Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13]CC)=[O:12])O1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:28][C:29]1[N:38]=[C:37]([C:39]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[C:34](I)[CH:35]=2)[N:30]=1>C(O)C.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]>[NH2:28][C:29]1[N:38]=[C:37]([C:39]([N:41]2[CH2:42][C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:49]2)=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]([OH:13])=[O:12])[CH:35]=2)[N:30]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C(=O)O)ccc2n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
266 mg of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 399 mg of potassium carbonate, 3 ml of water and 17.7 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added to a solution of 300 mg of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline (“A130”) in 10 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min, during which a clear solution forms. It is filtered through kieselguhr while hot. On cooling, ethyl 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzoate crystallises out (retention time LC-MS: 2.056 min; “gradient polar” method). The crystals are taken up in 10 ml of sodium hydroxide solution (2 N) and stirred at 25° C. for 12 h. The mixture is extracted three times with 10 ml of diethyl ether each time, the aqueous phase is adjusted to pH 7, and the mixture is re-extracted with 10 ml of diethyl ether each time. The organic phase is dried over sodium sulfate and filtered, the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22]2>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22]2)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CNCCO)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CNCCO[Si](C)(C)C(C)(C)C)ccc21
Yield: 86 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-[(2-hydroxyethyl)aminomethyl]-1-(tert-butoxycarbonyl)indole (5.40 g) was dissolved in DMF (50 mL) and the solution was treated with imidazole (940 mg, 13.8 mmol) and tert-butyl dimethylsilylchloride (2.08 g, 13.8 mmol), followed by purification by slurry using diisopropyl ether and hexane to obtain 5-{[2-(tert-butyldimethylsilyloxy)ethyl]aminomethyl}-1-(tert-butoxycarbonyl)indole (4.80 g, yield 86%, 2 steps).
Reaction SMILES: C[S:2]([OH:5])(=[O:4])=[O:3].[OH-].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20]>O1CCCC1>[S:2]([O-:5])([O-:15])(=[O:4])=[O:3].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)O
Agent: COC(=O)c1cnc(NC(C)C)[n+](C)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.09 mlg [sic] (16.78 mol; 1.61 g) of methane-sulfonic acid is added to a solution of 1-methyl-2-isopropylamino-5-methoxycarbonylpyrimidinium hydroxide (3.48 g; 15.35 mol) dissolved in 100 ml of anhydrous tetrahydrofuran. The mixture is stirred under argon at room temperature for one hour. The precipitate which forms is filtered and then rinsed with ether.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:29][CH:28]([CH2:30]OS(C)(=O)=O)[O:27][C:26]2=[O:36])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:29][CH:28]([CH2:30][N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3]3)[O:27][C:26]2=[O:36])[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(COS(C)(=O)=O)OC2=O)CC1
Reactant: COC(=O)CN1CCNCC1
Product: COC(=O)CN1CCN(CC2CN(C3CCN(C(=O)OC(C)(C)C)CC3)C(=O)O2)CC1

Procedure:
Analogously to Example 1, starting from methyl 2-piperazinoacetate [obtainable by reaction of methyl α-chloroacetate with piperazine] by reaction with 3-(1-BOC-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one, 3-(1-BOC-4-piperidyl)-5-[4-(methoxycarbonylmethyl)piperazino]methyloxazolidin-2-one is obtained after customary working up.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])O)[C:5]([Cl:18])=[CH:4][N:3]=1.CN(C)C=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.CCOCC.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([S:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: OC(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.1 %

