Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]3[CH:36]=[C:35]([NH2:37])[N:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([NH:37][C:35]1[CH:36]=[C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][N:18]([CH2:16][CH3:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)[N:32]=[CH:33][N:34]=1)=[O:15]
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: CCN1CCN(c2ccc(Nc3cc(N)ncn3)cc2)CC1
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2ccc(Nc3cc(NC(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.2 eq.) is added to a solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (350 mg, 1.18 mmol) in NMP (2 ml), at 70° C. and under an argon atmosphere. The resulting mixture is stirred at 70° C. for 2 h, allowed to cool to RT and concentrated. The residue is diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by trituration in MeOH followed by silica gel column chromatography (DCM/MeOH+1% NH3aq, 97:3) affords the title compound as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[C:45]=1[CH3:46]>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]4[C:45]=3[CH3:46])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1c(CCl)nc2ccccn12
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4nc5ccccn5c4C)cc3)C(=O)C(C)(C)O2)cc1
Yield: 1925.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1 g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.8 g, 77%,) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.25 (d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC: (96.3%, Condition-A).
Reaction SMILES: [C:1]1(=[O:15])[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:22]([N:2]2[CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7]([CH:6]3[C:1]2=[O:15])=[CH:8][CH:9]=[CH:10][CH:11]=4)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1NCCN2C(=O)c3ccccc3C12
Product: O=C(C1CCCCC1)N1CCN2C(=O)c3ccccc3C2C1=O
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 19.2 %

Procedure:
A mixture of 3,4-dihydropyrazino[2,1-a]isoindole-1,6(2H, 10bH)-dione (6.0 g, 0.03 mol, described in Example 6) and cyclohexylcarbonyl chloride (6.5 g, 0.045 mol) is stirred at 120° C. for 6.5 hr and evaporated. The residue is chromatographed on silica gel using 20% acetone in benzene and the eluates are evaporated. The residue is crystallized from acetone to obtain 2-(cyclohexylcarbonyl)-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1,6-dione (1.8 g), mp 167°-172° C., Anal. Calc'd. for C18H20N2O3 : C, 69.21% H, 6.45% N, 8.97% and Found: C, 69.25% H, 6.47% N, 8.93%.
Reaction SMILES: C(OC([NH:8][C@@:9]([CH3:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O.O.O=[Pt]=O>[NH2:8][C@@:9]([CH3:20])([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccccc1)C(=O)O
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@](N)(CC1CCCCC1)C(=O)O

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-2-methyl-3-phenylpropanoic acid (1.95 g, 6.98 mmol) was hydrogenated under H2 (50 psi), catalyzed by PtO2 (200 mg), in TFA/H2O (30/30 mL) overnight. The catalyst was filtered off and concentrated to give (S)-2-amino-3-cyclohexyl-2-methylpropanoic acid in quantitative yield. MS ESI +ve m/z 186 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:6][CH2:5]1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[Na+].[I-]>CC(N(C)C)=O>[Cl:21][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:13]/[C:12]([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[N:4]([CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:5][CH2:6]2)=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: C1COCCN1
Reactant: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCl)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A solution of 0.085 g (0.25 mmol) of 4-(2-chloro-ethyl)-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 1.3 ml of DMA was treated with 0.04 ml (0.50 mmol) of morpholine and stirred for 8 h at RT, a crystal of NaI was added and stirring was continued for 40 h. The reaction was extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (EtOAc) gave 0.008 g (8%) of the title compound as off-white viscous oil. MS: 392.0 (MH+, Cl).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[CH:21]=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].[OH-].[Na+]>[Cl-].[Na+].O.O>[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[C:21]([I:1])=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1c(Br)cc(C)c(C(=O)O)c1N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N-Iodosuccinimide (104 mg, 461 μmol) was put into an N,N-dimethylformamide (2.0 ml) solution of 2-amino-4-bromo-3-methoxy-6-methylbenzoic acid (I-3) (100 mg, 384 μmol), followed by stirring at room temperature for 40 minutes. The reaction liquid was put into water (30 ml), followed by controlling at pH of 4 with aqueous 2 N sodium hydroxide solution, then saturated brine (30 ml) was added, the product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→100:3) to obtain the entitled compound (84.9 mg, 57%) as a yellow white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:33])=O.C(Cl)(=O)C(Cl)=O>>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([Cl:33])=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: O=S(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(Cl)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O

