Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])O[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8]([O:11][CH2:14][CH3:15])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC([O-])[O-]
Reactant: CC(=O)NC1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC1=CCC(NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.7 g. of 4-acetamidocyclohexanone [prepared by the method of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970)], in 150 ml. of anhydrous ethanol were added 25 ml. of ethyl orthoformate containing a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred at ambient temperature for about 16 hours, after which time the volatile constituents were removed by evaporation in vacuo. The residue comprising the diethylketal was dissolved in 200 ml. of toluene and the toluene was removed by distillation under a nitrogen atmosphere, until all of the diethylketal had been converted to the 1-ethoxycyclohexene derivative. The solution was cooled, washed with aqueous sodium bicarbonate and dried. Evaporation of the toluene yielded a residue comprising 4-acetamido-1-ethoxycyclohexene melting at 100°-102° C. after recrystallization from an ether-hexane solvent mixture; yield=6.2 g.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)C>ClCCl>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOc1ccccc1O
Yield: 28.8 %

Procedure:
Catechol (35.0 g, 0.32 mol), potassium carbonate (109.0 g, 0.79 mol) and 1-bromohexane (52.5 g, 0.32 mol) were added to ethanol (300 ml) and heated under reflux for 48 h. After cooling, dichloromethane (300 ml) was added and the solid residues removed by filtration. The solvents were then removed in vacuo and the crude product was purified by column chromatography on silica gel to give title compound (17.9 g, 29%) as a colourless liquid. Found: C, 73.90; H, 9.20. C12H18O2 requires C, 74.19; H, 9.34. δH (CHCl3) 6.95-6.83 (m, 4H, ArH), 5.66 (s, 1H, OH), 4.04 (t, J 7, 2H, ArOCH2), 1.89-1.79 (m, 2H, ArOCH2CH), 1.55-1.35 (m, 6H, CH2), 0.95 (t, J 7, 3H, CH2CH3). MS (FAB), 194 (M+, 100%), 110 (45%), 95 (7%), 83 (12%), 69 (9%), 55 (18%).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.CCCCCC>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:14][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of compound (II) (0.0897 g, 16.5 mol %) and molecular sieve 4 Å (powder, 65 mg, dehydrated under the condition of 0.3 mmHg/300° C. for 24 h before use) in dichloromethane (2.5 ml) was added titanium tetraisopropoxide (0.045 ml, 15 mol %) under argon at room temperature. Stir for 1 hour. Trimethylsilyl cyanide (0.15 ml, 1.1 mmol) was added to the reaction mixture and stirred for additional 0.5 h. Then, the reaction mixture was cooled to −78° C. and benzaldehyde (0.1 ml, 1 mmol) was added to the reaction mixture. The resultant reaction mixture was stirred for 48 h. The disappearance of the aldehyde was monitored by thin layer chromatography (ethyl acetate/hexane=1/5). The reaction mixture was quenched with 1 N HCl (10 ml) and stirred vigorously at room temperature for 6 h. After filtering, the mixture was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with brine (2×10 ml) and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was distilled under reduced pressure to afford 2-hydroxyl-2-phenylacetonitrile (87%, 93.2% e.e. (enantiomeric excess)). The result is listed in table 1.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH:3]=1.[Li].N>CCOCC.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[OH:5][CH2:4][CH:3]=[C:2]([CH3:1])[C:11]#[C:10][C:11]1([OH:12])[C:10]([CH3:14])([CH3:13])[CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH:3]=[C:2]1[CH3:1]
Reactant: CC1=CC2(CC(C)(C)C1=O)OCCO2
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Product: CC(C#CC1(O)C(C)=CC2(CC1(C)C)OCCO2)=CCO

