Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1
Reactant: BrCCCCBr
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
Compound 175 (200 mg, 0.59 mmol) obtained in Reference Example 114 was dissolved in 4 ml of dimethylformamide. To the solution were added 163 mg (1.18 mmol) of potassium carbonate and 0.56 ml (1.18 mmol) of 1,4-dibromobutane, and the mixture was stirred at 50° C. for 4 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from hexane/ethyl acetate to give 170 mg (yield 61%) of Compound 177 as pale yellow grains.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CC(N(C)C)=O.[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]12([CH2:27][NH:28][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[N:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: Nc1cccc(C(=O)O)n1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-aminopyridine-2-carboxylic acid (10 g, 72.4 mmol) in DMF (200 mL) at RT, is sequentially added 25.2 mL of DMA (144.8 mmol), 12 g of 1-admantylmethylamine (72.4 mmol) and 38.4 g of BOP (86.88 mmol). The resulting mixture is stirred at RT for 16 h. The reaction mixture is added to 400 mL of ice/water. Filtration affords the title compound which is used in subsequent reactions without further purification.
Reaction SMILES: C([C:3]1[C:4]([C:16]([NH2:18])=[O:17])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)[C:7]=1[CH3:8])C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C1(C)C=CC=CC=1.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>[CH3:8][C:7]1[N:6]([C:9]2[CH:10]=[C:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([NH2:18])=[O:17])[CH:3]=1
Reactant: CCc1c(C(N)=O)nn(-c2cccc(Br)c2)c1C
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 90 °C
Yield: 93.4 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxamide (0.237 g, 0.8 mmol) and 2-trifluoromethoxyphenyl boronic acid (0.262 g, 1.2 mmol) in n-propanol/toluene (1.27 ml:0.42 ml) mixture were added tetrakis(triphenylphosphine)palladium (0.019 g, 0.01 mmol) and 2M sodium carbonate (0.84 ml). The reaction mixture was heated at 90° C. for 16 hours, and then cooled and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate and concentrated. The crude product was purified by silica-gel column chromatography (3.5:1.5 hexanes/acetone) to give the product (0.270 g, 88%) as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=c1cnc2cc(F)ccc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoroquinoxalin-2(1H)-one (Intermediate 145, 87 mg, 0.30 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (50 mg, 0.30 mmol), and sodium triacetoxy borohydride (200 mg, 0.90 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol (10 mL) and treated with 2.0M HCl in ether (3 eq). Solvent was removed under reduced pressure. The resulting solid was triturated with dichloromethane/hexanes (2 mL/10 mL). The precipitate was collected by filtration to give 45 mg (29%) of the bis-hydrochloride salt of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.FC(F)(F)C(O)=O>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: O=Cc1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1c(N)sc(N=Cc2cccs2)c1C(=O)OCC
Yield: 81 %

Procedure:
In a round bottom flask (50 mL), 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester (50 mg) was added to 20 mL isopropanol to which was added 2-thiophenecarboxaldehyde (24 mg) and a catalytic amount of trifluoroacetic acid (TFA). The mixture was refluxed for 20 hours. Complete removal of the solvent provides an orange solid which was purified by flash chromatography (SiO2), yielding the title compound as an orange solid (81%). M.p.: 114°-116° C. 1H-NMR (300 MHz, [D] acetone): δ=8.24 (s, 1H), 7.63 (d, 1H, 3J=5.0 Hz), 7.52 (dd, 1H, 3J=3.7 Hz and 4J=0.7 Hz), 7.48 (s, 2H), 7.14 (dd, 1H, 3J=5.0 Hz and 3.7 Hz), 4.32 (q, 2H, 3J=7.2 Hz), 4.19 (q, 2H, 3J=7.1 Hz), 1.37 (t, 3H, 3J=7.1 Hz), 1.26 (t, 3H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=165.0, 164.3, 161.1, 161.0, 146.1, 143.2, 132.8, 132.1, 130.5, 128.4, 101.8, 61.0, 60.0, 14.3, 14.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][NH:28][CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][N:28]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
Para toluene sulphonyl chloride (180 mg, )0.95 mmol) was added to a stirred solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.9 mmol) in dichloromethane (10 ml) and pyridine (0.9 mmol). Stirring was continued for 18 h, then the solution was partitioned between water (20 ml) and ethyl acetate (2×20 ml). The combined organic phases were dried over magnesium sulphate, and concentrated in vacuo to leave a yellow oil. Purfication on silica (20 g) eluting with hexane, followed by hexane:diethyl ether, 1:1, then diethyl ether gave 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (490 mg, 77%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:4](OCC)=O)=[O:2].C[O-].[Na+].[N+:20]([NH:23][C:24]([NH2:26])=[NH:25])([O-:22])=[O:21]>CO>[N+:20]([NH:23][C:24]1[NH:26][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:25]=1)([O-:22])=[O:21]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Yield: 27.3 %

