Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17])(=[O:20])[CH3:19]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
5-Amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (28.7 g) was heated at reflux in acetic anhydride (150 ml) for 8 hours. The reaction mixture was then evaporated to dryness and the solid residue was suspended in ethanol (250 ml). Saturated aqueous sodium bicarbonate solution was then added to give a pH of 8 and the suspension was then stirred magnetically for 16 hours. The solid obtained was separated by filtration, washed with water and dried, to give 5-acetamido-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (23.7 g), m.p. 222°-224° C., in the form of an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1Cl
Yield: 74 %

Procedure:
A suspension of 66 g of 2-chloro-4-iodo-benzoic acid (I.G.Farbenind. D.R.P. 565411 1930) in 690 ml of benzene is treated at 4° C. with 20.56 ml of thionyl chloride and 0.1 ml of dimethylformamide and the mixture is boiled at reflux under argon for 21 hrs. The reaction mixture is concentrated. Distillation of the residue at 160°/60 Pa yields 51.9 g (74%) of 2-chloro-4-iodo-benzoyl chloride as a colourless liquid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[CH3:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccccc1
Reactant: Cc1ccc(CNC2CCCC2)cc1
Solvent: CCCCCC
Product: Cc1ccc(CN(C(=S)Nc2ccccc2)C2CCCC2)cc1
Yield: 92.1 %

Procedure:
A solution of 14 g of phenyl isothiocyanate in 50 ml of hexane was added dropwise to 19 g of N-4-methylbenzyl-N-cyclopentyl amine in 400 ml of hexane while cooling and stirring. After the addition, the temperature of the reaction mixture was gradually raised, and the solution was stirred at 40° C. for about 5 hours. The mixture was cooled and filtered. The residue was recrystallized from a mixture of hexane and ethyl alcohol. 30 g of N-4-methylbenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Melting point: 109°-111° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])(=O)=O.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][NH2:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH2:30][CH2:31][NH:32][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1[N+](=O)[O-]
Yield: 90.5 %

Procedure:
1-Nitro-2-naphthyl trifluoromethanesulfonate (1.61 g, 5 mmol), N-(tert-butoxycarbonyl)ethylenediamine (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol), and toluene (20 mL) were mixed, and the mixture was refluxed by heating for 16 hours. This reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals, and the crystals were washed twice with hexane (20 mL) to obtain the title compound (1.50 g, yield 91%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(F)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc2nc(Cl)ccc2c1
Temperature: 95 °C

Procedure:
A mixture of 6-fluoroquinolin-2(1H)-one from Step C, (0.971 g, 6 mmol), phosphorous oxychloride (2.83 mL, 30 mmol), and toluene (20 mL) is heated at 95° C. for 2 hours. The reaction is cooled in an ice bath and basified with 50% aqueous sodium hydroxide. The mixture is extracted with ethyl acetate and the extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to an orange solid (1.01 g). The residue is flash chromatographed on silica gel Merck-60 with 5% ethyl acetate in hexane to provide the title compound as a light pink solid, m.p. 99–101° C.
Reaction SMILES: [CH2:1]([O:3]C(Cl)=O)C.[Cl:7][C:8]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][OH:22])=[NH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:20][C:1](=[O:3])[O:22][N:21]=2)=[CH:23][CH:24]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1[nH]c(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reaction time: 3 h

