Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([CH:35]2[CH2:37][CH2:36]2)([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[NH:5][S@@](C(C)(C)C)=O)[CH2:3][CH2:2]1.Cl>CO>[NH2:5][C:4]([CH:35]1[CH2:37][CH2:36]1)([CH:1]1[CH2:3][CH2:2]1)[C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)=[CH:15][N:16]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)s2)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N)(C3CC3)C3CC3)s2)c1
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
To a solution of (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-methylpropane-2-sulfinamide (125 mg, 0.227 mmol) in methanol (2 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 0.227 mL, 0.910 mmol). After 45 minutes, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with brine; dried over sodium sulfate, filtered, and concentrated to afford N-(3-{2-[amino(dicyclopropyl)methyl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.224 mmol, 99% yield) which was used without purification. MS ESI: [M-NH3]+ m/z 429.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1)[CH3:9]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: OC1CCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCC(O)C1
Temperature: 150 °C

Procedure:
A mixture of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (510 mg, 2.0 mmol), pyrrolidin-3-ol (870 mg, 10 mmol) and potassium 2-methylpropan-2-olate (1.56 g, 14.0 mmol) in dioxane (15 mL) was heated to 150° C. for 2 hours in a microwave reactor. The solvent was evaporated in vacuo to give the title compound as a yellow oil which was used without further purification (1.5 g). ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261. found 261.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[Br:16][C:17]1[N:27]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:20]2[C:21](=[O:26])[NH:22][CH2:23][CH:24](O)[C:19]=2[N:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCCC1>[Br:16][C:17]1[N:27]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:20]2[C:21](=[O:26])[NH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: CC(C)=CCn1c(Br)nc2c1C(=O)NCC2O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)=CCn1c(Br)nc2cc[nH]c(=O)c21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.55 g Burgess reagent (methoxycarbonylsulphamoyl-triethylammonium-N-betaine) are added to 1.60 g of 2-bromo-7-hydroxy-3-(3-methyl-2-buten-1-yl)-3,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-4-one in 20 ml methylene chloride and 4 ml of tetrahydrofuran. The reaction mixture is stirred for eight hours at 60° C., then another 0.3 equivalents Burgess reagent is added. After a further two hours the cooled reaction mixture is combined with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (1:0 to 10:1) as eluant.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:14]3[N:15]=[C:16]([CH3:28])[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]4)[C:13]=3[S:12][C:11]=2[CH3:29])=[C:5]([CH3:30])[CH:4]=1.[OH-].[Na+].C([O-])(O)=[O:34].[Na+]>OS(O)(=O)=O>[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:14]3[N:15]=[C:16]([CH3:28])[N:17]=[C:18]([N:19]4[CH2:20][CH2:21][CH:22]([CH2:25][C:26]([NH2:27])=[O:34])[CH2:23][CH2:24]4)[C:13]=3[S:12][C:11]=2[CH3:29])=[C:5]([CH3:30])[CH:4]=1
Reactant: Cc1nc(N2CCC(CC#N)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc(N2CCC(CC(N)=O)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
{1-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile hydrochloride (30 mg) was dissolved in c H2SO4 (0.5 mL) and the solution was stirred at room temperature for 20 hours. After addition of ice, the reaction mixture was made to alkaline (pH 7) with an aqueous NaOH solution and an aqueous NaHCO3 solution. The mixture was extracted with EtOAc and the organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: EtOAc) to obtain the title compound (20 mg) as a white crystal.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:13][OH:12])[CH2:10][CH2:11][CH2:11][CH2:10][CH2:9][CH2:13]1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CCCCCC1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
Methanol (20 ml) was cooled to 0° C. and acetyl chloride (2.0 ml) was added. The mixture was stirred for 10 minutes and cycloheptanecarboxylic acid (2.0 ml) was added. The cooling bath was removed and the mixture was heated to reflux and stirred for 8 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc. The organic layer washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated under reduced pressure, affording cycloheptanecarboxylic acid methylester (1.82 g) as a pale yellow liquid. This methylester intermediate (1.8 g) was dissolved in THF (25 ml) and cooled to −40° C. Lithium aluminium hydride (11.5 ml of a 1.0 M sol. in THF) was added drop-wise. The reaction mixture was allowed slowly to warm to 0° C. and stirring was continued at this temperature for 3 hours. Aqueous sodium hydroxide (5 ml of a 1 M sol.) was added and the mixture was filtrated. The filtrate was evaporated under reduced pressure and re-dissolved in EtOAc (20 ml), dried (Na2SO4) and evaporated under reduced pressure, and gave cycloheptyl-methanol (1.37 g) as a clear colourless oil. This alcohol intermediate was converted into the title compound, as described for preparation 66, using N-hydroxyphthalimide. 13C-NMR (DMSO-d6) δ 78.8, 37.1, 30.0, 27.9, 25.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][CH2:19][C:20](O)=[O:21])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:36][NH:37][O:38][CH3:39]>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:20](=[O:21])[CH2:19][CH2:18][CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CCC1Cc2ccccc2CN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
A solution of 3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)propanoic acid (7.7 g, 25.2 mmol) in dichloromethane (200 mL, 0.13 M) was treated with CDI (6.1 g, 37.8 mmol) in three portions over 10 min with vigorous stirring. After the addition was complete, the mixture was stirred for an additional 40 min and treated with N,O-dimethylhydroxylamine hydrochloride (3.7 g, 37.2 mmol) and stirred overnight. The resulting solution was washed successively with water, 1 M HCl, 1 M NaOH, sat'd aq sodium chloride, dried over anhydrous MgSO4, filtered and concentrated to give tert-butyl 3-(3-(methoxy(methyl)amino)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil (8.6 g, 98%). LCMS, C19H28N2O4 m/z [371.4 (M+23)]. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].C.Cl.O>CO.[Pd](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(CCCC(=O)O)ccc1F
Reaction time: 6 h
Yield: 94.3 %

