Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C([N-]C(C)C)(C)C.[Li+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([I:33])[CH:26]=1.O>C1COCC1.CCOC(C)=O>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:6]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]([C:2]([F:14])([F:15])[F:1])[CH2:8][CH2:7]2)=[C:27]([I:33])[CH:26]=1
Reactant: BrCc1ccc(Br)cc1I
Reactant: CCOC(=O)C1CCC(C(F)(F)F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Ethyl 4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 76, 1.492 g, 6.65 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to argon, and the solution was cooled to −78° C. Lithium diisopropylamide (1.8 M in THF/heptane/ethylbenzene) (4.07 mL, 7.32 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 30 min at −78° C. 4-Bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239, 2.50 g, 6.65 mmol) in THF (25 mL) was added via a syringe. The mixture was allowed to reach r.t., while stirred for 2 h. Water (10 mL) was added to the reaction mixture, followed by EtOAc (40 mL). The phases were separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: heptane/EtOAc 95/5) to give the title compound (2.41 g, 69% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.22-1.27 (m, 3 H) 1.29-1.43 (m, 4 H) 1.82-1.90 (m, 2 H) 1.82-1.90 (m, 3 H) 1.97 (br. s., 2 H) 2.28-2.36 (m, 3 H) 3.01 (s, 3 H) 4.18 (q, 3 H) 6.91 (m, 1 H) 7.38 (m, 1 H) 7.99 (m, 1 H); MS (ES+) m/z 520 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.OS(O)(=O)=O.[CH:21](=O)[CH2:22][CH3:23]>O>[CH2:22]([CH:23]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH3:21]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCC=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 74 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), water (300 ml), H2SO4 (0.05M, 30 ml) and propionaldehyde (8 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 24 h. After filtration, wash with water and drying, white solids (4.5 g, 74%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:20]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:20]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2I)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2I)C1=O
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (1.18 g, 2.73 mmol) in methanol (50 ml) at 35 ° C. is added 50% aqueous hydrogen peroxide solution (0.31 ml, 5.46 mmol), followed immediately by 2M aqueous lithium hydroxide (0.34 ml, 0.68 mmol). This mixture is stirred at 35 ° C. for 3 hours, then quenched with saturated aqueous sodium metabisulfite and extracted with dichloromethane. The organic phase is separated, and the aqueous phase extracted again with dichloromethane. All organics are combined then evaporated under reduced pressure to afford 2-(5-bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one as an oil which is used directly in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:14]=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][OH:36]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: O=c1oc2cc(N3CCNCC3)ccc2cc1-c1nc2ccccc2s1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(N3CCN(CCO)CC3)ccc2cc1-c1nc2ccccc2s1
Yield: 26 %

Procedure:
240 mg crude 3-benzothiazol-2-yl-7-piperazin-1-yl-chromen-2-one in 10 mL DMF are stirred for 72 h at room temperature in the presence of 858 mg (at least 4 eq.) cesium carbonate and 0.103 mL (at least 2 eq.) 2-iodoethanol. The reaction mixture is extracted with ethyl acetate and a saturated solution of sodium carbonate and washed with brine. The combined organic phases are dried with sodium sulphate and evaporated. The residue is column chromatographed (silica gel, dichloromethane/methanol 95:5+1% conc. NH4OH) to yield 70 mg (26%) desired product as an orange solid.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][C:35]([CH3:37])=O.[BH4-].[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH:35]([CH3:37])[CH3:34])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CC(C)=O
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
N-{(1R,2R)-2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (77 mg, 0.157 mmol) was placed in 1,2-dichloroethane (5 mL) and acetic acid (0.25 mL). Acetone (13.6 mg, 0.235 mmol, 17.2 μL, 1.5 eq) was added and the reaction was stirred for 5 minutes. Sodium borohydride (7.0 mg, 0.188 mmol, 1.2 eq) was added and the reaction was heated at 80° C. overnight. The reaction was then diluted with CH2Cl2 (20 mL) and washed with water (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 0-40% acetonitrile/water as the eluting solvent to obtain N-{(1R,2R)-2-[5-chloro-2-(10-Isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mixture of diastereomers as an orange foam (14.63 mg, 17%). LCMS (m/e) 533 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.26-7.18 (m, 2H), 7.01 (d, 1H, J=6.7 Hz), 6.90 (bs, 1H), 5.49 (bs, 1H), 5.39-5.33 (m, 1H), 3.92-3.78 (m, 1H), 3.30-3.17 (m, 1H), 3.00-2.92 (m, 2H), 2.92-2.75 (m, 3H), 2.77 (s, 3H), 2.40-2.27 (m, 2H), 2.26-2.10 (m, 4H), 1.87-1.75 (m, 2H), 1.65-1.50 (m, 2H), 1.42-1.25 (m, 4H), 0.94 (d, 6H, J=6.5 Hz).
Reaction SMILES: [OH-].[CH2:2]([N+:6](CCCC)([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5]>CO>[CH2:11]([N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CCCCN(CCCC)CCCC