Procedure:
90 mg of chloroformic acid ethyl ester in 1 ml of acetone are added dropwise at 5° C. to 400 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine and 127 mg of potassium carbonate in 3 ml of acetone. After 3 hours at 0-5° C., the reaction mixture is poured onto water and extracted with dichloromethane. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]2[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9]1.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]2[O:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=2)=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1
Reactant: O=C(N1CC(Cc2cc(Br)ccc2OCc2ccc(C(F)(F)F)o2)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)c1ccc(COc2ccc(Br)cc2CC2CNC2)o1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 1-{3-[5-bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1-yl}-2,2,2-trifluoro-ethanone (76 mg, 0.16 mmol) in methanol (10 mL) was added K2CO3 (94 mg, 0.70 mmol). After 1 h, TLC analysis indicated complete consumption of the starting material. Brine and EtOAc were added to the reaction mixture and the aqueous portion was extracted with EtOAc (3×). The combined organic layers were dried. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (50 mg, 76%). MS (ESI): mass calcd. for C16H15BrF3NO2, 390.2; m/z found, 393.2 [M+H]+. 1H NMR (CDCl3): 7.50-7.41 (m, 1H), 7.35-7.26 (m, 1H), 6.89-6.79 (m, 2H), 6.53 (s, 1H), 5.05 (s, 2H), 4.43-4.20 (m, 1H), 3.63 (t, J=8.2 Hz, 2H), 3.44 (t, J=7.7 Hz, 2H), 2.85 (d, J=7.6 Hz, 2H).
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)[C:4](OCC)=[O:5])#[N:2].[BH4-].[Na+].Cl>C(O)C>[C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)[CH2:4][OH:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(CO)Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution containing 0.85 g of ethyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylate (Example 81) in 70 ml of dry ethanol 0.3 g of sodium borohydride was gradually added. The solution was stirred for 0.5 h at room temperature, acidified with hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated yielding 0.55 g (75%) of yellow crystals, m.p. 149°-152° C.
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.C[S+](C)C.[OH-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])[CH:17]=O.C(Cl)Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.C(OCC)C>[CH3:13][C:14]1[CH:15]=[C:16]([CH:17]2[CH2:1][O:2]2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1ccc(C=O)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[S+](C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C2CO2)cc1C
Temperature: 50 °C
Yield: 77597 %

Procedure:
The procedure was based on methods described by Brandes and Jacobsen, (Tetrahedron Asym. 8:3927, 1997); and Kaufman (Syn. Commun. 23:473, 1993). A solution of trimethylsulfonium methylsulfate (3.95 g, 0.021 mol) in 8 mL water was added slowly to a biphasic mixture of 50% NaOH (20 mL), 3,4-dimethyl-benzaldehyde (1.34 g, 0.01 mmol), tetrabutylammonium bromide (0.025 g, 0.0782 mmol), and CH2Cl2 (26 mL). The reaction was heated at 50° C. for 13 hours and then cooled to room temperature. The reaction was diluted carefully with brine (50 mL) and diethyl ether (3×70 mL), then filtered to remove the solids. The aqueous layer was extracted with diethyl ether (3×70 mL), and the combined organic layers were washed with brine (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo to afford the product 3,4-dimethylphenyl oxirane as a light yellow oil (1.15 g, yield 78%). TLC Rf=0.9 (1:2 EtOAc/Hexane); 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.21 (d, 1H), 7.19 (s, 1H), 3.80 (m, 1H), 3.17 (m, 1H), 2.80 (m, 1H), 2.23 (s, 6H).
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11](SC)[NH:10][CH:9]2[CH3:16].[NH3:17]>C(#N)C.C(N(CC)CC)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH2:17])[NH:10][CH:9]2[CH3:16]
Reactant: N
Reactant: COc1cccc2c1N=C(SC)NC2C
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc2c1N=C(N)NC2C
Temperature: 80 °C
Yield: 46 %

Procedure:
A solution of 8-methoxy-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (610 mg, 1.7 mmol) in a mixture of acetonitrile (6 ml) and aqueous ammonia (25%, 1.2 ml) was heated in a sealed tube on a shaker for 48 h at 80° C. The title compound (158 mg, 46%, MS: m/e=192.1 [M+H+]) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 1-99% CH3CN in 0.05% triethylamine (aq) over 5.0 min, λ=230 nm, flow rate 40 ml/min) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([CH2:24][N+:25]#[C-:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:24]([N+:25]#[C-:26])([S:21]([C:18]1[CH:17]=[CH:16][C:15]([CH3:27])=[CH:20][CH:19]=1)(=[O:22])=[O:23])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:12])([CH3:13])[C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCCC(C)(C)C(=O)OCC)(CCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 130.5 %

