Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([OH:14])=[O:13]>>[CH2:10]([O:9][C:7]([C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)=[O:8])[CH3:11]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Yield: 94 %

Procedure:
29.0 g of ethyl isobutyrylacetate and 33.0 g of 4-carboxybenzaldehyde are heated with a water trap for 6 h. The reaction solution is concentrated, taken up in ethyl acetate and extracted with 20% strength ammonium chloride solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, concentrated and directly reacted further to 45. 50.0 g of an oil are obtained. C16H18O5 (290.3): MS (ESI+): 291.1 (M+H)+, tR=1.42 min (Gradient 2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:18]([CH3:19])[C:17]3[C:16](=[O:20])[N:15]([CH2:21][C:22]#[CH:23])[C:14](=[O:24])[N:13]([CH3:25])[C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C([O-])(O)=O.[Na+]>[C:26]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:18]([CH3:19])[C:17]3[C:16](=[O:20])[N:15]([CH2:21][C:22]#[CH:23])[C:14](=[O:24])[N:13]([CH3:25])[C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: C#CCn1c(=O)c2c(nc(C#Cc3cccc(O)c3)n2C)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCn1c(=O)c2c(nc(C#Cc3cccc(OC(C)=O)c3)n2C)n(C)c1=O

Procedure:
A mixture of 0.1 mmol of 8-(3-hydroxyphenylethynyl)-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione and 0.5 mL acetic anhydride was heated under reflux for 15 min. Subsequently the mixture was hydrolyzed with concentrated NaHCO3-solution (50 mL) and the product was extracted with dichloromethane. The organic extracts were dried over MgSO4 and filtered and concentrated under vacuum. The crystalline residue was treated with ether and filtered under reduced pressure yielding 8-(3-acetoxyphenylethynyl)-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione: colorless crystals (yield >95%), m.p. 238° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].CN(C)C(=O)C.C(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[S:4][C:5]([C:9]([Cl:20])=[O:11])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCc1nc(C)c(C(=O)O)s1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.0 g (0.09 mole) of 2-ethyl-4-methylthiazole-5-carboxylic acid were suspended in 150 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylacetamide. Under heating and reflux, phosgene was blown at a rate of 1.5 l/hr for 3.5 hours (0.23 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.1 g of 2-ethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.2% and 96.9%, respectively.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH:13]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:17]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[O:18])=[CH:7][CH:8]=1
Reactant: O=C=NC1CC1
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC(=O)c1ccc(Cl)cc1)NC1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1000 mg (4.853 mmol) of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride are placed in 20 ml dichloromethane, cooled to 0° C. and treated dropwise with a solution of 363 mg (4.367 mmol) of cyclopropyl isocyanate in 2 ml dichloromethane. It is stirred a further 10 mins at 0° C. and then a solution of 627 mg (4.853 mmol) of N,N-diisopropylethylamine in 4 ml dichloromethane is added dropwise. After two hours' stirring at room temperature the reaction mixture is evaporated and the crude product purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1). 1000 mg (73% of theory) of the target compound are obtained.
Reaction SMILES: [CH:1](=[PH3])[CH2:2][CH:3]=[CH2:4].[F:6][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=O>C1C=CC=CC=1>[F:6][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[CH:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCC=[PH3]
Reactant: CCOC(=O)C(F)(F)F
Solvent: c1ccccc1
Product: C=CCC=C(OCC)C(F)(F)F

