Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][NH:10][CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:34]([N:10]1[CH2:11][CH2:12][C@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)[C:15]2=[O:32])[C@H:8]([CH2:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])[CH2:9]1)([CH3:36])[CH3:33]
Reactant: CC(C)=O
Reactant: CC(C)S(=O)(=O)C[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A sample of N—((S)-1-((3R,4S)-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.05 g) was dissolved in 1,2-dichloroethane (3 mL) prior to the addition of acetone (0.38 mL, 0.525 mMol). After stirring at rt for 1 h, sodium triacetoxyborohydride (0.445 g, 0.21 mMol) was added to the reaction. Stirring was continued for 2 h when the reaction was quenched with saturated NaHCO3. Partitioned between EtOAc and water. Organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and chromatographed. The desired product, N—((S)-1-((3R,4S)-1-isopropyl-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.0086 g, yield=16%) was obtained as a white solid. MS found: (M+H)+=518.2.
Reaction SMILES: [CH3:1][C@:2]1([CH2:24][N:25]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[N:27]=[CH:26]2)[CH2:23][CH2:22][CH2:21][C:4]2(O[C@H](C3C=CC=CC=3)[C@@H](C3C=CC=CC=3)[O:5]2)[CH2:3]1>C(O)=O>[CH3:1][C@:2]1([CH2:24][N:25]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[N:27]=[CH:26]2)[CH2:23][CH2:22][CH2:21][C:4](=[O:5])[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Solvent: O=CO
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC(=O)C1
Temperature: 70 °C
Reaction time: 120 h
Yield: 77.7 %

Procedure:
A mixture of 1-{[(2R,3R,7S)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (235 g, 508 mmol) in formic acid (1948 mL) was heated to 70° C. for 18 h, then the solution was concentrated under reduced pressure, and diluted with sat. NaHCO3 until it was basic. The resulting mixture was extracted with DCM (3×), and the combined extracts were washed with brine and then concentrated under reduced pressure. To the residue was added EtOAc (1 L) and then it was concentrated at 60° C. to a volume of approximately 750 mL. The slurry was then allowed to cool. Once solids started to form, the slurry was slowly diluted with 500 mL of hexanes and the temperature was raised to about 60° C. An additional 500 mL of hexanes was slowly added and the temperature was raised to reflux (about 68° C.). Once at reflux, heating was stopped, and the solution was allowed to cool to RT and stir for 5 days. Then the slurry was filtered, the solids were washed with hexanes and dried under reduced pressure to give 105.5 g of product (78% yield). The filtrate was concentrated and loaded onto silica gel and purified on a 220 g column (like a plug of silica) using vacuum to pull solvent through the column, and eluted with 500 mL of DCM, then 1 L of 50% EtOAc/DCM, then 1 L of 100% DCM, then 1 L each of 2.5%, 5%, 7.5%, and 10% MeOH/DCM. Fractions were collected in 1 L portions. Fractions containing product were concentrated to afford an additional 20.4 g (15% yield) of product. MS (m/z) 268.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:15](=[O:30])/[CH:14]=[CH:13]/[C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:32]([CH3:31])[CH:33]4[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:8][CH:9]=3)=[CH:22][CH:21]=2)=[CH:28][CH:27]=1
Reactant: CNC1CCC(C)CC1
Reactant: CS(=O)(=O)OCc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(N(C)Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A reaction mixture of 100 mg (0.226 mmol) of 4-[(E)-2-(4′-chlorobiphenyl-4-ylcarbamoyl)vinyl]benzyl methanesulfonate, 37.34 mg (0.29 mmol) of methyl-(4-methylcyclohexyl)amine, and 0.1 mL of triethylamine in 10 mL of dichloromethane is stirred for 18 hours at ambient temperature. Then the reaction mixture is extracted between water and dichloromethane, the organic phase is separated off, dried, and evaporated down. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (90:10:1)). Yield: 52 mg (49% of theory); C30H33ClN2O (M=473.05); melting point: 227° C.-258° C.; calc.: molecular ion peak (M+H)+: 473/475 (Cl); found: molecular ion peak (M+H)+: 473/475 (Cl); Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(F)(F)F)cc4)ccc3o2)CC1
Yield: 42.8 %