Procedure:
Under Ar atmosphere, to a solution of 7-bromo-2,2-dimethylheptanoic acid ethyl ester (26.50 g, 100 mmol), tetra-n-butylammonium iodide (3.69 g, 10 mmol) and p-toluenesulfonyl methyl isocyanide (9.80 g, 50 mmol) in anhydrous DMSO (300 mL) was added sodium hydride (4.80 g, 20.5 mmol, 60% dispersion in mineral oil) at 5-10° C. The reaction mixture was stirred at room temperature for 20 h and quenched with ice-water (300 mL). The product was extracted with dichloromethane (3□100 mL). The combined organic layers were washed with water (200 mL), half-saturated NaCl solution (2′ 200 mL), and saturated NaCl solution (200 mL), dried over MgSO4, and concentrated in vacuo to get the crude 8-isocyano-2,2,14,14-tetramethyl-8-(toluene-4-sulfonyl)-pentadecanedioic acid diethyl ester (36.8 g) as an orange oil, which was used in the next step without purification. To a solution of this crude product (36.8 g) in dichloromethane (450 mL) was added concentrated hydrochloric acid (110 mL) and the mixture was stirred at room temperature for 1 h. The solution was diluted with water (400 mL) and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with saturated NaHCO3 solution (2×150 mL) and saturated NaCl solution (150 mL). The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, hexanes:ethyl acetate=11:1) to give 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (12.20 g, 66% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 4H, J=6.9 Hz), 2.37 (t, 4H, J=7.5 Hz), 1.58-1.47 (m, 8H), 1.35-1.10 (m, 8H), 1.24 (t, 6H, J=7.2 Hz), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 211.6, 178.3, 60.5, 43.1, 42.5, 40.9, 30.1, 25.5, 25.1, 24.1, 14.7. HRMS (LSIMS, nba): Calcd. for C23H43O5 (MH+): 399.3110. found: 399.3129.
Reaction SMILES: C1(N2C3([CH2:16][CH2:15][N:14]([C:17]4([CH3:35])[CH2:22][N:21]([C:23]5[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=5)[C:20]5[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:19]=5[O:18]4)CC3)C(=O)NC2)C=CC=CC=1.Cl>>[CH3:17][O:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[N:21]1[CH2:23][CH2:24][N:14]([C:17]2([CH3:35])[CH2:22][N:21]([C:20]3[CH:19]=[CH:33][C:32]([F:34])=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:18]2)[CH2:15][CH2:16]1
Reactant: CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CN(c2ccc(F)cc2)c2ccc(F)cc2O1
Agent: Cl
Product: COc1ccccc1N1CCN(C2(C)CN(c3ccc(F)cc3)c3ccccc3O2)CC1

Procedure:
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluorophenyl)-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine, m.p. 288°-292° C., as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:17](I)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C[Si]([C:23]#[CH:24])(C)C>C(N(CC)CC)C.C(OC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:17]([C:23]#[CH:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1c(I)cccc1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: C#Cc1cccc(C(=O)OCc2ccccc2)c1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of benzyl 2-amino-3-iodobenzoate (5.56 g), trimethylsilylacetylene (3.26 mL), bis(triphenylphosphine)palladium(II) dichloride (0.350 g) and copper iodide (0.299 g) in triethylamine (75 mL) was stirred under a nitrogen atmosphere at room temperature for 1.5 hr. The reaction mixture was diluted with diisopropyl ether, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (75 mL), 1.0 M tetrabutylammonium fluoride (25 mL) was added under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (3.06 g, yield 77%) as colorless crystals. melting point 42-43° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC>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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cscn3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 4-(tributylstannyl)-1,3-thiazole (0.12 g, 0.31 mmol, Synthonix) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 2 hours, then at 100° C. overnight. Solvent was removed in vacuo and the residue was dissolved in MeCN and filtered, then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (35 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][CH3:25])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH2:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[CH3:25]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCO
Product: CCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 75.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (19.8 g), N,N'-carbonyldiimidazole (21.1 g) and 2-amino-7-ethoxy-1,8-naphthyridine (18.5 g). The product produced by precipitation in water (28.9 g; m.p. 144° C.) is dissolved in boiling ethanol (280 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-ethoxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (24 g) is produced, m.p. 152° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[C:10]([CH3:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([OH:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:17]([OH:19])=[O:18])[CH:25]=2)=[C:10]([CH3:15])[CH:9]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)O)c1
Yield: 89.7 %