Procedure:
Keto-α-isophorone is acetalized. The resulting 7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-6-en-8-one is condensed with trans-1-hydroxy-3-methyl-pent-2-en-4-yne in the presence of lithium in liquid ammonia and iron-(III) nitrate in ether to give rac. 8-(5-hydroxy-3-methyl-pent-3-en-1-yn-1-yl)-7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-6-en-8-ol (XVI).
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7](SC)=[N:8]2.[OH-].[NH4+:17]>C(#N)C.C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7]([NH2:17])=[N:8]2
Reactant: CSC1=Nc2cccc(Cl)c2C(C)N1
Reactant: [NH4+]
Agent: I
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(N)=Nc2cccc(Cl)c21
Temperature: 130 °C
Yield: 62 %

Procedure:
5-Chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (100 mg, 0.28 mmol) was suspended in a mixture of ammonium hydroxide (1 ml, 25% in H2O) and acetonitrile (1 ml) and heated in a microwave oven to 130° C. (15 min) and subsequently to 170° C. (30 min). The title compound (35 mg, 62%) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH:21](OC)=[O:22]>C1COCC1.O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:15]=1)[CH:21]=[O:22]
Reactant: Fc1ccc(Br)cc1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of N,N-diisopropylamine (8.87 mL, 62.9 mmol, 1.1 eq) in dry THF (80 mL) at −78° C. was added n-BuLi (2.5M in hexane, 27.5 mL, 68.5 mmol, 1.2 eq). The resulting mixture was stirred for 30 min then 1-bromo-4-fluoro-benzene (10 g, 57.1 mmol, 1 eq) in dry THF (20 mL) was added. The resultant mixture was stirred at −78° C. for 2 h then methyl formate (3.8 g, 62.9 mmol, 1.1 eq) was added and the reaction was stirred a further 30 min at −78° C. The reaction was allowed to warm to room temperature and stirred a further 1 h. The reaction was then diluted with water (100 mL), and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a yellow oil (6.25 g, 54%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C>CO.[Rh]>[C:1]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC1CCCCC1
Reaction time: 20 h

Procedure:
N-BOC-2-phenylethylamine (3.1 g) and 5% rhodium on alumina (1.1 g) are combined in methanol (40 ml) containing acetic acid (1.0 ml). The mixture is shaken under hydrogen at 50 psi for about 20 hours. The mixture is filtered, evaporated in vacuo, and the residue taken up into ethyl acetate. The organic solution is washed with water, 5% sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give N-BOC-2-cyclohexylethylamine.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[C:15]([CH3:16])[C:3]=12.[Cl-].[CH2:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O.C(=O)(O)[O-].[Na+]>C(#N)C>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:15]([CH3:16])[C:3]=12
Reactant: CCOC(=O)c1cnc2scc(C)c2c1O
Reactant: C=[N+]1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)c(C)c2c1O
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A suspension of ethyl 4-hydroxy-3-methylthieno[2,3-b]pyridine-5-carboxylate (Preparation 26, 0.92 g) and 4-methylenemorpholin-4-ium chloride (1.57 g) in acetonitrile (40 mL) is heated to 60° C. for 4 h. The resulting suspension is allowed to cool to room temperature, poured into water, and adjusted to neutral pH with saturated aq. sodium bicarbonate. The solution is extracted with CH2Cl2 (3×100 mL). The combined organic layers are washed with brine (25 mL), dried (Na2SO4), and concentrated to afford 1.26 g of the title compound as a yellow solid. Physical characteristics. M.p. 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.64, 4.37, 3.70, 3.38, 2.51, 2.47, 1.35; MS (ESI−) m/z 335 (M-H). Anal. Found. C, 56.93; H, 6.10; N, 8.26; S, 9.34.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[C:4]=1[CH3:13].[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(C)c1C
Yield: 69.7 %

