Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH3:3].[OH:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1cccc(N2CCNCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Bromoethane (0.7 mL) was added to a mixture of 1,1-dimethylethyl 4-(3-hydroxyphenyl)-1-piperazinecarboxylate (Description 21, 500 mg, 1.8 mmol) and potassium carbonate (495 mg) in acetone (50 mL) and the mixture was heated under reflux for 13 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ether (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5). The residue was dissolved in dichloromethane (14 mL), cooled to 0° C. and trifluoroacetic acid (9 mL) was added. The mixture was stirred at 0° C. for 1 h., then allowed to warm to room temperature and saturated aqueous sodium bicarbonate solution (40 mL) was added. The mixture was extracted with dichloromethane, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale brown solid (210 mg, 46%). 1H NMR (250 MHz, CDCl3) δ1.43 (3H, t, J 7.6 Hz), 3.65-3.82 (8H, m), 3.98-4.13 (2H, m), 6.84-6.91 (2H, m), and 7.34-7.40 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7](OC)=[C:6]([O:10]C)[C:5]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:4][C:3]=1[N:24]1[C:32](=[O:33])[NH:31][C:30]2[C:25]1=[N:26][C:27]([CH3:36])=[N:28][C:29]=2[O:34][CH3:35].CO.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:10])[C:5]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:4][C:3]=1[N:24]1[C:32](=[O:33])[NH:31][C:30]2[C:25]1=[N:26][C:27]([CH3:36])=[N:28][C:29]=2[O:34][CH3:35]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)c(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxy-methyloxyphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (80 mg) in tetrahydrofuran (2 mL)-methanol (1 mL) was added concentrated hydrochloric acid (0.1 mL), and the mixture was stirred at room temperature for 2 hours, and then stirred at 60° C. for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/3) to give the title compound (22 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:10][C@H:9]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:4][CH:3]=1.Cl.C(OCC)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:10][C@H:9]([CH2:11][NH2:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC[C@H]1C[C@H](Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution in 1,4-dioxane (30 mL) of the compound (0.98 g) obtained in step (5) above, a solution (25 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 5 hours. After adding diethyl ether (120 mL), the mixture was stirred for another two hours and thereafter the precipitate was recovered by filtration. The recovered precipitate was dissolved in an aqueous solution of 1 mol/L sodium hydroxide and chloroform and two extractions were conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as a colorless oil (660 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g), dimethyl 6-chloro-2,3-pyridinedicarboxylate (1.58 g; Kenji Niiyama et al. Bioorg. Med. Chem Lett. 12, 21, 2002, 3041-3054) and cesium carbonate (4.4 g) in dry DMF (30 ml) was heated at 80° C. for 3 h. The cooled mixture was partitioned between water (20 ml) and ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (2×100 ml) and dried (Na2SO4). The solvent was evaporated to give an oil which was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E231); MS (ES+) m/e 411 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[CH2:2]1.O1CCCC1.[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]([OH:10])[CH2:2]1
Reactant: O=C1COc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1COc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a mixed solution of 2,3-dihydrobenzofuran-3-one (1.0 g) in methanol (10 mL)-tetrahydrofuran (10 mL), sodium borohydride (0.28 g) was added under ice-cooling and the resultant reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=100:00 to 85:15) to obtain the subject compound (0.87 g) as a yellow oil.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C-:9]#[N:10].[Na+]>C(OCC)(=O)C.O>[OH:8][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]#[N:10]
Reactant: [C-]#N
Reactant: C=CCCCCC=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCCCCC(O)C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyridinium chlorochromate (19.26 g, 0.088 mol) was added to a solution of hept-6-en-1-ol (5.0 g, 0.044 mol) and dichloromethane (600 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with diethyl ether, filtered through silica gel and concentrated in vacuo below room temperature to yield hept-6-enal as an oil, which was used in the next step without further purification. To a solution of hept-6-enal (4.9 g, 0.044 mol) in ethyl acetate (36 mL) was added a solution of sodium cyanide (6.4 g, 0.13 mol) in water (36 mL) and the resulting mixture was stirred at room temperature for 24 h. The layers were separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo to yield 2-hydroxyoct-7-enenitrile as a tan oil, which was used in the next step without further purification. A stream of HCl(g) was introduced into a solution of 2-hydroxyoct-7-enenitrile (6.0 g, 0.043 mmol) and methanol (130 mL) at −78° C. for 5 min. The resulting mixture was stored at −10° C. for 18 h, then concentrated in vacuo. The residue was diluted with ethyl acetate (106 mL) and water (106 mL) and the solution was stirred at room temperature overnight. The layers were separated, and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield methyl 2-hydroxyoct-7-enoate. 1H NMR (400 MHz, CDCl3) δ 5.48-5.82 (m, 1H), 4.89-5.08 (m, 2H), 4.31-4.52 (m, 1H), 3.79 (s, 3H), 2.78-3.12 (bs, 1H), 2.02-2.28 (m, 2H), 1.75-1.89 (m, 1H), 1.68-1.70 (m, 1H), and 1.38-1.52 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Cn1ccc(Br)n1
Product: Cn1ccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 9.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-1H-pyrazole (70 mg, 0.43 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (89 mg, 0.43 mmol, Example 146(B)). Microwave conditions: The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 12 mg (42 μmol, 10%) of 4-chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=[O:14])[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[H-].[Na+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[H-].[Na+]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:12](=[O:14])[O:11][C:9](=[O:10])[C:8]=2[CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.7 %