Procedure:
Three grams of coal liquid derived from Illinois No. 6 coal and having a boiling range of 340° to 565° C. was mixed with 8 cc of 2 M tetrabutylammonium hydroxide in methanol. The resulting quaternary ammonium organic salt was then heated to 250° C. A thermal rearrangement took place which produced an O-butylated coal liquid and tributylamine.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Br)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Brc1ccc2oc(Cc3ccccc3)cc2c1

Procedure:
A mixture of 42.2 g. (0.14 mol.) of 2-benzoyl-5-bromobenzofuran and 35 ml. of 98% hydrazine in 70 ml. of diethylene glycol is warmed for a few minutes on a steam bath. Then 23.3 g. of potassium hydroxide is added and the reaction mixture is refluxed for two hours. After cooling, water is added to the mixture and the resulting aqueous solution is extracted with benzene. The extract is washed with water, 10% aqueous hydrochloric acid and water, dried (MgSO4) and concentrated to yield 2-benzyl-5-bromobenzofuran.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[C:10](=[CH:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1cccs1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester as prepared in Preparation I (3.66 g) in acetic anhydride (10 ml) is treated with sodium acetate (1.37 g) and 2-thiophenecarboxaldehyde (2.24 g). The solution is heated at reflux temperature for 56 hours. The cooled mixture is diluted with toluene, filtered and the filtrate evaporated to a solid residue. The residue is triturated with hexane and filtered to yield a residue of 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (1.91 g) m.p. 117° C.-118° C. The filtrate residue is purified on silica gel (70 g) with 9:1 Skelly B:ethyl acetate as eluent. Fractions 7-13, 20 ml each, provide additional 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (0.73 g). An analytical sample, m.p. 117° C.-118° C. is obtained by hexane recrystallization.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[Li]CCCC.[CH3:13][O:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH2:16][CH2:15][O:14][CH3:13]
Reactant: Brc1ccsc1Br
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCc1sccc1Br
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
To a solution of 2,3-dibromothiophene (12.6 g, 50 mmol) in THF abs. (125 mL) was added at −75° C. n-BuLi (1.6M/hexane, 31 mL) over 30 minutes. The reaction mixture was further stirred at −75° C. for 30 minutes, and p-toluenesulfonic acid-2-methoxyethylester (11.8 g, 50 mmol) was added dropwise over 1 h. The mixture stirred for 2 h without cooling, quenched with brine, and extracted with ether. The organics were washed, dried, and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 3-bromo-2-(2-methoxy-ethyl)-thiophene (1.8 g) as a colorless liquid. MS (EI): 221.1 (M)
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[Cl-].[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[C:11](=[O:13])[C:9]3[CH:10]=[CH:1][CH:2]=[C:3]4[C:8]=3[C:7](=[CH:6][CH:5]=[CH:4]4)[C:14]2=[O:15])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: NCCCCn1ccnc1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: [Cl-]
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.0 g of 1,8-naphthalic anhydride, 50 ml of methyline chloride and 2.1 g of 1H-imidazole-1- butanamine was stirred at room temperature for 20 hours. The insoluble product was isolated by filtration, washed with methlene chloride and then ether and dried in vacuo. The solid was placed in a round-bottom flask and immersed in an oil bath at 150° C., and the temperature was increased over a 45 minute period to 165° C. The reaction mixture was allowed to cool and the residue was triturated with ethyl acetate and recovered by filtration. After recrystallization from ethanol, the desired product melted at 153°-155° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:14][C:15]1[C:19]([N:20]=[C:21]=[O:22])=[C:18]([CH3:23])[O:17][N:16]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:21]([NH:20][C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:23])=[O:22])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: Cc1noc(C)c1N=C=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 48.2 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.23 mmol) and 3,5-dimethylisoxazol4-yl isocyanate (31 mg, 0.23 mmol) in 1.0 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (40 mg, 49%). LC-MS (m/z) 361.0 (M+).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(C(C)(C)C)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNc1ccccc1
Reactant: COc1ccc(C2=NN(C(C)(C)C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound A (see starting compounds) and phenylhydrazine as described for compound 14. Crystallized from ethyl acetate/petroleum ether (60°-95° C.). M.p. 122°-124° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[CH2:25][CH3:26])C1C=CC=CC=1.[H][H].C>CN(C)C=O.[Pd].C(OCC)(=O)C>[CH2:25]([C:10]1[N:11]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[CH3:26]
Reactant: [H][H]
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)(C)C
Yield: 534.9 %

