Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N+:8]([O-])=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.O1CCCC1>[Ni].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-n2cnc(N3CCCC3)c2C1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ccccc1C1=NCc2c(N3CCCC3)ncn2-c2ccc(Cl)cc21
Reaction time: 15 h

Procedure:
A mixture of 1 g of 8-chloro-6-(2-fluorophenyl)-3-pyrolidinyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide, 5 g of Raney nickel, 25 ml of tetrahydrofuran and 25 ml of ethanol was hydrogenated at atmospheric pressure for 15 hours. The catalyst was removed by filtration over Celite and the filtrate was evaporated. The residue was passed over silica gel using 5% (v/v) of ethanol in methylene chloride. Crystallization from ether/hexane gave end product as yellowish crystals with mp 114°-118° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2](/[CH:18]=[CH:17]/[C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/c2ccc(F)cc2C=O)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A solution of 10 g (49.26 mmol) of 2-bromo-5-fluorobenzaldehyde in 200 ml of dry DMF is mixed with 7.27 g (54.18 mmol) of 4-methoxystyrene, 1.5 g (4.93 mmol) of tri-2-tolylphosphine, 330 mg (1.48 mmol) of palladium(II) acetate and 10.3 ml (73.89 mmol) of triethylamine under argon and stirred at 100° C. for 12 hours. After reaction is complete, the reaction solution is cooled to room temperature and concentrated to dryness. The resulting residue is taken up in 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases are dried over sodium sulfate. After filtration, the solution is concentrated to dryness, and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 7.79 g (55% yield) of a colorless solid are obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cccc(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-fluorobenzene and isolated as light-yellow gum. MS(m/e): 425.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: COC(=O)C=Cc1ccc(C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C)cc1
Yield: 88.2 %

Procedure:
1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) prepared by above Step 1 was dissolved in methanol solution (7.9 mM) under nitrogen atmosphere. Then Pd—C was added thereto, hydrogenated under a hydrogen balloon for 1 to 2 hrs at room temperature. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexane (1:10) as an eluant to give 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) (yield: 95%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=O)[NH:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([Cl:24])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc[nH]c2=O)cc1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2cncnc2Cl)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4-(3,4-Dihydro-4-oxo-5-pyrimidinyl)-o-phenylene diacetate (194 mg) (0.67 mmol) are added to 5 ml of phosphorus oxychloride. After stirring at 100° C. for 6 hours the mixture is concentrated in a vacuum at 40° C. The residue is dissolved in dichloromethane/methanol (99:1 v/v) and the solution is washed with water. The solution is dried over sodium sulphate and concentrated. The residue is crystallized using ethanol. The beige crystals are filtered off under suction, washed with petroleum ether and dried in a high vacuum at room temperature. There are obtained 90 mg of 4-(4-chloro-5-pyrimidinyl)-o-phenylene diacetate of m.p. 108° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:35])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:49](OC(=O)C)([F:51])[F:50]>O>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:49]([F:51])[F:50])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)(=[O:28])=[O:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of {2-ethyl-8-fluoro-3-[4-(morpholine-4-sulfonyl)benzyl]-4-oxo-1,4-dihydroquinolin-5-yloxy}acetic acid methyl ester (0.14 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.12 g) and acetic acid chlorodifluoromethyl ester (0.15 mL) was stirred at 80° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 by volume) gave title compound, 0.092 g.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]([CH2:9][CH3:10])=[N:28]2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)c1cccnc1Cl
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCc1nn(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Temperature: 170 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
1-(2-Chloropyridin-3-yl)propan-1-one (600 mg) and [4-(benzyloxy)phenyl]hydrazine hydrochloride (976 mg) were dissolved in ethanol (10 ml), and the mixture was stirred under microwave irradiation at 170° C. for 3 hr, and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (300 mg). MS (API+): [M+H]+ 330.1.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]([CH2:27][CH3:28])[C:22](=[S:29])[N:21]=1.CO.N>O1CCOCC1>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:29][C:22]3[N:21]=[C:20]([NH2:19])[CH:25]=[C:24]([NH2:26])[N+:23]=3[CH2:27][CH3:28])[CH2:7][S:8][C@H:9]12
Reactant: CCn1c(N)cc(N)nc1=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CC[n+]1c(N)cc(N)nc1SCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3cephem-4-carboxylic acid and 1.8 g of 4,6-diamino-1-ethyl-2-(1H)-pyrimidinethione suspended in 20 ml of dry dioxane was cooled to 0° C.; and 3 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 40° C.; the solution was stirred for one hour; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.6 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 2.87 g of the title compound as a solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:24])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (for a preparation See Intermediate 10)(58 mg, 0.128 mmol) and N1,N1-dimethylethane-1,2-diamine (22.50 mg, 0.255 mmol) in DMF (3 mL) were added HATU (72.8 mg, 0.191 mmol) and DIPEA (0.067 mL, 0.383 mmol). The resulting mixture was stirred for 30 min, then reaction mixture partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-(dimethylamino)ethyl)propanamide (34.6 mg, 48%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.71 min, MH+=525.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15]C)=O)[N:7]2[CH3:12].[CH3:17][NH2:18]>CO>[CH3:17][NH:18][C:13]([C:6]1[N:7]([CH3:12])[C:8]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)=[O:15]
Reactant: CN
Reactant: COC(=O)c1cc2c(OC)cccc2n1C
Solvent: CO
Product: CNC(=O)c1cc2c(OC)cccc2n1C
Temperature: 57.5 °C

