Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(CCCC2)C[CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:23])[CH2:21][CH:20]([CH3:22])[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13]1.ICC>>[CH2:2]([N:13]1[CH:14]2[CH:19]([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([CH3:22])[CH2:21][C:12]1([CH3:23])[CH3:11])[CH3:3]
Reactant: C1CCC2NCCCC2C1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCI
Product: CCN1C2CCCCC2C(C)CC1(C)C
Temperature: 105 °C
Reaction time: 3 h

Procedure:
1-ethyl-2,2,4-trimethyl decahydroquinoline was prepared by the reaction of the intermediate saturated decahydroquinoline with the alkyl halide. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was placed into a reactor vessel equipped for heating and agitation. 15.6 grams (0.1 mole) of iodoethane was added dropwise to the reactor vessel. The mix was heated to 105° C. while stirring for 3 hours. A thick slurry formed which was filtered out and washed wih acetone. The acetone wash liquid was then concentrated and distilled using a 3 inch Vigreaux column to yield 7.1 grams of a product boiling at 58° - 60° C. at 0.25 mm Hg. The NMR spectra of the product was consistent with the desired product, 1-ethyl-2,2,4-trimethyl decahydroquinoline. Calculated carbon, hydrogen, nitrogen content for the formula C14H27N is 80.31% carbon, 13.00% hydrogen, and 6.69% nitrogen while the measured contents were 79.93% carbon, 13.54% hydrogen, and 6.35% nitrogen respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:13][C:14]1[C:19]2=[C:20]([CH:26]([CH3:28])[CH3:27])[C:21]([C:23]([OH:25])=O)=[CH:22][N:18]2[N:17]=[CH:16][N:15]=1.Cl.[CH2:30]([NH2:32])[CH3:31].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH2:30]([NH:32][C:23]([C:21]1[C:20]([CH:26]([CH3:27])[CH3:28])=[C:19]2[N:18]([CH:22]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:3]1[CH:4]=[C:5]([C:8]([NH:10][O:11][CH3:12])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:25])[CH3:31]
Reactant: CONC(=O)c1ccc(F)c(Nc2ncnn3cc(C(=O)O)c(C(C)C)c23)c1
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)c1cn2ncnc(Nc3cc(C(=O)NOC)ccc3F)c2c1C(C)C
Yield: 51 %