Procedure:
The 2,5-dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (580 mg, 2.0 mmol) obtained in Referential Example 24 was dissolved in thionyl chloride (3.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added toluene, followed by further concentration. The residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (375 mg, 2.6 mmol) and potassium carbonate (414 mg, 3 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 17 hours. After the reaction mixture was cooled to room temperature, diethyl ether (60 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography (hexane:ether=10:1) to give the title compound (484 mg, 58%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=1)#[N:2].C([O-])([O-])=[O:37].[K+].[K+].OO>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=1)(=[O:37])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Nc2cc(-c3ccccc3)no2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C(N)=O)c(Nc2cc(-c3ccccc3)no2)c1
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (38 mg, 0.080 mmol) in DMSO (1 mL), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.800 mL) were added. After being stirred at 100 C for 10 min, the mixture was purified by HPLC to give tert-butyl (1S,2R)-2-(4-carbamoyl-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (6 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:18][CH2:19][CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[Br:27][CH2:28][CH2:29][CH2:30]Br>CN(C)C=O.C(OCC)(=O)C.[Cl-].[NH4+]>[Br:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[C:3]([CH2:18][CH2:19][CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2
Reactant: CCCc1c(O)ccc2c1ccn2-c1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCBr)ccc2c1ccn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-hydroxy-4-propyl-N-(4-chlorophenyl)indole (Step D; 500 mg, 1.75 mmol) and potassium carbonate (484 mg, 3.50 mmol) in 7 mL of dimethylformamide (DMF) was added 1,3-dibromopropane (1.77 g, 8.75 mmol). The mixture was stirred at ambient temperature for 2 hours and diluted with ethyl acetate and saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue was used as is in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Cl.Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)CCC.O.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>[N:22]1[CH:23]=[CH:24][C:19]([C:9]2[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: Brc1ccncc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.33 g, 6.07 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 4-bromopyridine hydrochloride (0.608 g, 3.13 mmol) and Cs2CO3 (3.0-6 g, 9.39 mmol) in H2O (15 mL) was added. The mixture was degassed three times with Ar/vacuum cycle before being charged with Pd(Ph3P)4 (0.270 g, 0.230 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice-bath. The precipitates were collected, dried on vacuum to give a solid (0.420 g). MS 171.0 (M+H)
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH:17]1([C:20]2[C:29]([CH:30]=[CH:31][C:32](N(OC)C)=[O:33])=[C:28]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:19][CH2:18]1.C(O)(=O)C.[Na+].[Cl-]>O1CCCC1.O>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]1[C:20]([CH:17]2[CH2:18][CH2:19]2)=[N:21][C:22]2[C:27]([C:28]=1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CON(C)C(=O)C=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (100 mg, 4.17 mmol) in tetrahydrofurane (4 ml) under argon is added at −5° C. ethyl acetoacetate (546 mg, 4.19 mmol), butyllithium (n-heptane solution (soln.), 1.55 ml, 4.19 mmol), and a solution of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-N-methoxy-N-methyl-acrylamide in tetrahydrofurane (9 ml). After 5 h stirring at room temperature, the reaction mixture is added to a suspension of sodium hydride (200 mg, 8.33 mmol), ethyl acetoacetate (1.09 g, 8.39 mmol), and butyllithium (n-heptane soln., 3.1 ml, 8.37 mmol) in tetrahydrofurane (8 ml) at −5 to 0° C. After 60 minutes at 0° C., acetic acid (100%, 2.25 g, 37.5 mmol), 25% aq. NaCl (5 ml), and water (3 ml) are added and the mixture is stirred vigorously for 10 min. The (upper) organic phase is successively washed with 25% aq. NaCl (5 ml) and water (5 ml), and evaporated to dryness under reduced pressure. The residue is dried under vacuum at 40° C. and purified by silica gel chromatography (hexane/ethyl acetate 3:1) to give (E)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dioxo-hept-6-enoic acid ethyl ester, semisolid honey. MS (ES): [M+H]+ 446.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 89.8 %

Procedure:
To a suspension of 6-benzyloxy-4-(4-chlorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (4.25 g, 9.5 mmol) in toluene (50 ml) was added thionyl chloride (1.4 ml, 19 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.98 g, 89.8%) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8](O)=O.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:8]([CH:3]3[CH:2]([OH:1])[CH2:7][CH2:6][CH2:5][NH:4]3)=[N:22][C:17]=2[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)C1NCCCC1O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc2[nH]c(C3NCCCC3O)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0.2M solution of 3-hydroxypiperidine-2-carboxylic acid (500 μL, 100 μmol) in DMA was added to a 0.2M solution of 4-tert-butyl-1,2-diaminobenzene (500 μL, 100 μmol) in DMA followed by BOP (44 mg, 100 μmol). The reaction was stirred at room temperature for 16 hours before concentrating in vacuo. A solvent mixture of THF/AcOH (5/1, 1 mL) was added to the residue, and the reaction heated to 60° C. for 16 hours. The reaction was cooled, concentrated in vacuo, dissolved in DMSO (1 mL) and purified using preparative HPLC (XTERRA-C18 (250×19 mm, 10μ, mobile phase A: Acetonitrile, mobile phase B: 10 mM ammonium acetate in water; eluting with a gradient of 10-70% organic with a flow rate of 16 mL/min over 18 minutes) to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH:12]C(=O)C)[CH3:2]>CCO.Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH2:12])[CH3:2]
Reactant: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Agent: Cl
Solvent: CCO
Product: CCc1cccc([N+](=O)[O-])c1N
Yield: 64.6 %