Procedure:
A mixture of (4-bromo-3-methyl-phenyl)-carbamic acid tert-butyl ester (765 mg), 3-carboxyphenyl boronic acid (446 mg), cesium carbonate (875 mg) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (30 ml) was heated to reflux for 18 h. The mixture was then allowed to cool and was then partitioned between 1M HCl and dichloromethane. The dried extracts were then evaporated giving the title compound as a pale brown foam (785 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:22]=CN(C)C)[C:16]4=[N:15][C:14]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][CH:20]=[C:21]([NH2:22])[C:16]4=[N:15][C:14]=3[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=Nc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Yield: 88.5 %

Procedure:
N′-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide (70 mg, 0.16 mmol) was dissoved in methanol. To this solution was added 1N aqueous sodium hydroxide and the resulting mixture heated at reflux for 6 hours. The resulting mixture was concentrated in vacuo followed by addition of ethyl acetate and water. The phases were separated and the ethyl acetate phase dried (magnesium sulfate), filtered and concentrated. The resulting solid was purified by silica gel chromatography (ethyl acetate) to give 55 mg (88%) of 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-amine as a solid. 1H NMR (CDCl3): δ 8.97 (d, 1H), 8.12 (d, 1H), 7.68 (q, 2H), 7.15 (t, 2H), 6.78 (t, 1H), 6.54 (d, 1H), 6.41 (d, 1H), 5.24 (d, 1H), 4.60 (s, 2H), 4.40 (m, 1H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −113.7; MS m/z 389 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=[O:6].[CH2:15]([N:19]=[C:20]=[S:21])[CH:16]([CH3:18])[CH3:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH:8][C:20]([NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[S:21])=[O:6]
Reactant: COc1ccc(C(=O)NN)c(OC)c1
Reactant: CC(C)CN=C=S
Solvent: CCO
Product: COc1ccc(C(=O)NNC(=S)NCC(C)C)c(OC)c1
Yield: 90 %

Procedure:
Ex-109B: A solution of 2,4-dimethoxy-benzoic acid hydrazide (Ex-109A, 1.0 g, 5.1 mmol) and isobutyl-isothiocyanate (0.70 g, 6.1 mmol) in ethanol (30 mL) was refluxed for 8 hours. The precipitate was filtered, washed with ethanol, dried in vacuo to afford 1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (1.43 g). Additional product (0.1 g, 96% overall) was obtained by concentrating the mother liquid. 1H NMR (CDCl3) δ 10.71 (bs, 1H), 9.23 (bs, 1H), 8.03 (d, J=8.6 Hz, 1H), 6.98 (bs, 1H), 6.59 (dd, J=8.6, 2.6 Hz, 1H), 6.51 (d, J=2.6 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.41 (dd, J=6.4, 6.6 Hz, 2H), 1.96–1.87 (m, 1H), 0.91 (d, J=6.5 Hz, 6H).
Reaction SMILES: O=[C:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6](OC)=[O:7].C([O-])(=O)C.[NH4+].[BH3-]C#[N:29].[Na+].Cl>CO>[CH3:21][O:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[NH:29][C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: COC(=O)CCCC(=O)c1c(OC)cc(OC)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1cc(OC)c(C2CCCC(=O)N2)c(OC)c1
Temperature: 75 °C

Procedure:
A sealed tube containing a mixture of methyl 5-oxo-5-(2,4,6-trimethoxyphenyl)pentanoate (200 mg; 0.67 mmol), ammonium acetate (520 mg; 6.75 mmol), and NaBH3CN (44 mg; 0.67 mmol) in anh. MeOH (3 ml) was heated to 75° C. for 18 h. After cooling to rt, 2 M aq. HCl was added, and the volatiles were removed under reduced pressure. The aq. solution was extracted with DCM (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded 6-(2,4,6-trimethoxyphenyl)piperidin-2-one as a colorless solid. LC-MS (conditions D): tR=0.86 min.; [M+H]+: 266.84 g/mol.