Procedure:
4-Methoxy-2,3-dimethylnitrobenzene (21.1 g, 0.15 mol) was dissolved in ethanol (300 mL), and 10% palladium carbon (50% hydrate, 1.36 g) was added. The mixture was reacted at 40° C. for 2 hours under the hydrogen atmosphere. After cooling, the catalyst was removed, ethanol was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The dilution was washed with 5% sodium hydrosulfite, dried over sodium sulfate, and purified by small amount silica gel column chromatography (ethyl acetate, 1:1). The solvent was distilled off under reduced pressure, followed by recrystallization from hexane, to obtain 15.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([SH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[CH:16]12[O:21][CH:20]1[CH2:19][O:18][CH2:17]2>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@@H:20]2[CH2:19][O:18][CH2:17][C@H:16]2[OH:21])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Reactant: C1OCC2OC12
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
3,5-Bis(1,1-dimethylethyl)benzenethiol (0.0078 mole) and the title compound of Example 18 (0.0074 mole) are added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction is heated to reflux for 24 hours. The reaction is cooled to room temperature and poured into water (125 ml). The solution is made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts are dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator. The product is purified by silica gel chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.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>[NH2:7][C:11]1[CH:12]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]([CH:10]=2)=[N:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=3[C:18]([NH:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
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: OBO
Solvent: CCO
Product: CNC(=O)c1c2ccc(-c3cccc(N)c3)cc2nn1-c1ccc(F)cc1
Temperature: 8 °C
Yield: 222 %

Procedure:
A suspension of compound (xvii) (10 mg, 0.03 mmol), boronic acid (5.9 mg, 0.04 mmol), cesium carbonate (14 mg, 0.04 mmol) and tetrakis(triphenylphosphine)palladium (2 mg, 0.001 mmol) in ethanol (2 mL) were degassed and stirred under an atmosphere of nitrogen then heated to 8° C. After 3 h the reaction mixture was concentrated and the residue was partitioned between EtOAc (25 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and concentrated to give 6-(3-aminophenyl)-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (16) (12 mg) as a pale brown oil. The crude material was used directly. ESI-MS m/z calculated for [M+H]+: 361.13; found: 361.14.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][C:7]=1[NH:18][CH:19]=[CH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:5])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:5][C:4]1[C:20]([C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[CH:19][N:18]=[C:7]2[S:8][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([CH3:11])[C:6]=12
Reactant: CCOC(=O)c1c(NC=CC(=O)C(C)C)sc(-c2ccccc2)c1C
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Yield: 80.6 %

Procedure:
The compound obtained in Example 13 (50 g) and diphenylether (500 ml) were mixed and the ethanol formed as the reaction proceeded was distilled off while continuing the heating under reflux for 4 hours. After allowing to cool followed by distilling diphenylether off under reduced pressure a crude crystal was precipitated and washed with n-hexane to obtain the title compound (35.1 g, 80.6%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].S(Cl)([Cl:16])=O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:16][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: CNC(=O)c1ccc(CO)cc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide (2.11 g) in THF (46.1 mL) was added dropwise thionyl chloride (1.01 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane). The objective fractions were collected, and washed with diisopropyl ether, and the precipitate was collected by filtration. The filtrate was concentrated, and the residue was washed with diisopropyl ether. This procedure was repeated three times to give the title compound (0.96 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[N:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[CH:23][CH:22]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A slurry of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (int BB) (1.22 g, 0.00274 mol) in acetone was cooled to 0° C. and 5 N aqueous hydrochloric acid (15 mL) was added dropwise keeping the temperature less than 5° C. After the addition was complete, the mixture was stirred at ambient temperature for three hours. The solution was filtered through celite and neutralized with a saturated aqueous solution of sodium bicarbonate. The precipitate which formed was filtered, washing with water and dried in vacuo overnight to give 4{-4-amino-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-cyclohexanone as a white solid (0.937 g, 0.00243 mol): 1H NMR (DMSO-d6, 400 MHz) 8.68(d, 2H), 8.29(s, 1H), 7.56 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 5.25-5.30 (m, 1H), 2.67-2.75 (m, 2H), 2.24-2.43 (m, 6H).
Reaction SMILES: [CH3:1]C1C=C(C=CC=1C)C(Cl)=O.[C:12]1([N:18]2[C:22]3[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O>[Pd].C1(NC2C=C(C=CC=2OC)N)C=CC=CC=1>[C:12]1([N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH3:1])[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2nc3ccc(O)cc3n2-c2ccccc2)cc1C
Reactant: Cc1ccc(C(=O)Cl)cc1C
Agent: [Pd]
Agent: COc1ccc(N)cc1Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(-c3ccc(C)c(C)c3)n(-c3ccccc3)c2c1