Procedure:
A mixture of Example 13 (20 mg, 0.052 mmol), ethylamine hydrochloride (6 mg, 0.08 mmol), BOP reagent (34 mg, 0.08 mmol), and N-methyl morpholine (0.012 mL, 0.1 mmol) in dimethyl formamide (0.5 mL) was stirred at RT for 18 h. The mixture was purified by reverse phase HPLC. The appropriate fractions were concentrated and the residue was converted to the HCl salt to obtain the desired product as a white solid (11 mg, 50%). LC/MS; (M+H)+=415.2
Reaction SMILES: [C:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][N:14]([O:17][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:13][CH2:12]2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][N:14]([O:17][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:13][CH2:12]2)[CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)ON1CCC(C(CCO)c2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)C(=O)ON1CCC(C(CC=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)propan-1-ol (4.6 g, 14.4 mmol) in DCM (100 mL) was added Dess-Martin periodinane (6.1 g, 14.6 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 2M aqueous sodium hydroxide (3×50 mL), dried and evaporated to give the title compound.
Reaction SMILES: CN.[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1.[N:29]1C=CC=[CH:31][CH:30]=1>>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:29][CH2:30][CH3:31])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: c1ccncc1
Agent: CN
Product: CCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (250 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was heated and stirred overnight at 70° C. The solvent was distilled off under reduced pressure, ethanol (2 ml) was added to the residue, and solids were collected by filtration to obtain the title compound (87 mg) as an orange powder.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]1[C:5]([Cl:33])=[N:6][C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]([NH2:32])=[O:31])[CH:21]=2)=[N:8][C:9]=1[N:10]([CH3:12])[CH3:11].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:33][C:5]1[C:4]([CH2:3][C:2]#[N:1])=[C:9]([N:10]([CH3:12])[CH3:11])[N:8]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]([NH2:32])=[O:31])[CH:21]=2)[N:6]=1
Reactant: CN(C)c1nc(Cc2ccccc2-c2cc(C(N)=O)cc3ccccc23)nc(Cl)c1CC(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(C)c1nc(Cc2ccccc2-c2cc(C(N)=O)cc3ccccc23)nc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a solution of N-(4-{([5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide (0.360 g, 0.76 mmol) in pyridine (15 mL) at rt was added trifluoroacetic anhydride (0.161 mL, 1.14 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 15 hours. The volatiles were removed in vacuo and the remaining residue was partitioned between EtOAc and saturated aqueous ammonium chloride solution. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the resulting crude product by silica gel chromatography eluting with 20% EtOH in CHCl3 gave N-(4-{([4-chloro-5-(cyanomethyl)-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as an amorphous solid (0.345 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([F:25])([F:24])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:24][C:16]([F:25])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(N1CCCC1)C(F)(F)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(N1CCCC1)C(F)(F)Oc1cccc(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-fluoro-phenol (4.5 g, 40.0 mmol), and K2CO3 (6.1 g, 44.0 mmol) in 40 g of DMAC at 100° C. was added 2-bromo-2,2-difluoro-1-pyrrolidine-1-yl-ethanone (9.1 g, 40.0 mmol). The mixture was kept at that temperature for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 120 mL of H2O and 30 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 10% NaOH (10 g) and H2O (2×15 g) and dried over Na2SO4. The product (8.3 g, >90% purity by NMR) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[C:15]([CH3:23])=[C:16]([C:19]([F:22])=[CH:20][CH:21]=1)[C:17]#[N:18])=[O:13].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:37][OH:38])[CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CCOC(C)=O>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]2[C@@H:33]([CH2:37][O:38][C@:12]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[C:16]([C:17]#[N:18])[C:15]=3[CH3:23])([OH:13])[CH2:11]2)[CH2:32]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c([C@@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylethylamine (156 mL, 894 mmol) was added to a stirred, room temperature mixture of 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (176 g, 688 mmol) and (R)-4-N-Boc-2-hydroxymethyl-piperazine (149 g, 688 mmol) in THF (3500 mL) and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 3 L EtOAc, washed 2× with 1500 mL 10% w/w NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient), to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c(C(=O)O)c1-c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (1.71 g, 7.26 mmol) and DIPEA (1.39 mL, 7.98 mmol) in DCM (50 mL) were added morpholine (664 μL, 7.62 mmol), HOAt (99 mg, 726 μmol) and EDCI (1.53 g, 7.98 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was washed with brine (100 mL) and the organic layer was dried (Na2SO4) and concentrated. Purification by column chromatography (silica, DCM/(7 M NH3 in MeOH), 98:2) afforded the desired product (1.73 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:26][CH:25]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:26][CH:25]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC(C)(O)C1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-white crystalline product. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 7) m/z=474.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[N:9]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: CCOC(=O)CBr
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc2c(-c3ccco3)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (4 mL) was treated with 4-(N,N-dimethylamino)pyridine (5 mg, 0.04 mmol) and ethyl bromoacetate (55 mL, 0.5 mmol), stirred at room temperature for 16 h and purified directly by chromatography [SiO2; EtOAc:Heptane (1:2)] to give the title compound (50 mg, 35%) as a white solid.
Reaction SMILES: [H-].[Na+].Cl.[Br:4][C:5]1[CH:9]=[N:8][NH:7][C:6]=1[O:10][CH3:11].CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Br:4][C:5]1[C:6]([O:10][CH3:11])=[N:7][N:8]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COc1[nH]ncc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
Sodium hydride (354 mg, 60% dispersion in oil) was added portionwise to a solution of 4-bromo-3-methoxy-2H-pyrazole, hydrochloride salt (755 mg) in degassed DMF (12 ml) under argon at room temperature. The resulting suspension was stirred at room temperature for 10 minutes. tert-butyl 4-methylsulphonyloxypiperidine-1-carboxylate (1.087 g) was added to the stirred suspension. The resulting mixture was stirred at 90° C. for 20 hours. The reaction mixture was allowed to cool to room temperature, quenched with water, diluted with ethyl acetate then water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-methoxy-pyrazol-1-yl)piperidine-1-carboxylate (670 mg). NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 2.03-2.10 (m, 2H), 2.78-2.93 (m, 2H), 3.93 (s, 3H), 3.99-4.07 (m, 1H), 4.13-4.31 (m, 2H), 7.24 (s, 1H)
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12]([C:22]([C:24]3[C:25]([F:39])=[N:26][C:27]([NH:30][C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:28][CH:29]=3)=[O:23])=[CH:11]2)(=O)=O)C=CC=CC=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:19]1([C:18]2[C:13]3[C:12]([C:22]([C:24]4[C:25]([F:39])=[N:26][C:27]([NH:30][C:31]5[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[CH:28][CH:29]=4)=[O:23])=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(Nc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ccc(C(=O)c3c[nH]c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To (7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone (78, 0.235 g, 0.432 mmol) in 10.0 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is added. The reaction is stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fraction are combined and concentrated under vacuum to provide the desired compound (P-4022, 104.5 mg). MS (ESI) [M+H+]+=405.0.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:13]=[CH:14][CH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1>C1COCC1.N12CCCC1=NCCC2.C1C=CC=CC=1>[CH2:17]([C:16]1[C:2]2[C:1](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4](=[O:11])[C:3]=2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CC1CC=CCC1
Reactant: O=C1CCC(=O)C2CC=CC=C12
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=CCCc1cccc2c1C(=O)C1=C(CCCC1)C2=O
Reaction time: 65 h
Yield: 34 %