Procedure:
To a solution of 3-benzyloxy-2-ethyl-1-(2-pivaloyloxyethyl)pyridin-4-one (0.5 g) in dimethylformamide (25 ml) was added 5% palladium on charcoal catalyst (0.1 g) and the reaction mixture was stirred at room temperature under a constant stream of hydrogen for 24 hours. The dimethylformamide was then removed under high vacuum by rotary evaporation to give an oil. The solid obtained on cooling the oil was dissolved in hot ethyl acetate and the solution treated with activated charcoal, refluxed for 5 minutes, filtered and rotary evaporated. The resultant residue was recrystalized from petroleum ether (boiling point 40°-60° C.) to give the title compound (2 g, 53%) as colourless crystals, m.p. 113°-115° C., νmax (nujol) 1580, 1630, 1725, 3130 cm-1 ; δ(90 MHz, CDCl3), 7.25 (1H, d), 6.43 (1H, d), 5.25 (1H, s, br), 4.29 (2H, t), 4.21 (2H, t), 2.85 (2H, q), 1.27 (3H, t), 1.28 (9H, s).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[O:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:8]=[CH:9][CH:10]=1.[ClH:27]>O1CCOCC1>[ClH:27].[OH:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[O:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(CCc2ccccc2OCC2CCCN2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1COc1ccccc1CCc1cccc(O)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
660 mg of 2-{2-[2-(3-methoxymethoxyphenyl)ethyl]phenoxymethyl}-1-methylpyrrolidine [prepared as described in step (a) above] were dissolved in 5 ml of a 4N solution of hydrogen chloride in dioxane, and the solution was allowed to stand at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting solid residue was recrystallized from isopropyl alcohol, to give 529 mg (yield 82%) of the title compound as colorless needles, melting at 232°-233° C. (with decomposition).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=[C:2]([CH3:30])[C:10]=2[N:9]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cn2c(C)nc3c(C)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), trimethylboroxine (0.239 mL, 1.708 mmol), Pd(Ph3P)4 (49.4 mg, 0.043 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-Dioxane (2.5 mL)/Water (0.25 mL) was irradiated at 120° C. in a microwave synthesizer for 40 min, then cooled and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by RP-HPLC (25-45% AcCN in water plus 0.1% TFA) to give the desired compound (77 mg, 0.181 mmol, 42.5% yield) as a white solid (contains 3-5% of the 4-H compound). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.08 Hz, 1H), 7.12 (t, J=7.83 Hz, 1H), 6.80 (d, J=1.01 Hz, 1H), 6.51 (d, J=7.83 Hz, 1H), 6.40 (d, J=1.77 Hz, 1H), 5.26 (s, 2H), 3.78-3.91 (m, 4H), 3.01-3.15 (m, 4H), 2.67 (s, 3H), 2.56 (s, 3H), 2.50 (s, 3H). MS(ES+) m/e 404.1 [M+H]+. (NOTE: The reaction was repeated using PdCl2(dppf) as catalyst. Less (to negligible) reduction was observed).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH:14][CH:15]1[CH2:17][CH2:16]1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:14][CH:15]1[CH2:16][CH2:17]1
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1NC1CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)ccc(N)c1NC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A mixture of 2-cyclopropylamino-6-fluoro-3-nitrobenzoic acid methyl ester (865 mg, 3.40 mmol) in EtOAc (25 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (116 mg) and was stirred at RT under a hydrogen atmosphere for 20 h. The suspension was filtered and the filtrate was concentrated in vacuo to afford the title compound as a dark yellow oil (756 mg, 99%). LCMS (Method C): RT 2.29 min [M+H]+ 225.18.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([O:17]C1C=CC=CC=1)(=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.ClC1C=CC(Cl)=CC=1Cl>>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:8](=[O:17])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]
Reactant: Cc1ccccc1N
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Solvent: Oc1ccccc1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Cc1ccccc1NC(=O)c1ccccc1O
Yield: 90.2 %

Procedure:
Phenol was distilled from a boiling mixture of phenyl salicylate (42.8 gm, 0.20 mol), 2-toluidine (26.7 gm, 0.25 mol), and 1,2,4-trichlorobenzene (41 mL) as described in the literature procedure (Organic Syntheses, Coll. Vol. 3, 765). The cooled product mixture was transferred to an 250 mL Erlenmeyer flask and boiled with hexanes (75 mL) for 30 minutes. The solid product was isolated from the hot mixture by vacuum filtration. The solid was washed with more hexanes until the filtrate was colorless. Drying gave the pure 2′-methyl-salicylanilide (41 gm, 90%) as an off-white solid.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)C1CCCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
Step 1): A solution of bromodiphenylmethane (48.2 g, 195 mmol) in DMSO (30 ml) was added dropwise to a solution of nipecotamide (25 g, 195 mmol) and K2CO3 (27 g, 195 mmol) in CH3CN (100 ml) and DMSO (50 ml) under stirring and cooling in an ice-bath for 1 hour. After the addition was complete, the mixture was stirred overnight at room temperature. The insoluble precipitates were filtered off and then the filtrate was evaporated. To the residue was added H2O and AcOEt, and agitated. The organic layer was washed with H2O, dried over MgSO4 and evaporated to give 1-diphenylmethylpiperidin-3-carboxamide, 33 g (57.5%): mp 86°-87° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]([CH3:45])[CH3:44])=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]([CH3:44])[CH3:45])=[CH:39][CH:38]=2)=[O:36])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.3 g), 2-bromo-4'-dimethylaminoacetophenone (0.2 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using toluene-ethyl acetate (2:1) as an eluent. Fractions containing objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-dimethylaminophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.26 g).