Procedure:
Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(trifluoromethyl)phenylboronic acid (124 mg, 0.65 mmol) as an off-white solid. M.P.: 123-126° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.88 (d, J 1, 1H), 7.72-7.68 (m, 4H), 7.60-7.53 (m, 2H), 4.95 (septet, J 6.3, 1H), 4.20 (d, J 13.3, 2H), 3.22-3.12 (m, 1H), 3.04 (t, J 11.3, 2H), 2.17 (dd, J 2.6, 13.2, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ncc[nH]1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccnc2C)cc1
Yield: 41 %

Procedure:
A mixture of 16.4 parts of 2-methyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 1 part of copper(I)bromide, 20 parts of potassium carbonate and 270 parts of N,N-dimethylformamide is stirred and refluxed for one week. The reaction mixtuure is cooled, poured onto water and the whole is extracted with 2,2'-oxybispropane. The extract is washed twice with a diluted hydrochloric acid solution. The acid aqueous phase is separated and alkalized with sodium hydroxide. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 4 parts (41%) of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10](Cl)(Cl)=[S:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[S:11])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: S=C=Nc1ccc(Cl)c(Cl)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3,4-Dichloroaniline (19.44 g., 120 mM.) is added with vigorous stirring to a solution of thiophosgene in H2O (100 ml.) while maintaining the temperature at 15° C during the addition. The reaction is allowed to warm slowly to room temperature and is stirred for 1 hr. The aqueous layer is separated and extracted with 3 × 50 ml. CHCl3 ; the combined organic layers are dried over CaCl2 and filtered. The filtrate is evaporated in vacuo to give 3,4-dichlorophenylisothiocyanate (20.5 g.) which is used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:27]([O:29]CC)=[O:28])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][N:20]=3)[CH:14]=2)=[CH:11][CH:12]=1)=[O:5].C(OC(=O)C1C=C(NC(=O)C2C(F)=CC=CC=2F)C=CC=1Br)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:27]([OH:29])=[O:28])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[O:21][N:20]=3)[CH:14]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2c(F)cccc2F)ccc1-c1cccc(C2=NOC(C)(C)C2=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)c1cc(NC(=O)c2c(F)cccc2F)ccc1Br
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)ON=C(c2cccc(-c3ccc(NC(=O)c4c(F)cccc4F)cc3C(=O)O)c2)C1=O
Temperature: 120 °C

Procedure:
Step-2: Ethyl 4-(2,6-difluorobenzamido)-3′-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[1,1′-biphenyl]-2-carboxylate: To a solution of ethyl-2-bromo-5-(2,6-difluorobenzamido)benzoate (180 mg, 0.47 mmol, 1.0 eq), in dioxane (5 mL), successively intermediate 9 (150 mg, 0.47 mmol, 1.0 eq) sodium carbonate (100 mg, 0.95 mmol, 2 eq) and Pd(PPh3)2Cl2 (33 mg, 0.047 mmol, 0.1 eq) were added. The resulting solution was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was then heated at 120° C. in microwave (Biotage) for 30 min. The resulting mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane system as eluent) to afford 90 mg of the title compound as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.13-8.09 (m, 2H), 8.05-8.01 (m, 2H), 7.88 (s, 1H, D2O exchangeable), 7.52-7.42 (m, 4H), 7.04 (t, J=8.0 Hz, 2H), 4.14 (q, J=7.0 Hz, 2H), 1.49 (s, 6H), 1.09 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 493 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(N2CCOCC2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N5CCOCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(6-bromo-pyridin-2-yl)-morpholine.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>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]>[CH3:26][C:27]1[C:31]([C:2]2[N:7]=[N:6][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:9]=3)=[N:4][C:3]=2[NH2:25])=[C:30]([CH3:35])[O:29][N:28]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 154 mg (purity 70%, 0.767 mmol) of (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. The reaction mixture was again stirred for 60 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 25 mg of the target compound (purity 95%; 18% of theory).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]([CH2:15][OH:16])[CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.Br[CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:29]([O:28][CH2:27][CH2:26][CH2:25][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH:6]([CH2:15][OH:16])[CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(O)cc2)C(CO)C1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(CO)C1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with benzyl 3-bromopropyl ether in the presence of potassium carbonate in butan-2-one there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate as a colourless oil; MS: 472 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].P(OC)(OC)(OC)=O>O>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:12])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COP(=O)(OC)OC
Solvent: O
Product: COc1ccc(C=O)cc1OC
Temperature: 85 °C
Yield: 98.5 %