Procedure:
A solution of methyl 4-methoxy-1-methyl-1H-indol-2-carboxylate (1.03 g, 4.7 mmole) in 2.0 M methylamine in methanol (40 mL) was sealed in a pressure bottle and heated at 55-60° C. for 60 hr. Concentration in vacuo yielded the title compound (1.05 g, quantitative) as a white solid: MS (ES) m/e 219.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].C(Cl)Cl.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](Cl)=[S:25])=[CH:19][CH:18]=1>O>[C:20]1([O:23][C:24](=[S:25])[O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([F:11])([F:12])[F:10])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: OC(c1ccccc1Br)C(F)(F)F
Reactant: S=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)C(OC(=S)Oc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
The title compound was prepared by an adaptation of the method described in Robins, M. J. et al. (J. Am. Chem. Soc. 1983, 105, 4059-4065). 1-(2-Bromo-phenyl)-2,2,2-trifluoro-ethanol (615 mg, 2.41 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar. DCM (4 mL) and TEA (1.2 eq., 0.403 mL, 2.89 mmol) were added via syringe. Phenyl chlorothionoformate (1.1 eq., 0.367 mL, 2.65 mmol) was added dropwise via syringe to the water-cooled solution. After completion of the addition, the reaction was stirred at RT for 16 h, poured into water, and extracted three times with DCM (10 mL). The combined organic extracts were dried over anhydrous MgSO4 filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 695 mg (74%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.58-7.68 (m, 2H), 7.36-7.48 (m, 3H), 7.27-7.36 (m, 2H), 7.04-7.15 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[Al](CC)(CC)[CH2:18][CH3:19]>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.O1CCOCC1>[CH2:18]([C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1)[CH3:19]
Reactant: CC[Al](CC)CC
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1nsc(-c2ccc(C)cc2F)c1C#N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (500 mg, 1.98 mmol, 1.00 equiv), 1,4-dioxane (20 mL), Pd(PPh3)4 (343 mg, 0.30 mmol, 0.15 equiv), Al(Et)3 (6.0 mL). The resulting solution was stirred for 3 h at 110° C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 150 mg (31%) of 3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17].[H-].[Na+]>COCCOC>[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:2]3[N:3]=[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]4[C:10]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17]
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1c(Oc2ccc(-n3c(=O)n(CC)c4cc(C)cnc43)cc2)nc2ccccn12
Temperature: 50 °C
Yield: 12.1 %

Procedure:
The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (504 mg), 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (302 mg) and NaH (67.3 mg) in DME (4 mL) was heated at 50° C. for 1 h. The mixture was heated at 200° C. for 3 h under microwave irradiation. The mixture was poured into sat. NaHCO2, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (62.0 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[CH:1][N:2]([CH3:4])[CH3:3])[CH2:17]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 80 °C
Yield: 75.4 %

Procedure:
DMF dimethyl acetal (5.82 ml, 0.044 mol) was added to a stirred solution of 1-boc-4-piperidone [Ashwood et al., J. Chem. Soc., Perkin 1, 641 (1995)] (8.73 g, 0.044 mol) in DMF (80 ml) and the reaction mixture was heated to 80° C. under N2 for 18 h. After cooling, the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated to afford the subtitle compound as a solid (8.44 g, 76%). Rf 0.33 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 255 (MH+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:20])=[C:17]([Cl:30])[CH:16]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH:29]=[CH:28][C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: O=C(Cl)OCCl
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCCl)cc1Cl
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of chloromethyl chloroformate (4.27 mmol) in EtOAc (20 ml) was slowly added a solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (4.0 mmol) and triethylamine (4.45 mmol) in EtOAc (20 ml) under stirring. Stirring was continued at room temperature for 4 h. The reaction mixture was washed with water and 0.5 M tartaric acid, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography using Et2O/hexane 4:1 as eluent to give the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[C:21]1([NH:27][C:28](N)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: NC(=O)Nc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccccc2)cc1C(C)(C)C
Yield: 9148 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.4 g (19.2 mmol) of 3,5-Bis(1,1-dimethylethyl)-4-(methoxymethoxy) benzylamine (prepared substantially in accordance with the procedures described in Example 1), 2.61 g (19.2 mmol) of N-phenylurea, 0.96 g (16 mmol) of acetic acid and 160 ml of toluene. Such reaction provided 700 g of N-[[3,5-bis-(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]-N'-phenylurea. (m.p. 168°-170° C.). The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 600 mg of the above-titled compound. m.p. 199°-202° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH2:52][C@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC[C@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 55% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z=506.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.[Cl-].[NH4+]>C(OCC)C.O>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 42.5 %

Procedure:
A solution of 2.72 g (10 mmoles) of 1,4-dibromo-2,5-difluorobenzene in 50 ml of ethyl ether, under an argon atmosphere stirred at -75° C., was treated dropwise with 4.2 ml of 2.5 M n-butyl lithium (hexane solution). The mixture was treated dropwise with a solution of 1.20 g (10.6 mmoles) of N-methyl-4-piperidone in 10 ml of ethyl ether, stirred a further 0.75 hours at -75° C., let warm to -30° C., and poured into a solution of 0.56 g (10.5 mmoles) ammonium chloride in 15 ml of water. The ether layer was washed with two 10 ml portions of water, dried (MgSO4), and evaporated to give 2.85 g of crude product which was purified by chromatography on a column of silica gel and crystallized to give 1.30 g of the title compound; mp 133°-135° C.