Procedure:
The nitro group of the above-described intermediate was then reduce to an amino group by catalytic hydrogenation using a palladium on activated carbon catalyst, essentially as previously described, resulting in 3-phenylamino-4-methoxyaniline with was then reacted with 3,4-dimethylbenzoyl chloride as previously described. This intermediate was then cyclized to the corresponding benzimidazole with phosphorous oxychloride as previously described to yield 1-phenyl-2-(3,4-dimethylphenyl)-6-methoxybenzimidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:15][CH:16]=1.O.NN>CCO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH2:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1C#Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1C#Cc1cccc(CCCN)c1
Reaction time: 4 h

Procedure:
A solution of 2-(3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propyl)isoindoline-1,3-dione (13) (0.094 g, 0.24 mmol) and hydrazine hydrate (0.038 g, 0.75 mmol) in dry EtOH (5 mL) was heated under reflux for 3 h. Additional hydrazine hydrate (0.038 g, 0.75 mmol) was added and heating continued for a further 4 h. The solvent was removed under reduced pressure and the residue was sonicated in a mixture of hexanes and aqueous Na2SO4. The mixture was filtered through Celite and washed with hexanes. The organic layer was concentrated under reduced pressure. Purification by flash chromatography (10:1:9 EtOAc/7 M NH3 in MeOH/hexanes)gave 3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propan-1-amine as a colorless oil. Yield (0.015 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.39 (m, 3H), 7.25 (m, 1H), 7.13-7.22 (m, 3H), 2.65 (t, J=7.6 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.46 (s, 6H), 1.61-1.69 (m, 2H), 1.40 (br s, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[Cl:12][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OCc1cccc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: OCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2-acetoxymethyl-6-chloropyridine (17.3 g; 93.3 mmol), prepared as in step 2, in 250 mL 10% aqueous HCl was heated at reflux for 1.5 hours. The reaction mixture was cooled to room temperature and poured into 300 mL saturated aqueous sodium bicarbonate. The solution was adjusted to pH 9 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The 6-chloro-2-hydroxymethylpyridine was used with no further purification.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH2:5][C:6]([C:9]2[N:10]=[CH:11][N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH:22]([CH3:24])[CH3:23])[C:14](=[O:25])[C:13]=23)=[N:7]O)[CH2:3][CH2:2]1>C(O)C.Cl>[CH:1]1([C:4]2[O:26][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH:22]([CH3:24])[CH3:23])[C:14](=[O:25])[C:13]=34)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)n1c(=O)c2c(C(CC(=O)C3CC3)=NO)ncn2c2ccccc21
Agent: Cl
Solvent: CCO
Product: CC(C)n1c(=O)c2c(-c3cc(C4CC4)on3)ncn2c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 3-(3-cyclopropyl-1-hydroximino-3-oxopropyl)-4,5-dihydro-5-isopropyl-4-oxo-imidazo[1,5-a]quinoxaline (0.3 g) in ethanol (25 ml) was added one drop of 4 M hydrochloric acid and the mixture was heated at reflux for 10 min. Cooling the resulting solution to room temperature gave the title compound as a white crystalline precipitate, which was collected by filtration and dried. M.p. 247°-249° C. (Compound 8).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[CH:27][CH:26]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]=[CH:26][CH:27]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=Cc1ccnc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
1.95 g (5.37 mmol) of (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 0.93 g (5.90 mmol) of quinoline-4-carboxaldehyde and 0.9 g of magnesium sulfate in 18 ml of toluene and subsequently reduced with 223 mg (5.90 mmol) of sodium borohydride in 18 ml of methanol. The title compound ##STR65## is obtained (2.2 g, 82%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.35, FD-MS: M+ =503, 505, [α]D =19.3 (c=l, MeOH), IR: 1635, 1595, 1565 cm-1.