Procedure:
In methanol, 10.0 g of 4-(4-fluoro-3-methylphenyl)-4 -oxobutanoic acid were dissolved, followed by the addition of 1.5 g of activated charcoal (Norit EXW) and 12.4 ml of a palladium chloride solution (a solution obtained by dissolving 2.2 ml of concentrated hydrochloric acid and 2.5 ml of water to 1.0 g of palladium chloride with heating to give a total volume of 50 ml). The resulting mixture was subjected to catalytic reduction at room temperature and atmospheric pressure for 6 hours. After the completion of the reaction, the catalyst was filtered out by a glass filter paper, followed by washing with 12 ml of methanol. To the filtrate, 100 ml of a 5% aqueous solution of sodium hydroxide were added and the mixture was stirred for one hour. After the completion of the reaction, methanol was evaporated and the residue was adjusted to acidic with 12 ml of concentrated hydrochloric acid under ice cooling. The crystals so precipitated were collected by filtration, whereby 8.8 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Yield: 16.3 %

Procedure:
Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(CC2CC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.75 g) and (bromomethyl)cyclopropane (1.36 mL) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.55 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27](OC)=[O:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[C:32]([Mg]Cl)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27](=[O:28])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of methyl {4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}(oxo)acetate (Example 137, 95 mg, 0.21 mmol) in THF (4 mL) at −78° C. was treated with tert-butylmagnesium chloride (1M in THF, 0.26 mL, 0.26 mmol). The mixture was stirred at −78° C. for 3 h. Additional tert-butylmagnesium chloride (1M in THF, 0.22 mL, 0.22 mmol) was added. The mixture was stirred at −78° C. for 3 h. More tert-butylmagnesium chloride (1M in THF, 0.25 mL, 0.25 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a viscous light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give 50 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.9 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.77 (m, 2H), 7.73 (dd, 1H, Ja=10.3 Hz, Jb=1.5 Hz), 7.30-7.25 (m, 1H), 4.65-4.55 (m, 1H), 3.95-3.85 (m, 2H), 3.55-3.45 (m, 1H), 3.15-3.05 (m, 4H), 2.80-2.70 (m, 1H), 2.25-2.10 (m, 1H), 2.00-1.85 (m, 2H), 1.50-1.30 (m, 2H), 1.27 (s, 9H); LRMS (ESI), m/z 477 (M+H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]1>>[CH:1]1([C:8]2([OH:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C1C=CCCC1
Product: OC1(C2CCCC2)C=CCCC1
Yield: 92 %