Procedure:
A solution of ethyl 2-formyl-3-(6-methyl-3-pyridyl)-propionate (1.55 g) in methanol (20 ml) was added to a stirred solution of sodium methoxide (from 0.161 g sodium) in methanol (20 ml). Dried nitroguanidine (0.73 g) was added and the mixture was heated under reflux overnight and evaporated to dryness. The residue was dissolved in water (50 ml) and the solution was extracted with chloroform and the aqueous phase was adjusted to pH 5 with acetic acid. The solid which precipitated was filtered off and recrystallised from methanol-acetic acid to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.5 g, 27%), m.p. 215°-6° (decomp).
Reaction SMILES: [CH2:1](/[C:8](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:16]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O.[OH-].[K+]>[CH2:1](/[C:8](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:17][C:16]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of ethyl (E)-2-benzyl-3-(2,4-dibenzyloxyphenyl)acrylate (1.5 g) and aqueous potassium hydroxide in methanol (50 mL, 15%) is stirred and heated at reflux for 3 hours. The reaction mixture is diluted with water (30 mL) plus 3 N potassium hydroxide solution (5 mL), acidified to pH 1 by addition of concentrated hydrochloric acid and the resulting solid filtered. Recrystallisation from a mixture of ethyl acetate and pentane gives E-2-benzyl-3-(2,4-dibenzyloxyphenyl)acrylic acid (1.13 g) as a white solid, m.p. 175-176° C. [Elemental analysis:- C,79.7; H,5.72%. Calculated:- C,80.0; H,5.82%].
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:23]([OH:27])[OH:24])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.78 g (11.4 mmol) 1-bromo-4-methylnaphthalene and 20 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 5.49 mL (13.7 mmol) of a 2.5M solution of n-butyl lithium in hexane was added over 5 minutes, and the reaction stirred at −70° C. for 10 minutes. The solution was then treated with 2.34 mL (13.7 mmol) triethyl borate, stirred 5 minutes at −70° C., then warmed to room temperature and stirred 40 hours. The reaction was quenched with aqueous ammonium chloride solution, poured into 0.5 N hydrochloric acid, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to a white solid after trituration with hexane, mp 224-228° C., 1.9 g (90%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine (1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was successively washed with 1N hydrochloric acid (3×100 mL), water (3×100 mL), a mixture of water and saturated aqueous sodium hydrogen carbonate (1:1, 2×100 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptane containing a little diethyl ether to afford 1.3 g (43%) of (3,5-bis-trifluoromethylphenyl)carbamic acid phenyl ester as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][N:9](C)[C:10](=O)OC(C)(C)C)=[C:4]([CH:20]=[O:21])[CH:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][NH:9][CH3:10])=[C:4]([CH:3]=1)[CH:20]=[O:21]
Reactant: CN(CCOc1ccc(Br)cc1C=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCOc1ccc(Br)cc1C=O
Reaction time: 9 h

Procedure:
To a solution of t-butyl 2-(4-bromo-2-formylphenoxy)ethylmethylcarbamate (1.26 g, 3.52 mmol) in CH2Cl2 (50 ml) was added TFA (4.01 g, 2.71 mmol 35.17 mmol) at 0° C., followed by stirring for 9 hours. Thereafter, the reaction solution was concentrated in a vacuum and completely dried to afford the object compound (dark brown oil, suitable amount).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a mixture of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolyl)methoxypyridine (0.91 g), methyl 2-(2-hydroxyphenyl)acetate (0.44 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.12 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate as an oil (0.81 g, 70%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH3:21])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 83.8 %

Procedure:
A mixture of 8.0 g (0.026 mol) of product of Example 2, 3.6 g (0.026 mol) of potassium carbonate, 20 g of methyl iodide, and 50 ml of acetone was held at reflux for 6 hours and concentrated. The residue was treated with water and extracted with ether. The ether extract was washed once with 30 ml of 10% NaOH, dried, and concentrated. The residue was crystallized from hexane to give 6.91 g (82.5%) of product; mp 58.5°-59.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:14]1([C:5]2[N:4]=[C:3]([CH2:2][C:20]#[N:21])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1nc(-c2ccccc2)nn1-c1ccccn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)nn1-c1ccccn1
Temperature: 50 °C
Yield: 87.7 %

Procedure:
A mixture of 2-(5-(chloromethyl)-3-phenyl-1H-1,2,4-triazol-1-yl)pyridine (130 mg, 480 μmol) and potassium cyanide (43.8 mg, 672 μmol) in DMSO (3.5 mL) was heated to 50° C. for 1.5 h. The cooled reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with water (2×25 mL), dried over MgSO4 and concentrated in vacuo to give 110 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (30 mg, 114 μmol, 23.7%).
Reaction SMILES: C(O)C.C(Cl)(Cl)Cl.[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:26])[C:10]=1[C:27](=O)[CH2:28][CH3:29].[Cl:31][CH:32]=[CH:33][CH2:34][O:35][NH2:36].Cl>C(O)C>[Cl:31][CH:32]=[CH:33][CH2:34][O:35][N:36]=[C:27]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH2:14][C:9]=1[OH:8])[CH2:28][CH3:29]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reactant: NOCC=CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCC(=NOCC=CCl)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into 40 ml of mixture solvent of ethanol-chloroform (1:1) was dissolved 2 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 10 ml of ethanol containing 10% of 3-chloroallyloxyamine at room temperature. The mixture was kept for 3 hours and it was poured into ice water. The mixture was acidified with hydrochloric acid and the oil separated was extracted with chloroform. The chloroform solution was dried with anhydrous magnesium sulfate and the chloroform was removed from it under reduced pressure and 1.5 g of the desired crude compound was obtained. It was purified by column chromatography and trans-cis mixture which was pale pink crystal having a melting point of 125°-127° C. was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Yield: 92.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.2 g, 0.41 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.07 g, 0.41 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.2 g, 90%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[CH3:29]I.[H-].[Na+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH3:29])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: CI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(N3CCn4c3nc3ccccc34)cc2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (57 mg) and methyl iodide (0.012 mL) in DMF (2.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h, and then added H2O. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (43 mg) as white powder.