400 MHz, CDCl3): δ 1.24-1.42 (m, 22H), 1.65-1.67 (m, 2H), 1.82-1.89 (m, 2H), 2.38-2.42 (dd, J=15.41, 7.58 Hz, 2H), 2.66-2.83 (m, 2H), 2.97-3.05 (m, 2H), 3.41 (t, J=6.82, 2H), 3.47-3.72 (m, 16H), 3.82-3.99 (m, 4H), 4.22-4.40 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ 25.5 (CH2), 28.5 (CH2), 29.1 (CH2), 29.8 (CH2), 29.8 (CH2), 29.9 (CH2), 30.0 (CH2), 33.1 (CH2), 33.2 (CH2), 34.5 (CH2), 45.8 (CH2), 48.7 (CH2), 49.6 (CH2), 50.3 (CH2), 50.8 (CH2), 50.8 (CH2), 67.3 (CH2), 67.8 (CH2), 70.3 (CH2), 70.9 (CH2), 71.1 (CH2), 71.3 (CH2), 71.8 (CH2), 72.6 (CH2), 168.9 (C═O), 169.5 (C═O), 174.5 (C═O).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:19])=[C:12]([CH2:14][O:15]C(C)C)[N:13]=2)=[CH:5][CH:4]=1.Cl>O>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11]([CH3:19])=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1[nH]c(-c2ccc(Cl)cc2)nc1COC(C)C
Agent: Cl
Solvent: O
Product: Cc1[nH]c(-c2ccc(Cl)cc2)nc1CO
Reaction time: 6 h
Yield: 126.9 %

Procedure:
A mixture of 2-(p-chlorophenyl)-4-isopropoxymethyl-5-methylimidazole hydrochloride (45.9 g, 0.152 mole) and 250 ml of water is stirred and refluxed. To this mixture is added 25 ml of concentrated hydrochloric acid and stirring and refluxing are continued for 6 hours. This mixture is chilled and filtered. The solid is dried in a vacuum desiccator and then recrystallized from isopropyl alcohol to give 25 g (64%) of 2-(p-chlorophenyl)-4-hydroxymethyl-5-methylimidazole hydrochloride, m.p. 181° C (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[BH3-]C#N.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(methyloxy)-1H-indole (5.0 g, 34 mmols) in acetic acid (150 mL) was added NaBH3CN (5.12 g, 81.6 mmol) in several small portions. After stirring overnight at rt, the solvent was removed, the residue redissolved in ethyl acetate (300 mL), washed with saturated NaHCO3 (600 mL), filtered through a cotton plug and concentrated under reduced pressure to provide the crude indoline. ESIMS (M+H)+=150. The residue was then dissolved in glacial acetic acid (150 mL) and acetic anhydride (3.45 g, 33.86 mmol) was added. After stirring at rt for two hrs, the solvent was removed, residue resuspended in ethyl acetate (200 mL), washed with saturated NaHCO3 (600 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, filtered through a cotton plug, and concentrated under reduced pressure to provide 1-acetyl-6-(methyloxy)-2,3-dihydro-1H-indole which was used without any further purification. ESIMS (M+H)+=192.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:55].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:40]3[CH:41]=[CH:42][C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]4)=[CH:44][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(C4CCN(CC(C)C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.092 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.37 (d, J=6.78 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.67-7.75 (m, 2H), 7.64 (d, J=8.06 Hz, 1H), 7.41-7.46 (m, 1H), 7.32-7.40 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.15 Hz, 2H), 6.94-6.98 (m, 2H), 6.78 (dd, J=8.24, 1.46 Hz, 1H), 6.59 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.84 Hz, 2H), 3.82 (s, 3H), 2.90 (d, J=10.44 Hz, 2H), 2.42-2.46 (m, 1H), 2.02 (d, J=7.14 Hz, 2H), 1.91 (t, J=10.44 Hz, 2H), 1.65-1.75 (m, 5H), 1.41 (t, J=6.87 Hz, 3H), 0.84 (d, J=6.41 Hz, 6H). MS (ESI): 732 [M+H]+.