Procedure:
A solution of N-(2-ethyl-6-nitrophenyl)actamide (Example 139e) (0.62 g, 2.98 mmol) in EtOH (21 mL) and concentrated HCl (13 mL) was refluxed for 24 h. EtOH was evaporated, the residue was diluted with water (10 mL) and the pH was adjusted to pH˜8 with NaOH (2.0M aqueous solution). The neutralized solution was extracted with EtOAc (3×50 mL), the combined extract was washed with water and brine, and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified on HPLC to give 0.32 g (64%) of 2-ethyl-6-nitroaniline as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.87 (m, 1H), 7.27-7.32 (m, 1H), 7.16 (broad s, 2H), 6.55-6.62 (m, 1H), 2.55 (q, J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:49](Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:23][CH:24]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.65 g), potassium carbonate (0.533 g) and dimethylformamide (6 ml) is added benzyl bromide (0.33 g). The mixture is stirred at room temperature for one hour, then diluted with ethyl acetate. The solution is washed with water, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-5-benzyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.49 g).
Reaction SMILES: C(O)(=O)CC.[CH3:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:10]=[CH:9][C:8]=1[CH:22]=[CH:23][CH:24](O)[CH3:25].[CH2:27]([O:29][C:30](OCC)([O:32]CC)[CH3:31])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:32])[CH2:31][CH:22]([C:8]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][C:7]=1[CH3:6])[CH:23]=[CH:24][CH3:25])[CH3:28]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cc(OCc2ccccc2C)ccc1C=CC(C)O
Solvent: CCC(=O)O
Product: CC=CC(CC(=O)OCC)c1ccc(OCc2ccccc2C)cc1C
Temperature: 105 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Propionic acid (cat.) was added to a solution of 31.5 (69 mg, 0.24 mmol) in 1,1,1-triethoxy-ethane (440 μL, 2.4 mmol). The reaction was stirred at 105° C. overnight. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (5% ethyl acetate in hexanes) to yield 33 mg (39%) of 3-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-hex-4-enoic acid ethyl ester (31.6). LC/MSD m/e: 375.0 (M+Na).
Reaction SMILES: [OH-].[Ba+2:2].[OH-].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([O-:6])=[O:5]>O>[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O-:13])([O-:6])=[O:5].[Ba+2:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O-:13])([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccccc1[O-]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Heat 3 1. of distilled water in a 4-1. flask to 75° C. on a steam bath. Add 16.67 g. of barium hydroxide, [Ba(OH)2.8H2O] and 21.67 g. of o-nitrophenol. Stir vigorously for 1 hour at 75° C. and let stand overnight at room temperature. Decant to another flask, heat to 75° C., add 4.17 g. of o-nitrophenol, stir and let stand overnight at room temperature. Decant and filter on a Buchner funnel through Whatman No. 4 paper and adjust the filtrate to 3 1. with distilled water.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:16]([O:15][C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110° C. (0.37 mm).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:22]1([CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1)N1CCCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 34A (0.1 g, 0.4 mmol) and pyrrolidine (0.13 mL, 1.6 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.05 g, 0.8 mmol) and acetic acid (0.2 mL) and the mixture stirred overnight at 70° C. The residue was concentrated and purified by flash chromatography on silica gel using 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to provide the title compound, which was dissolved in methanol (1 mL), treated with a solution of 1M hydrochloric acid in ether (2 mL) and stirred at ambient temperature for 2 hours. The precipitate was filtered to give the title compound as the hydrochloride salt. 1H NMR (DMSO-d6) δ 11.26 (s, 1H), 8.34 (d, J=8.4 Hz, 2H), 7.85-7.91 (m, 3H), 7.79 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 4.51 (qd, J=7.4, 7.2 Hz, 1H), 3.70 (dd, J=11.4, 4.5 Hz, 1H), 3.12-3.20 (m, 1 Hz), 2.95-3.02 (m, 1H), 2.89 (dq, J=11.2, 8.1 Hz, 1H), 1.91-2.00 (m, 2H), 1.79-1.88 (m, 1H), 1.69 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-])=O)=[C:4](Cl)[N:3]=1.[O-2].[Mg+2]>[Pd].O1CCOCC1>[NH2:13][C:5]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(Cl)ncc1N
Reaction time: 48 h
Yield: 55 %

Procedure:
In a Parr hydrogenator, ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (2.16 g, 8.12 mmol), 10% Pd/C (2.0 g, 0.94 mmol), magnesium monoxide (1.60 g, 39.7 mmol) and 1,4-dioxane (100 mL) were charged. The hydrogenation was allowed to go at room temperature under 50-60 psi for 2 days while monitored by LCMS. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated and purified via flash chromatography eluting with 50 to 100% ethyl acetate in heptane to give ethyl 5-amino-2-chloropyrimidine-4-carboxylate (0.90 g, 55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH:2]=[O:1]
Reactant: Cc1ccc(O)c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
2-Hydroxymethyl-4-methylphenol (3.1 g, 22.4 mMol) was dissolved in CHCl3 (95 ml). The solution was treated with manganese dioxide (8.7 g, 100 mmol) and the reaction stirred at ambient temperature overnight under an argon atmosphere. The reaction was then filtered through Celite and the solvent evaporated. The residue was subjected to chromatography (eluant: ethyl ether/hexane) to give 2-hydroxy-5-methylbenzaldehyde as a pale green solid (0.63 g, 20.7%).