Procedure:
A 45 g sample of the tetrahydronaphthoquinone-butadiene dimer adduct of Example 1 was dissolved in 400 ml THF and 20 drops of 1,5-diazabicyclo[4.3.0]non-5-ene were added. The solution was stirred for 65 hours while exposed to air. The THF was then blown off with air and the residue was dissolved in benzene. The benzene solution was filtered to remove insoluble impurities and the solution was then chromatographed on Florisil. The product was eluted with a 4:1 mixture of benzene/ethyl acetate, and the yield of crude product was 15 g (34% yield). An analytical sample, after recrystallization first from ethanol, then from hexane, had a mp of 111° to 113° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[NH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([O-:60])=[O:59].[Na+]>COCCOCCOC>[CH:44]1([O:43][N:38]2[C:37]([CH3:51])([CH3:50])[CH2:36][CH:35]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:4]3[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]4[CH2:14][C:15]([CH3:28])([CH3:29])[N:16]([O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[C:17]([CH3:19])([CH3:20])[CH2:18]4)[N:7]=[C:2]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[N:3]=3)[CH2:40][C:39]2([CH3:42])[CH3:41])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC1(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Yield: 69.5 %

Procedure:
A mixture of 20.0 g (27.3 mmol) of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine, 25.1 g (0.164 mol) of sodium 6-aminohexanoate, and 200 ml of diglyme is heated at 140° C. for seven hours. The reaction mixture is partitioned between 1N HCl (500 ml) and ether (400 ml), and the aqueous phase is extracted with ether (200 ml). The combined organic layers are washed with water (2×200 ml) and saturated aqueous sodium chloride solution (200 ml), and then dried over anhydrous magnesium sulfate, and finally concentrated to obtain a glass. Purification by flash chromatography on silica gel (2:1 heptane:ethyl acetate) affords 15.7 g (69% yield) of the title compound as a white powdery glass.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](I)=[N:12][N:11]3[CH:17]=2)=[O:6])[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([CH2:4][C:5]([NH:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[C:20]([NH:26][C:27]([C:29]5[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=5)=[O:28])[CH:21]=4)=[N:12][N:11]3[CH:17]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(CC1CC1)Nc1cn2nc(I)ccc2n1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CC5CC5)cn4n3)ccc2F)n(C)n1
Yield: 22.9 %

Procedure:
Using 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (171 mg, 0.5 mmol), N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (150 mg, 0.6 mmol), potassium carbonate (104 mg, 0.75 mmol) and N,N-dimethylformamide (4 mL), and by a reaction in the same manner as in Example 191, the title compound (53 mg, 23%) was obtained as pale-pink crystals.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1.[N:57]1([CH2:63][CH2:64]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:48])([F:50])[F:49])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([O:38][CH2:64][CH2:63][N:57]5[CH2:62][CH2:61][O:60][CH2:59][CH2:58]5)=[O:37])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1
Reactant: OCCN1CCOCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C(=O)CCC(=O)O)CC3)CC2)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C(=O)CCC(=O)OCCN4CCOCC4)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 100 mg (0.12 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1′-(3-carboxy-propionyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 17 μL (0.14 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13](=[O:18])[NH:12][C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([N:16]([CH3:17])[C:14]1[C:13](=[O:18])[NH:12][C:11](=[O:19])[N:10]([C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])[CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCCCNC(=O)n1cc(NC)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(N(C)C(=O)c2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
N-hexyl-5-methylamino-2,4-dioxo-pyrimidine-1-carboxamide (0.08 g, 0.30 mmol) was dissolved in dry pyridine (4 mL). To the resulting solution, benzoyl chloride (0.04 mL, 0.39 mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hrs, then concentrated under reduced pressure. The crude was purified by column chromatography using SI (5 g) cartridge (cyclohexane:EtOAc 84:16) to afford the title compound (0.05 g, 45%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.9 Hz, 3H), 1.28-1.33 (m, 6H), 1.53-1.59 (m, 2H), 3.29 (s, 3H), 3.34 (dt, J=5.7, 7.0 Hz, 2H), 7.33-7.43 (m, 5H), 8.22 (br s, 1H), 8.31 (br s, 1H) 8.88 (t, J=5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 13.96, 22.48, 26.44, 29.04, 31.31, 37.17, 41.41, 121.47, 127.17, 128.43, 130.27, 135.29, 137.63, 149.03, 150.05, 159.01, 171.78. MS (ESI) m/z: 371 [M-H]−.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:20](=[O:24])[C:21]([CH3:23])=[O:22])=[CH:8][CH:7]=[CH:6][N:5]2[C:25]=1[CH2:26][C:27]#[CH:28].C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(O)C>[C:20]([NH:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][O:10][C:9]1[C:4]2[N:5]([C:25]([CH2:26][C:27]#[CH:28])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:24])[CH:21]([CH3:23])[OH:22]
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)C(C)=O)cccn12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)C(C)O)cccn12
Yield: 47.8 %

Procedure:
To a solution of 2-methyl-3-(2-propynyl)-8-(2-pyruvamido-6-methylbenzyloxy)imidazo[1,2-a]pyridine (287 mg) in the mixture of acetic acid (0.13 ml) and ethanol (3 ml), sodium cyanoborohydride (72 mg) was added portionwise for 2.5 hours at 5° C. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (10 g) and eluted with a mixture of chloroform and methanol (100.1) to give 8-(2-lactamido-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (138 mg).