Procedure:
The [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid is reacted with a suitably selected chlorinating agent such as thionyl chloride, oxalyl chloride, and the like, preferably thionyl chloride; according to known methods; to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH:16]=[CH2:17])[CH:5]=1.[O:18]([C:25]1[C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[C:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][C:27]([C:36]([F:37])([F:38])[F:39])=[CH:28][CH:29]=1)#[CH:17]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccccc1
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Oc2ccccc2)cc(F)c1NS(C)(=O)=O
Yield: 75 %

Procedure:
N-(4-Aminomethyl-2-ethenyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (35 mg, 0.13 mmol) was reacted with 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (17 mg) to give the title compound (22 mg, 75%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:18])[O:13][C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=1.[C:20]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH3:21].[Li]>>[C:24]([O:23][C:20](=[O:22])[CH2:21][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:18])[O:13][C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=1)=[O:19])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCc1oc(C)nc1-c1cccc(C(=O)OC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CCCc1oc(C)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(2-Methyl-5-propyl-oxazol-4-yl)-benzoic acid methyl ester (0.47 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(2-methyl-5-propyl-oxazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (0.58 g) as a light-brown oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of phenol (13.16 g) in DMF (10 ml) was added in portions over 10 minutes to a stirred suspension of sodium hydride (3.12 g) in DMF (100 ml). After 2 hours, a solution of 3-(chloromethyl)thiophene (14.50 g) in DMF (30 ml) was added in one portion and the resulting mixture was stirred at room temperature for 3 hours then poured into water and extracted with ether. The extracts were washed successively with water, dilute aqueous sodium hydroxide, and aqueous sodium chloride, then dried and concentrated to give 3-(phenoxymethyl)thiophene (18.86 g, 91% yield) as a white solid. An analytical sample, recrystallised from methanol, had mp 49°-50° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:16]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)#[N:17]>C(O)C>[C:16]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20][N:21]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:22][CH2:23]1)#[N:17]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: N#CC1(c2ccccc2)CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
A solution of 5.0 parts of 1,2-epoxy-3-(1-naphthoxy)-propane and 5.0 parts of 4-cyano-4-phenylpiperidine in 79 parts of ethanol is refluxed for 24 hours. Evaporation of the solvent from the reaction mixture under reduced pressure affords 3-(4-cyano-4-phenylpiperidino)-1-(1-naphthoxy)-2-propanol. The hydrochloride salt is then prepared by addition of a solution of hydrochloric acid in isopropanol to an isopropanol solution of the free amine. The resulting salt is separated by filtration and recrystallized from isopropanol to afford 3-(4-cyano-4-phenylpiperidino)-1-(1-naphthoxy)-2-propanol hydrochloride, melting at 213°-215° C. and represented by the following structural formula ##STR7##
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)#[N:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccccc1C#N)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 890 mg, 6.06 mmol), 2-cyanophenylboronic acid (CombiBlock; 1.00 g, 6.8 mmol), copper(II) acetate (1.25 g, 6.9 mmol) and triethylamine (2 mL, 14.4 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 60° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(2-cyano-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (439 mg, 29%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[F:30][C:31]1[CH:65]=[CH:64][C:34]([C:35](/[N:37]=[C:38]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:36])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:35](/[N:37]=[C:38]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:4][C:3]=3[N:17]\2[C@H:18]2[CH2:19][CH2:20][C@@H:21]([C:24](=[O:25])[NH:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23]2)=[O:36])=[CH:64][CH:65]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2N)CC1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(OCCN4CCCCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. The product was isolated as an off-white solid (96 mg, 15% yield). M/Z calc'd for C31H40FN5O3: 549.68. found 550 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][O:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=[C:25]([NH2:38])[N:24]=1>>[CH3:21][O:22][C:23]1[C:28]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=[C:4]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:3]=2)=[CH:27][N:26]=[C:25]([NH2:38])[N:24]=1
Reactant: Clc1nc(OC2CCOCC2)cc(N2CCOCC2)n1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1nc(N)ncc1-c1nc(OC2CCOCC2)cc(N2CCOCC2)n1