Procedure:
According to Example 2, cyclopentylmagnesium bromide (1.00 M in THF, 2.10 mL; 2.10 mmol; 1.05 equiv) was reacted with cyclohexenone (192 mg; 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Gel filtration (silica; pentane:Et2O 9:1, 0.5 vol-% NEt3) afforded 1-Cyclopentyl-cyclohex-2-enol (7) as colorless oil (306 mg, 93%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].[NH2:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:35]4[CH2:36][CH2:37][C@H:33]([NH2:32])[CH2:34]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: N[C@H]1CCNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 60 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 60 mg of (3S)-3-aminopyrrolidine, and the mixture was heated under reflux with stirring at 90° C. for 1 hour. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 41 mg of the title compound as a pale brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][C:3]=1[O:16][CH3:17].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[O:23][CH:24]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COc1cc(CCCn2ccnc2)ccc1O
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(-c2ccc(C)s2)n1
Yield: 72 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 72%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 92-93° C.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[OH:31][C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[OH:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:34][CH:33]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(O)nc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 6-hydroxy-pyridin-3-yl-boronic acid pinacol ester to give the title compound as off-white solid. MS: 500.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]3[CH2:17][NH:18][CH2:19][CH:13]3[C:12]2=[O:20])=[CH:7][CH:6]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30]C.C(O[K])(C)(C)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.FB(F)F>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[OH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:18]1[CH2:17][CH:14]2[CH:13]([C:12](=[O:20])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[CH:6][CH:7]=3)[CH2:16][CH2:15]2)[CH2:19]1
Reactant: COc1ccccc1I
Reactant: O=C1C2CNCC2CCN1c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C1C2CN(c3ccccc3O)CC2CCN1c1ccc(OCC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
A mixture of 5-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-octahydro-pyrrolo[3,4-c]pyridin-4-one (200 mg, 0.6 mmol), 1-iodo-2-methoxybenzene (300 mg, 1.3 mmol), Pd2(dba)3 (100 mg, 0.1 mmol), tBuOK (200 mg, 1.8 mmol) and 2-(Di-tert-butylphosphino)biphenyl (200 mg, 0.7 mmol) in toluene (20 mL) was refluxed overnight under nitrogen atmosphere. The mixture was cooled and filtrated, the resulting solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to yield the intermediate ether (30 mg, 11%). This was taken up in anhydrous dichloromethane (20 mL). The mixture was cooled to −78° C., trifluoroborane (1 mL) was added drop-wise to the mixture and the mixture was stirred at −78° C. for 2 h, 1 h at room temperature and at reflux for 1 h. The mixture was poured into water (20 mL), extracted with dichloromethane (3×20 mL), the organic layers was combined, dried over anhydrous sodium sulphate, filtrated and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate/petroleum ether=½) to yield the title compound (20 mg, 69%). 1H NMR (300 MHz, CDCl3): 7.29-7.13 (m, 4H), 7.10-6.86 (m, 5H), 4.38 (q, 2H, J=8.1 Hz), 3.79-3.26 (m, 6H), 3.08-2.92 (m, 2H), 2.27-1.92 (m, 2H). LC-MS: [M+1]+=407.2.
Reaction SMILES: S(=O)(=O)(O)O.O.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[CH2:11][OH:12].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:18])([F:19])[F:20])[CH:11]=[O:12]
Reactant: OCc1ccc(OC(F)(F)F)c(Br)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A mixture of 29.4 g (0.3 mol) of sulphuric acid, 50 ml of water and 2 ml of "Aliquat" 336 (tricaprylmethylammonium chloride) was added to a solution of 27 g (0.1 mol) of 3-bromo-4-trifluoromethoxybenzyl alcohol in 250 ml of methylene chloride at room temperature. Thereafter, 9.7 g (0.033 mol) of potassium dichromate were added to the reaction mixture, and the temperature was kept at approx. 25° C. for 2 hours by slight cooling. After 100 ml of water had been added to the mixture, the organic phase was separated off and the water was once again extracted by shaking with 100 ml of methylene chloride. The organic phases were washed twice with 100 ml of water, then once with 100 ml of saturated sodium bicarbonate solution, and once again with 100 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuo. The residue was distilled. In this manner, 20.4 g (75.8% of theory) of 3-bromo-4-trifluoromethoxybenzaldehyde were obtained as a colorless oil of boiling point 97° C./10 mm Hg. ##STR23##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16](=O)[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1.[CH3:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([NH:23][CH3:22])[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1
Reactant: CN
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Product: CNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Yield: 69.6 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (16.5 g, 0.057 moles) and methylamine (8 ml, 0.18 moles). Recrystallization from ethyl acetate gave the product (12.0 g), mp 109°-111° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[O:14][CH3:15].[C:18]1([O:24][C:25](=O)[O:26]C2C=CC=CC=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:25]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1cc2c(nc1C(OC)OC)NCCC2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(nc1C(OC)OC)N(C(=O)Oc1ccccc1)CCC2
Reaction time: 0.42 h

Procedure:
A solution of 7-(dimethoxymethyl)-6-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 309, 76 mg, 0.319 mmol) and diphenylcarbonate (137 mg, 0.638 mmol) in THF (2 ml) at −15° C. was treated drop wise with LHMDS (1 M in THF, 0.35 ml, 0.35 mmol) and stirred for 25 min. The reaction mixture was then quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a yellow oil. (UPLC-MS 1) tR 0.93 min; ESI-MS 360.1 [M+H]+.