Procedure:
A mixture of 20 ml of 1-bromo-3-butyne and 25 mmole of tirphenylphosphine in 50 ml of benzene is heated at reflux for 3 days. The solid which separates upon cooling is filtered, washed with benzene and dried under reduced pressure is afford triphenyl-3-butenylphosphonium bromide. To a solution of 100 ml of liquid ammonia is added 0.26 g of finely divided sodium and a catalytic amount of ferric nitrate. When the blue solution turns gray finely powdered triphenyl-3-butenylphosphonium bromide (2.10-2 mole) is added. The reaction mixture is stirred for 15 minutes after which the ammonia is evaporated under a stream of nitrogen. To the resulting residue is added 100 ml of benzene, and the heterogeneous mixture is heated at reflux temperature for 10 minutes. The solid residue is filtered off and the filtrate is evaporated to dryness to give 3-butenylidenephosphorane. To a solution of salt free 3-butenylidenephosphorane (2.10-2 mole) in 100 ml of benzene is added 6.6 g (5.10-2 mole) of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature for 12 hours under nitrogen. Concentration of the solvent leaves an oily residue which is purified by distillation to give 1-trifluoromethyl-1-ethoxy-1,4-pentadiene. A suspension of 10 g of 1-trifluoromethyl-1-ethoxy-1,4-pentadiene in 20 ml of 1 N aqueous sulfuric acid is stirred for 20 minutes. Continuous extraction of the mixture with ether affords 1-trifluoromethylpent-4-ene-1-one.
Reaction SMILES: [CH3:1][N:2]1[C:19](=O)[C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.C(O)(=O)C>O1CCCC1.B#B>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Agent: B#B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the suspension of 12.8 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 93.5 %