Procedure:
According to Example 1 the reaction of 2-chloro-4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (20 mg, 0.067 mmol) with 4-methoxy-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (50 mg, 0.200 mmol) afforded 4′-methoxy-4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)-2,5′-bipyrimidin-2′-amine. The crude product was treated with morpholine (0.058 mL, 0.667 mmol) in NMP (2 mL) and heated under microwave irradiation (high absorption, fixed hold time) for 60 minutes at 200° C. Additional morpholine (0.058 mL, 0.667 mmol) was added and the solution heated at 200° C. under microwave irradiation for another 30 minutes, then another 60 minutes at 210° C. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the TFA salt of 2-amino-5-(4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-2-yl)pyrimidin-4(3H)-one was isolated as an off white solid (17.1 mg, 68%), LCMS (m/z): 375.1 (MH+). Rt: 1.74 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)c(CO)cc1OC
Solvent: ClCCl
Product: COc1cc(Br)c(CCl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Bromo-4,5-dimethoxy-phenyl)-methanol (2.47 g) is dissolved in methylene chloride (30 ml) and thereto is added thionyl chloride (875 μl), and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and thereto is added hexane and the resulting crystal is filtered to give 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene (2.25 g). MS (m/z): 229/231
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[CH:9][N:8]=[C:7]1[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:5])=[O:4].C>C(OCC)(=O)C.[Pd]>[CH3:29][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH2:19])[CH:13]=2)=[CH:9][N:8]=[C:7]1[Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])(=[O:4])=[O:5]
Reactant: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1N
Reaction time: 14 h
Yield: 48.6 %

Procedure:
2-(tert-Butyl-dimethyl-silyl)-5-(4-methyl-3-nitro-benzyl)-imidazole-1-sulfonic acid dimethylamide (2.32 g) was dissolved in 125 ml of ethyl acetate and 0.50 g of 10% palladium over charcoal (PdWC) was added. The reaction mixture was hydrogenated on a Parr shaker at 44 lb/in2 for 14 hr. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (1:3), giving 1.05 g of 5-(3-amino-4-methyl-benzyl)-2-(tert-butyl-dimethyl-silyl)-imidazole-1-sulfonic acid dimethylamide as a white solid. ##STR127##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:40])/[C:10](/[CH2:28][O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:11]/[C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][O:19]C3CCCCO3)=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:40])/[C:10](/[CH2:28][O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][OH:19])=[O:17])=[CH:26][CH:27]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)NOC3CCCCO3)cc2)COc2cccc3ccccc23)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)NO)cc2)COc2cccc3ccccc23)CC1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
(E)-4-(3-(1-Methylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide obtained in Example (1-1-3) (333 mg, 0.61 mM) was dissolved in methanol (5 ml) and the resulting solution was cooled to 0° C. To the resulting solution, trifluoroacetic acid (0.23 ml, 5 eq.) was slowly added, and the resultant was reacted at room temperature for 18 hrs. After the completion of reaction, the solvent was removed under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 250 mg of the title compound as a white solid (yield 89%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:26][C:27]1[C:32]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])(=[O:36])=[O:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:31][C:32]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
A mixture of tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (Intermediate 24) (0.050 g, 0.137 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.065 g, 0.151 mmol), PdCl2(dppf)-CH2Cl2Adduct (5.61 mg, 6.87 μmol) and 1 N aq. sodium bicarbonate (0.275 ml, 0.275 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (Hex:EtOAc=1:2) to give tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (3.90 mg, 4.5%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.48 (9H, s), 1.55-1.72 (2H, m), 2.05-2.22 (2H, m), 2.92-3.12 (2H, m), 4.02-4.25 (2H, m), 4.30-4.48 (1H, m), 6.90-7.04 (2H, m), 7.14 (1H, J=8.0 Hz), 7.80-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8.69 (1H, s), 8.70 (1H, br s), 8.79 (1H, br s). m/z=632.2 [M+1]+.