Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.O.N.Cl.C([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([NH2:37])=[O:30])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(=O)O)co3)c1)C2=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(N)=O)co3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylic acid (300 mg, 0.685 mmol) obtained in Step 1 of Example 124 was dissolved in DMF (7 mL), and the mixture was stirred at room temperature for 2 hours after adding 28% ammonia water (0.0830 mL, 1.37 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (263 mg, 1.37 mmol), and 1-hydroxybenzotriazole.monohydrate (210 mg, 1.37 mmol). Thereafter, ethyl acetate was added to the mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (261 mg, 87%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][SH:6].Br[CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)=[CH:17][C:16]=1[Cl:39])=[O:12].[Cl-].[NH4+]>O1CCCC1>[Cl:39][C:16]1[CH:17]=[C:18]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:29])([F:27])[F:28])[O:23][N:22]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11](=[O:12])[CH2:10][S:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: FC(F)(F)CS
Reactant: O=C(CBr)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CSCC(F)(F)F)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 0 °C

Procedure:
To a suspension of 0.0271 g of 55% oily sodium hydride in 2 mL of tetrahydrofuran, a solution of 0.0802 g of 2,2,2-trifluoroethanethiol and 0.20 g of 2-bromo-N-[2-chloro-4-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl]methylacetamide in 2 mL of tetrahydrofuran was added while stirring the suspension at 0° C., and the resultant mixture was stirred at room temperature for 10 minutes. After the completion of the reaction, 2 mL of a saturated ammonium chloride aqueous solution was added to the reaction mixture and the resultant mixture was extracted with ethyl acetate (3 mL×2). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:9 to 1:3) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.074 g of the objective substance as a colorless resinoid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(CN)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CNS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Aminomethyl)-3,4-dimethoxybenzene (18 ml., 120 mmole, 2 eq.) was added to a solution of methanesulfonyl chloride (4.64 ml., 60 mmole, 1 eq.) in dichloromethane (30 ml., 2.0M) at 0°. Additional dichloromethane (90 ml., final concentration of 0.5M) was then added. The reaction was allowed to warm to room temperature and stirred 2 days. The solid which had precipitated was filtered off and washed with additional dichloromethane. The filtrate was washed with 0.5N HCl (2×200 ml.) and water (200 ml.), dried (MgSO4), filtered, and concentrated to give 13.93 g. of yellow solid. This material was recrystallized from ethyl acetate:hexane (1:1, 75 ml.). The crystalline product was washed with ethyl acetate:hexane (1:1) and ether and dried to give 12.41 g. of N-[(3,4-dimethoxy)methyl]methanesulfonamide; m.p. 78°-81°.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: OCc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
NaH (0.22 g, 5.60 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), cooled to 0° C. and pyrazin-2-yl methanol (0.49 mL, 5.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (0.66 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. An additional such portion of NaH and pyrazin-2-yl methanol in THF was added after 18 h. After 2 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was dissolved in EtOAc (120 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 100% (over 12 min) then 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (62.9 mg, 10.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: C1CCNCC1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 48.7 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and piperidine (0.8 g) are suspended in N-methylpyrrolidone (10 ml), and the mixture is heated at 110°-120° C. for 5 hours in a sealed tube. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-2-methyl-6-oxo-9-(1-piperidyl)-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.3 g) as yellow cubic crystals. m.p. 273°-276° C. (decomp.)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
The mixture of 702 mg of 6-chloronicotinonitrile, 954 mg of t-butylpiperazin-1-carboxylate, 1.2 g of potassium carbonate, and 10 mL of N,N-dimethylacetamide, was stirred at room temperature for 3 hours, then heated to 60° C. and stirred further for 4 hours. After cooling the reaction mixture back to room temperature, water was added thereto, and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 1.39 g of t-butyl-4-(5-cyanopyridin-2-yl)piperazin-1-carboxylate [140-1] was obtained as a white solid.
Reaction SMILES: C[C:2]1[O:3][C:4]([CH:7]=O)=[CH:5][CH:6]=1.Cl.[NH2:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].[OH-].[Na+]>O>[CH3:7][C:4]1[O:3][C:2](=[N:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:6][CH:5]=1
Reactant: NN1CCNC1=O
Reactant: Cc1ccc(C=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=CCC(=NN2CCNC2=O)O1
Reaction time: 8 h