Procedure:
In a 3 L, 3-neck RBF equipped with mechanical stir, thermocouple and N2 inlet, 90 g (0.455 mol) of 5-chloroisatoic anhydride was suspended in anhydrous THF (0.9 L). Under N2, 4-methoxybenzylchloride (75 g, 0.48 mol) was added followed by the addition of tetrabutylammonium iodide (84 g, 0.23 mol). The reaction mixture was stirred for 5 min at room temperature and then 20 g (0.5 mol) of NaH was added portion-wise over 20 min (reaction temperature increased to 29° C. due to an exotherm and therefore reaction mixture was placed into water bath to keep the temperature below 30° C.). Reaction was stirred for 16 h (RT). Next day HPLC showed about 26% unreacted 5-chloroisatoic anhydride. Additional NaH (1 g) was added and the reaction mixture was heated to 32° C. and stirred for another 5 h. NMR showed that all of the starting material had been consumed. Reaction was quenched by adding 10 g of glacial acetic acid slowly followed by stirring for 30 min. Reaction mixture was filtered through celite and filter cake was washed with THF. Filtrate was concentrated to give 280 g of crude product (yellow-brown solid), which was used with no further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.8 (s, 3H), 5.25 (s, 2H), 6.8 (d, 2H), 7.2 (m, 3H), 7.75 (d, 1 H), 7.9 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[N:7][CH:8]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C[Si](Cl)(C)C>>[OH:14][CH:13]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][N:7]=2)[CH:11]=1
Reactant: O=Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)Cl
Product: CCOP(=O)(OCC)C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To an ethereal solution of 3-(5-(trifluoromethyl)pyridin-2-yloxy)benzaldehyde (1.6 g, 5.98 mmol) and LiClO4 (5 mL, 5 M solution in diethylether) was added triethyl phosphite (1.24 g, 7.48 mmol) and TMSCl (0.813 g, 7.48 mmol) at 0° C. The reaction mixture was allowed to reach RT and stirred for 10 min. The reaction was quenched by adding distilled water (10 mL), extracted with CH2Cl2, dried and concentrated to dryness. The residue was purified by column chromatography (1:1 EtOAc:Hexane) to afford pure title compound (1.3 g). 1H NMR (500 MHz, CDCl3): δ 1.2 (m, 6H), 2.9 (m, 1H), 4.0 (m, 4H), 5.0 (d, 1H, J=11 Hz), 7.0 (d, 1H, J=8.5 Hz), 7.1 (d, 1H, J=7.5 Hz), 7.3 (s, 1H), 7.4 (m, 1H), 7.8 (m, 1H), 8.4 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)[CH3:3].Br>C(O)(=O)C>[CH2:2]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:3]
Reactant: CCn1ccnc1-c1ccc(OC)cc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ccnc1-c1ccc(O)cc1

Procedure:
A mixture of 7 parts of 1-ethyl-2-(4-methoxyphenyl)-1H-imidazole monohydrochloride and 75 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and a refluxed for 2 hours. The reaction mixture is concentrated and a small amount of water is added to the concentrate. The whole is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from a mixture of ethanol and water, yielding 3.3 parts of 4-(1-ethyl-1H-imidazol-2-yl)phenol.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH2:6][C:5]=12.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][C:9]1([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]2[CH:3]=[N:2][CH:1]=[C:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(-c2ccccc2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile (53 mg, 0.177 mmol) in THF (2 mL) at −40° C. is added LHMDS (1.0 M in THF, 0.27 mL, 0.27 mmol). The resulting brown solution is stirred at −30° C. for 0.5 h. To the reaction mixture is added methyl iodide (0.017 mL, 0.272 mmol) and the mixture is warmed up to ambient temperature and stirred overnight. The reaction mixture is quenched by saturated aqueous NH4Cl and the reaction is partitioned between CH2Cl2 and brine. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subject to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 314 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[C:25](=[O:27])[CH3:26]>>[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:29]1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)N(C)[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(=O)N(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N-methyl-N-(pyrrolidin-3-yl)acetamide (1.2 equiv) to give 180 (24.3 mg, M+1 438.1)
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of 0.5 g (1.4 mMol)[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol) Red-Al® (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C). The reaction mixture was stirred 2 hours at 50° C. in CH2Cl2, extracted with ethyl acetate and cooled to 0° C. 4 ml Aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])([OH:16])=[O:2]
Reactant: CC(C)=O
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC(=O)O

