Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:33]1[CH:34]=[C:29]([CH3:28])[CH:30]=[C:31]([O:38][CH3:39])[CH:32]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: COc1cc(C)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C)cc(OC)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-methyl-2-methoxylphenylboronic acid (92 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil which was purified by flash column eluted with 30% ethyl acetate in hexane, then recrystallization from ethyl ether to yield 4-(3-methoxy-5-methyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
Piperidine (660 μl, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of 4-chloro-3-nitrotoluene (358 mg, 2.08 mmol, commercially available product). The resulting mixture was stirred at 100° C. for 17 hours. The mixture was cooled to room temperature, and then water was added thereto. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=50/1). Thus, 1-(4-methyl-2-nitrophenyl)piperidine (212 mg, 46.2%) was yielded as a colorless oily material. TLC Rf 0.54 (hexane/ethyl acetate=10/1).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)=[O:2].CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C=O>[C:27]1([CH2:26][CH2:25][CH2:24][CH2:23][N:5]2[C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:3]([CH:1]=[O:2])=[CH:4]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCCc1ccccc1
Reactant: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(C=O)cn2CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
A solution of methyl 3-formylindole-5-carboxylate (2.234 g, 11.0 mmol) and potassium tert-butoxide (1.259 g, 11.2 mmol) in dry N,N-dimethylformamide (50 ml) was added with 1-bromo-4-phenylbutane (2.385 g, 11.2 mmol) and left under stirring at room temperature for 18 h. After that the solvent was evaporated off under reduced pressure, the resulting residue was partitioned between a NaCl saturated solution (50 ml) and chloroform (50 ml) and the aqueous phase was extracted with chloroform (3×50 ml). After drying and evaporating off the solvent under reduced pressure, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 70:30, thereby obtaining 2.847 g of the title compound (87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[S:22])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1OC
Yield: 95.1 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (1.57 g) and phosphorus pentasulfide (3.3 g) in pyridine was refluxed for 15 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.58 g).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[OH2:7]>>[CH2:4]([OH:7])[C@@H:2]([OH:3])[C@H:1]([OH:6])[C@H:4]([OH:7])[C@@H:2]([OH:3])[CH2:1][OH:6]
Reactant: CC(O)C(=O)O
Reactant: O
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
It appeared that the fatty acid soap could be well acidified with 3-5 parts by weight of lactic acid per 100 parts by weight of reaction product. In example XXIII poorly water-soluble crystals of non-esterified dulcitol, which formed in the first water extraction, are eliminated by filtration.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:35]([C:27]3[C:28]4[O:33][CH2:32][O:31][CH2:30][C:29]=4[CH:34]=[C:25]([F:24])[CH:26]=3)=[O:36])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cc(F)cc4c3OCOC4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=513.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
The compound (817.3 mg) obtained in Example 102-2 was dissolved in anhydrous methanol (24.5 ml) and added with 1-methyl-2-imidazolealdehyde (309.4 mg) and sodium cyanoborohydride (235.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (910.0 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:16](#[N:18])[CH3:17]>Cl.O1CCOCC1>[CH3:17][C:16]1[NH:18][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(C)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (0.50 g, 2.4 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (4.8 mL) was added acetonitrile (1.0 mL, 19.0 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Ether was added and the mixture was extracted with water (2×). The combined aqueous phases were then concentrated to afford methyl 2-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.52 g, quant). LC-MS: (FA) ES+ 219.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cl)c1N
Reaction time: 6 h
Yield: 50.4 %

Procedure:
To 2-amino-3-chlorobenzoic acid (1.72 g, 10 mmol) in DMF (5 mL) were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and was stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-chlorobenzamide (860 mg). LCMS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>CCCCCC.O1CCCC1>[C:1]1([S:7][CH2:8][Li:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: CSc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]CSc1ccccc1

Procedure:
To a solution of 1.17 ml. of thioanisole in 20 ml. of dry tetrahydrofuran were added 8.4 ml. of a 1.2M solution of n-butyllithium in n-hexane at -20° C. and the mixture was stirred at the same temperature of 1.5 hours to give a 0.28M solution of phenylthiomethyllithium in tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[O:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 150 °C
Reaction time: 120 h
Yield: 45.7 %