Procedure:
98.3 pts. by wt. of 2-methylfuran-5-aldehyde ar added to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 1,000 pts. by vol. of water which has been brought to pH 4.5 with sodium hydroxide solution and the mixture is stirred overnight. The precipitae is filtered off, washed with water and recrystallised from ethanol. 126 pts. by wt. of 1-(5-methylfurylideneamino)-2-oxo-imidazolidine of melting point 194°-6° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.O[CH:29]([C:32]1[CH:48]=[C:47]2[N:35]([CH2:36][C:37]3[C:38]2=[N:39][C:40]2[C:45]([CH:46]=3)=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34](=[O:49])[C:33]=1[CH3:50])[CH2:30][CH3:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:50][C:33]1[C:34](=[O:49])[N:35]2[C:47](=[CH:48][C:32]=1[CH:29]([O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6])[CH2:30][CH3:31])[C:38]1=[N:39][C:40]3[C:45]([CH:46]=[C:37]1[CH2:36]2)=[CH:44][CH:43]=[CH:42][CH:41]=3
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]glycine (1.15 g, 6.6 mmol) in CH2Cl2 (50 mL) under an argon atmosphere was added 1,3-dicyclohexylcarbodiimide (1.35 g, 6.5 mmol). After stirring at room temperature for 0.5 h, (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (1.0 g, 3.3 mmol) was added followed by a few mg of 4-dimethylaminopyridine. The resulting mixture was allowed to stir at room temperature overnight and then was filtered. The filtrate was washed successively with 2.5% aqueous NaHCO3 (100 mL), 0.1N HCl (100 mL) and H2O (100 mL), dried over sodium sulfate and concentrated in vacuo. The solid residue was purified by column chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH/CH2Cl2 to provide the title compound. 1H NMR (CDCl3) d 8.34 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.91, (d, J=8.3 Hz, 1H), 7.81, (m, 1H), 7.63, (m 1H), 7.32 (s, 1H), 5.96 (apparent br t, J=7.0 Hz, 1H), 5.25 (s, 2H), 5.03 (br s, 1H), 4.15-3.94 (m, 2H), 2.36 (s, 3H), 2.04-184 (m, 2H), 1.44 (s, 9H), 0.99 (t, J=7.4 Hz, 3H). Anal. Calcd for C26H29N3O5.1/8 H2O: C, 67.04; H, 6.33; N, 9.02. Found: C, 66.95; H, 6.54; N, 8.83.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(O)cc1
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(O)c([N+](=O)[O-])c1

Procedure:
It is further contemplated that 1,3-dihydro-6(4-hydroxyphenyl)-5-methyl-2H-imidazo[4,5-b]pyridin-2-one (Example 16) can be nitrated with nitric acid to obtain 6-(4-hydroxy-3-nitrophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar 3-O2N-4-HOC6H3, R1 and R3 =H, R5 =CH3 ], which in turn can be reduced by catalytic hydrogenation to obtain 6-(3-amino-4-hydroxyphenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one I; Ar =3-H2N-4-HOC6H3, R1 and R3 =H, R5 =CH3 ].
Reaction SMILES: FC(F)(F)C(O)=O.Cl.Cl.C([NH:17][C:18]1[CH:46]=[CH:45][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:20][CH:19]=1)(OC(C)(C)C)=O>ClCCl>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:45][CH:46]=1
Reactant: COc1cc2c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(N)cc3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Trifluoroacetic acid (1.00 ml, 13.1 mmol) was added to a suspension of 4-(4-(N-Boc-amino)anilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline dihydrochloride (100 mg, 0.172 mmol) in dichloromethane (2.0 ml) and the reaction stirred for 1 hour at ambient temperature. The solvents were removed in vacuo, the residue was suspended in water (2.0 ml) and saturated aqueous sodium bicarbonate solution (4.0 ml) was added. The aqueous phase was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with brine (25 ml) and evaporated in vacuo. Drying of the solid in vacuo yielded 4-(4-aminoanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (53 mg, 75% yield) as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:43]=[CH:42][C:25]([CH2:26][N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30](C(OC(C)(C)C)=O)[C@H:29]([CH3:41])[CH2:28]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>Cl.CC#N>[CH3:33][CH:31]1[NH:30][CH:29]([CH3:41])[CH2:28][N:27]([CH2:26][C:25]2[CH:42]=[CH:43][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:23][CH:24]=2)[CH2:32]1
Reactant: C[C@@H]1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)C[C@@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC(C)N1
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of (2R,6R)-tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2,6-dimethylpiperazine-1-carboxylate (72 mg, 0.12 mmol) in HCl—CH3CN (2 mL) was stirred for 2 hours. After removal of solvents, the residue was purified by prep-HPLC to afford the title product as a white solid (33 mg, 53%). LC-MS (ESI) m/z: 497 (M+1)+. 1H-NMR (400 MHz, DMSO) δ (ppm): 1.02-1.03 (d, J=6.4 Hz, 6H), 1.58 (t, J=10 Hz, 1H), 2.66 (d, J=10 Hz, 1H), 2.91 (t, J=6.8 Hz, 2H), 3.41 (s, 2H), 4.20 (d, J=10 Hz, 1H), 4.58 (d, J=10 Hz, 1H), 4.98 (s, 1H), 6.97 (t, J=2.4 Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=2.4 Hz, 2H), 7.16 (d, J=2.4 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 10.34 (s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[ClH:1].[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C1CCCCC1
Agent: Cl
Product: O=C(CNC1CCCCC1)OCc1ccccc1