Procedure:
A solution of 25 g of 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene in 1200 ml of acetone was treated at -10° C with 55 ml of Jones reagent. The resulting brown mixture was poured on to ice/sodium bicarbonate solution. Ether extraction, washing neutral with sodium bicarbonate solution, saturated sodium chloride solution and water, drying of the extract with magnesium sulphate and removal of the solvent under reduced pressure yielded 20 g (80%) of a weakly yellow oily crude product from which there were obtained by distillation 15 g of pure 2-(2-carboxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.01 = 102° C; IRfilm : νmax = 3600-2400, 1720, 1645, 1450, 1420, 1380, 1330, 1290, 1220, 1085, 945 and 900 cm-1. The compound has a woody, spicy, weakly sweetish and somewhat musty fragrance.
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([CH:22]=[O:23])=[C:6]([O:5][C:2]([F:4])([F:3])[F:1])[CH:11]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
5-bromo-2-iodophenyl trifluoromethyl ether (500 mg, 1.37 mmol) was dissolved in 10 mL of anhydrous THF and cooled to −70° C. Then, n-butyllithium (0.55 mL of a 2.5 M solution, 1.37 mmol) was added dropwise over the course of 30 minutes. DMF (0.19 mL, 2.74 mmol) was added and the reaction was stirred for 30 minutes at −70° C. and then allowed to warm to 0° C. and stir for three hours. The reaction was quenched with 5 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to provide 4-bromo-2-[(trifluoromethyl)oxy]benzaldehyde (100 mg, 0.37 mmol, 27%) as a yellow solid. 1H NMR (400 MHz, DMSO-D6) □ 10.1 (s, 1H), 7.9 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:17]([CH2:20][CH3:21])(=[O:18])=[O:19])[CH3:23])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NS(=O)(=O)CC)c2c1C
Reactant: CI
Product: CCOC(=O)c1oc2cccc(N(C)S(=O)(=O)CC)c2c1C

Procedure:
4-Ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (prepared according to Example 68, Step 1) was alkylated with iodomethane according to Example 60, Step 2, to give 4-(ethanesulfonyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (m, 9 H) 2.7 (s, 3 H) 3.3 (s, 2 H) 4.4 (q, J=7.1 Hz, 2 H) 7.5 (dd, J=7.7, 0.9 Hz, 1 H) 7.6 (m, 1 H) 7.7 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CN(C)C(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[C:11]2=[O:13]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: COCCN1C(=O)c2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
A mixture of 4-hydroxyphthalic acid (0.91 mg, 5.0 mmol) and carbonyldiimidazole (0.85 g, 5 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 45 min. To this mixture was added 2-methoxyethylamine (0.47 g, 6.0 mmol) and the resulting mixture heated under reflux for 15 min. After cooling to room temperature, the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 19:1 to 9:1) to afford the title compound (1.1 g, 95%) as a light yellow solid. MS: m/e=220.1 (M−H−).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][CH:27]5O[CH2:31][CH2:30][NH:29][CH2:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(OCC1CCN(C(OC(C)(C)C)=O)C1)(=O)=O.C(O)(C(F)(F)F)=O>CC(N(C)C)=O.C(Cl)Cl.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][CH:27]5[CH2:31][CH2:30][NH:29][CH2:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OCC5CNCCO5)c4n3)cnc2c1
Agent: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5CCNC5)c4n3)cnc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 29 %

Procedure:
To a solution of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol [prepared as in Example 16; 204 mg, 0.61 mmol] in anhydrous DMA (5 mL) was added cesium carbonate (0.60 g, 1.8 mmol) followed by tert-butyl 3-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (221 mg, 0.79 mmol). The heterogeneous mixture was stirred at 70° C. for 20 hours and allowed to cool. The mixture was treated with water (50 mL) and extracted with chloroform and EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford the crude product (386 mg, 122% yield) as a viscous oil. MS ESI (+) m/z 519.1 (M+1) detected. The oil (315 mg) was dissolved in CH2Cl2 (2 mL) and treated with TFA (1 mL). After stirring for 2 hours at ambient temperature the mixture was concentrated. The residue was treated with excess (20 ml) saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with chloroform and EtOAc. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated to afford a viscous oil. The oil was purified by column chromatography on silica gel (elution with 7 N NH3/MeOH-chloroform) to provide the title compound (74 mg, 36% yield over two steps) as a solid. MS ESI (+) m/z 419.3 (M+1). detected.