Procedure:
In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 85° C. The mixture was a clear to amber melt of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125° C. The mixture was maintained at about 80° C. for one hour and then cooled to 40° C. The mixture was poured into 20 ml water and extracted two times with 20 ml of methylene chloride. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4 g (99%) of veratraldehyde as a pale oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:35]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: O=C(CNCCCC1CCCNC1)c1ccccc1
Product: O=C(CNCCCC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1)c1ccccc1

Procedure:
Prepared analogously to Example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[3-[(benzoyl)methylamino]-propyl]piperidine. Purification is carried out by chromatography on silica gel using a mixture of methylene chloride/methanol =99:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[CH3:16])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl[CH2:28][CH2:29][CH2:30][CH:31]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1>O.CC(C)CC(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:28][CH2:29][CH2:30][CH:31]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[CH2:12][CH:11]3[CH3:16])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC1CNCCC1n1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCC1n1c(=O)[nH]c2cc(Cl)ccc21
Reaction time: 18 h

Procedure:
A mixture of 5.3 parts of 5-chloro-1,3-dihydro-1-(3-methyl-4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, there are added 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)butane and stirring at reflux temperature is continued for 18 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. Methylbenzene is added to the oily residue and the whole is acidified with a diluted hydrochloric acid solution. After shaking thoroughly, the methylbenzene-phase is decanted and discarded. The aqueous acid phase, together with the residual oil, is alkalized with ammonium hydroxide and the product is extracted again with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, yielding 5-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-3-methyl-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 141.7° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]=[C:34]=S.C(Cl)CCl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: COCCN=C=S
Solvent: ClCCCl
Solvent: CCO
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (35 mg, 0.093 mmol) was dissolved in ethanol (5 ml) and 2-methoxyethyl isothiocyanate (22 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo. The residue was dissolved in THF (5.0 ml) and EDC (35.7 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo and the residue purified by MDAP (formate) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-amine (25 mg, 0.055 mmol, 58.5% yield) as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([F:21])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][C:15]=1[C:17]([F:18])([F:19])[F:20]
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: Fc1ccc(-c2ccncc2)cc1C(F)(F)F
Yield: 53.6 %

Procedure:
First, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine 73 was prepared as follows. To a suspension of pyridine-4-boronic acid (2.59 g, 21.1 mmol) in 1-propanol (60 mL) was added 5-bromo-2-fluorobenzotrifluoride (5.12 g, 21.1 mmol) and triphenylphosphine (0.160 g, 0.610 mmol), followed by sodium carbonate in water (2.0 M, 12 mL). The mixture was purged with nitrogen gas for 10 minutes. To it was added palladium(II) acetate (0.044 g, 0.196 mmol) and it was then heated under reflux for 4 hours. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated, washed with brine (3×200 mL), dried over MgSO4, then filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 60% ethyl acetate in hexane to give a white solid 73 (2.73 g, 54%). 1H-NMR (CDCl3, 400 MHz) δ 7.34–7.42 (m, 1H), 7.61–7.65 (m, 2H), 7.80–7.93 (m, 2H), 8.73–8.84 (m, 2H); MS (DCI) m/z 242, 243 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[C:21]([CH:25]=O)=[N:22][NH:23][CH:24]=2)=[O:19])[CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[C:21]([C:25]3[NH:10][C:4]4[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=4[N:9]=3)=[N:22][NH:23][CH:24]=2)=[O:19])[CH2:13][CH2:12]1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1n[nH]cc1C(=O)NC1CCOCC1
Product: Cc1cc2nc(-c3n[nH]cc3C(=O)NC3CCOCC3)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 235(i) above but using 4,5-dimethyl-1,2-phenylenediamine and 3-formyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide [Reference Example 6(p)] and recrystallising the reaction product from methanol there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide (228 mg) as a white solid. LC-MS (METHOD R): RT=9.40 minutes, 360 (M+H)+.