Procedure:
Following the procedure as described in Example 26, STEP A, glycine benzylester hydrochloride was reacted with cyclohexanone to yield cyclohexylamino-acetic acid benzyl ester hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:8][Br:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncccc1Br
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Heat a mixture of 3-bromo-2-methylpyridine (J. Med. Chem. 1987, 30, 871-880) (2.7 g, 15.8 mmol), NBS (3.10 g, 17.42 mmol), and benzoyl peroxide (190 mg, 0.78 mmol) in carbon tetrachloride (50 mL) overnight at 85° C. Cool to ambient temperature, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with toluene to provide the title compound as a white solid (1.81 g, 45%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([F:25])=[C:6]([CH:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[C:5]([F:25])=[C:6]([CH:10]([O:24][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2F)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a stirred suspension of NaH (0.608 g, 15.2 mmol) in THF (100 mL) at 0-5° C. was added dropwise a solution of (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)-piperidine-1-carboxylate (4.35 g, 12.68 mmol) in THF (30 mL). The reaction mixture was stirred for an additional 1 h at rt. A solution of ethyl bromoacetate (2.52 g, 15.2 mmol) in THF (30 mL) was added dropwise and the mixture was refluxed for 5 h. Tlc showed the starting material had disappeared. The reaction mixture was poured into satd aq NH4Cl, extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (4.368 g, 80%). 1H NMR (400 MHz, CDCl3): 0.861 (m, 2H), 1.25 (m, 6H), 1.38&1.43 (s, 9H), 1.59-2.10 (m, 3H), 2.75 (m, 1H), 3.80 (s, 1H), 3.96 (m, 2H), 4.18 (m, 2H), 4.62 (m, 1H), 7.12 (m, 1H), 7.33 (m, 2H); MS (E/Z): 430 (M+1)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[NH:19][C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH:29]([CH3:31])[CH3:30].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[N:19]([CH:29]([CH3:31])[CH3:30])[C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)I
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1

Procedure:
NaH (84 mg) was added to a solution of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (346 mg) and 2-iodopropane (0.208 mL) in DMF (dry) (4 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, EtOAc/hexane) to give the title compound (283 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)[C:12]([F:26])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH2:29][OH:30]>>[CH2:24]1[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[C:12]([F:26])=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:28][CH2:29][OH:30])[CH:3]=4)[N:14]=3)=[CH:17][C:18]=2[O:25]1
Reactant: OCCBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: OCCNc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 2-bromoethanol were reacted together to give N4-(3,4-ethylenedioxyphenyl)-N2-[3-(hydroxyethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 15.44 min.; purity: 98.6%; MS (m/e): 398.05 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:21][O:20][C:15]1[N:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:12][N:13]([CH3:22])[C:14]=12
Reactant: Nc1ccccn1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3F)cn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Nc3ccccn3)cn(C)c12
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 77 %

Procedure:
A mixture of Example 23a (0.122 g, 0.405 mmol) and 2-aminopyridine (0.042 g, 0.445 mmol) in dimethyl sulfoxide (6 mL) was treated with potassium 2-methylpropan-2-olate (0.091 g, 0.81 mmol) and stirred at ambient temperature for 23.5 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% ethyl acetate in dichloromethane) to give 0.117 g (77%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(N)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Solvent: NCc1ccccc1
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)c2)c1
Yield: 121.9 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 ml) was heated at 175° C. for six hours. After cooling, excess benzylamine was removed by high vacuum distillation and ethyl acetate added to the residue. After washing the organic phase with water and drying over magnesium sulfate, the solvent was removed in vacuo and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179–180° C.