Procedure:
2-Amino-4-chloropyridine (5.0 g), N-methyl pyrrolidone (40 ml), 2-hydroxy-5-nitrotoluene (11.9 g) and diisopropylethylamine (20.1 g) were put in a reaction vessel, followed by heating and stirring under a nitrogen atmosphere at 150° C. for 5 days. The reaction mixture was cooled down to room temperature and concentrated under a reduced pressure. To the resultant residue was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature overnight. To the reaction mixture was added tetrahydrofuran (200 ml) to partition. The aqueous layer was extracted with diethyl ether (100 ml). The organic layer was washed with brine (100 ml×2), dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The precipitated solid was suspended in diethyl ether and filtered off. The solid was washed with diethyl ether:ethyl acetate=1:1, and dried under aeration to provide the titled compound (4.36 g, 45.7%) as a yellow solid.
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:6]=1[F:24].C(#N)C.C[Si](I)(C)C>C(OCC)(=O)C>[NH2:4][C:5]1[C:6]([F:24])=[C:7]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
Into a reaction flask under nitrogen, [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid methyl ester (6, 15.00 g, 36.6 mmol) is combined with 300 mL of anhydrous acetonitrile and trimethylsilyl iodide (21.95 g, 109.7 mmol). The reaction is stirred at room temperature overnight, then diluted with 500 mL of ethyl acetate and washed with 2×500 mL of 10% aqueous sodium thiosulfate. The aqueous layers are combined and back extracted with 1×500 mL of ethyl acetate. The organic layers are combined and washed with 1×500 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (7, 13.34 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.Cl.[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CCNC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3-fluorobenzoic acid (2.00 g, 9.13 mmol) was dissolved in dichloromethane (20 mL) and cooled in an ice/water bath as EDCl (2.10 g, 10.9 mmol) was added. After addition, the reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes before adding isoamylamine (1.59 g, 18.3 mmol). After 12 hours, water was added and the reaction mixture was extracted with ethyl ether. The combined organic layers were washed sequentially with 1N HCl, 1N NaOH and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on silica gel eluting with 5% ethyl acetate in heptane to afford the title compound (I-5a).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:33]=[O:34])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C., followed by adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was added and the reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 350%, to 100% ethyl acetate in hexane to give a light yellow solid (569, 2.84 g, 71.7%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:27])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)=[O:2].S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)=[CH:40][N:39]=[CH:38]1
Reactant: O=Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1c(-c2ccccc2-c2cnco2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
13 mg of 3-(2-formylphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of methanol. To the mixture were added 11 mg of tosylmethylisocyanide and 8 mg of potassium carbonate, followed by heating under reflux overnight. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. It was filtered through NH silica gel and silica gel, and the filtrate was evaporated. The resulting precipitates were washed with ether and dried, to give 9 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([CH2:7][NH2:8])=[N:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([N:19]2[CH2:24][CH2:23][O:22][C@@H:21]([CH2:25][NH:26][C:27](=O)[O:28]C3C=CC([N+]([O-])=O)=CC=3)[CH2:20]2)[CH3:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([N:19]2[CH2:24][CH2:23][O:22][C@@H:21]([CH2:25][NH:26][C:27]([NH:8][CH2:7][C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[O:28])[CH2:20]2)[CH3:18])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Cn1nnc(CN)n1
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)NCc2nnn(C)n2)C1

Procedure:
Prepared in similar fashion to Example 16 but using C-(2-methyl-2H-tetrazol-5-yl)-methylamine and 4-nitrophenyl {(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate Isomer II (prepared as described in WO 02/26723).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=O)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.[NH:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.CC(O)=O>C(Cl)Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH2:45][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1)[CH:27]=2
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc2ccc(CN3CCCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.008 g, 0.01 mmol) (from Example 15, step 5) was mixed with pyrrolidine, DCM (0.20 mL) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol). The reaction mixture was stirred at room temperature for 2 h. HBr in AcOH (8.0 M; 0.20 mL, 1.6 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After concentration to remove the solvent, the crude product was diluted with MeOH and neutralized with a small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C25H32N7O (M+H)+: m/z=446.2. Found: 446.1.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH3:23]>CN(C)C=O>[C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][O:16][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCBr
Reactant: Cc1cc(C)c(-c2cccc(CO)n2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOCc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
(6-Mesitylpyridin-2-yl)methanol (1.03 g, 4.54 mmol) was dissolved in N,N-dimethylformamide (5 mL) and the solution was charged with sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.7 mmol). The reaction stirred for 0.5 h at room temperature. Bromopropane (0.52 mL, 5.7 mmol) was added last. The reaction ran for 2.5 h. The solution was quenched with water, extracted with ether, dried, and concentrated. Flash chromatography (15% ethyl acetate/hexanes) gave 0.65 g (53% yield) of the desired product.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][CH2:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:12][CH2:13][C:14]1([CH3:19])[CH2:17][O:18][C:1]([CH3:6])([CH3:2])[O:16][CH2:15]1
Reactant: CC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Reaction time: 5 h
Yield: 8383.8 %

Procedure:
1.0 g of p-toluenesulfonic acid is added to 96.2 g (0.80 mol) of 2-(hydroxymethyl)-2-methyl-1,3propanediol in 600 ml of acetone, and the mixture is heated to reflux. After 5 hours, the solution is neutralized while still hot by adding 3.0 g of potassium carbonate, and the mixture is stirred for a further 30 minutes and subsequently allowed to stand at room temperature overnight. The mixture is filtered through kieselguhr, and the solvent is removed by distillation in vacuo, leaving about 180 ml of a turbid, oily residue, which is purified by distillation in a high vacuum, giving 78 g of the alcohol 31 as a colorless, viscous oil.