Procedure:
A solution of 9.20 g of ethyl 5-(1-tritylimidazol-4-yl)-1-pent-2-enoate in 460 ml of anhydrous ethanol is hydrogenated with 1.88 g of 10% palladium on charcoal at atmospheric pressure for 20 min. The catalyst is removed by filtration through celite. Evaporation provides a solid which is recrystallised from hexane to yield 8.64 g of ethyl 5-(1-tritylimidazol-4-yl)-1-pentanoate, m.p. 84°-86°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[N:3]1.S(Cl)([Cl:17])=O>C1COCC1.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: Cn1ccc(-c2ccc(CO)cc2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc(-c2ccc(CCl)cc2)n1
Temperature: 17 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(1-methyl-1H-pyrazol-3-yl)phenyl]methanol (1.00 g) in THF (15.0 mL) was added dropwise thionyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at 17° C. for 16 hr. The reaction mixture was diluted with water and ethyl acetate, and saturated aqueous sodium bicarbonate was added thereto. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.65 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:15])[CH2:13][Cl:14])[S:9][CH:10]=1)C.[OH-].[K+]>C(O)C>[C:20]([O:19][C:17]([NH:16][CH:5]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:15])[CH2:13][Cl:14])[S:9][CH:10]=1)[C:4]([OH:24])=[O:3])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of 920 mg of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid ethyl ester in 20 ml of ethanol is added 1.4 ml of aqueous solution containing 681 mg of potassium hydroxide and the mixture is stirred for 15 minutes at room temperature. The reaction solution is concentrated to dryness under reduced pressure and the residue is dissolved in water. The aqueous solution is adjusted to pH 2.0 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled to obtain 690 mg of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid as crystals (yield, 81%). Melting point: 169°-170° C. (dec.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]([N:10]1[C:4]2[CH:3]=[C:2]([NH:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[N:7]=[CH:6][C:5]=2[N:8]=[CH:9]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2cnc(Br)cc21
Reactant: COc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2cc3c(cn2)ncn3C(C)C)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 6-bromo-1-isopropyl-1H-imidazo[4,5-c]pyridine (intermediate 256, 2.134 g, 8.80 mmol), 4-methoxybenzylamine (1.389 ml, 10.38 mmol), NaOt-Bu (1.308 g, 13.20 mmol), Pd(OAc)2 (0.14 g, 0.616 mmol) and Xantphos (0.367 g, 0.616 mmol) in toluene (90 ml) was evacuated and purged with argon (3×) and then heated to 100° C. After 17 h, the reaction mixture was quenched with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(Cl)Cl.COCCOC>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH2:16][C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:7]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: COC1(CN(C(=O)OC(C)(C)C)c2cccc(Br)n2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC1(CN(C(=O)OC(C)(C)C)c2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A mixture of tert-butyl 6-bromo-pyridin-2-yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (50 mg, 0.125 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (43.7 mg, 0.249 mmol), PdCl2(dppf).CH2Cl2 adduct (15.2 mg, 0.019 mmol), DME (1.5 Ml) and 2M aqueous Na2CO2 (0.25 Ml, 0.5 mmol) was sealed and stirred at 100° C. for 3 hours. After cooling to room temperature the mixture was diluted with EtOAc (15 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 12 g, EtOAc/hexane=5/100 to 50/50] to provide tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (32 mg, 57% yield). LCMS (m/z): 452.2 [M+H]+; retention time=1.068 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl>[CH2:47]([N:46]([CH3:45])[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
(S)-N-tert-butoxycarbonyl-2-phenylglycine (250 g) and 1-hydroxybenzotriazole hydrate (136.2 g) and N,N′-dicyclohexylcarbodimide (205.1 g) were combined in dichloromethane (3000 mL) at 0-5° C. and the mixture stirred for 15 minutes. A solution of N-methylbenzylamine (128.1 mL) in dichloromethane (835 mL) was added slowly, maintaining 0-5° C. The resulting slurry was allowed to warm to room temperature overnight before being filtered, washing the by-product solids with dichloromethane (500 mL). The combined filtrate was twice washed with saturated aqueous sodium hydrogen carbonate (2×1500 mL), twice washed with 50% saturated aqueous sodium hydrogen carbonate solution (2×1500 mL), once washed with 2.5% aqueous citric acid solution (1500 mL) and once washed with demineralized water (1500 mL), providing a dichloromethane solution of tert-butyl (S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate. Analysis by chiral HPLC showed that 2% of the wrong enantiomer (tert-butyl (R)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate) to be present at this stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:42][NH:43][O:44][CH3:45]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17](=[O:19])[N:43]([O:44][CH3:45])[CH3:42])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)O
Reactant: CNOC
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Yield: 70.9 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (0.078 g ) was prepared from 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid (0.1 g, 0.179 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.017 g, 0.179 mmol) following general procedure A
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[N:11]([C:17]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:13][C:14]=3[C:15]#[N:16])=[CH:4][CH:3]=1.[OH2:24]>CS(C)=O.ClCCl>[NH2:9][C:10]1[N:11](/[C:17](=[N:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cnn2c(NC3CCCC3)c(-c3ccc(Br)cc3)[nH]c12
Reactant: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cnn(/C(=N/C2CCCC2)C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A dilute solution of 2-(4-bromophenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (500 mg, 1.35 mmol) in DMSO (100 mL) was stored at RT for more than 60 days. The yellow DMSO solution was poured into water (1 L) and the organic compound was extracted into ethyl acetate (2×75 mL). The combined extracts were washed with water and brine solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give the crude yellow solid which was not soluble in dichloromethane even at hot condition. Then, after cooling to RT, the solids were collected by filtration and washed with dichloromethane and the 1H NMR of this solid indicated that it is mostly starting material. Whereas, the mother liquor was removed under vacuum and the crude residue was purified using an ISCO (80 g) column eluting with 0-35% ethyl acetate in hexanes. The pure fractions were combined and the solvent was removed under vacuum to obtain 113 mg (21.7% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-bromophenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.80 (br m, 8H), 3.63 (p, 1H), 7.72 (s, 1H), 7.78 (d, J=6.1 Hz, 2H), 7.83 (d, J=6.2 Hz, 2H), 8.14 (br s, 2H). LC/MS calcd. for C17H16BrN5O (m/e) 386.25, obsd. 387.2 (M+H, ES+).
Reaction SMILES: [CH3:1][NH:2][C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[CH3:1][N:2]([C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1)[C:16](=[O:17])[CH2:15][Cl:14]
Reactant: CNC12CCCC(C1)C1CCC2C1
Reactant: O=C(Cl)CCl
Product: CN(C(=O)CCl)C12CCCC(C1)C1CCC2C1
Yield: 85 %

Procedure:
Under the same conditions as described in section (A) of Example 4, 1-methylaminotricyclo[4.3.1.12,5 ]undecane was reacted with 2-chloroacetyl chloride to obtain N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloroacetamide in a yield of 85%.
Reaction SMILES: F[B-](F)(F)F.C(S[N:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C.Cl.[NH2:17][CH2:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:24]([O:23][C:21]([CH2:20][C:19]1[N:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:17][CH:18]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C=NSCC
Reactant: CCOC(=O)CC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c[nH]c(C(=O)OCC)n1
Yield: 66.9 %

Procedure:
A mixture of 2.5 g of ethyl (ethylthio)iminoacetate tetrafluoroborate, 110 ml of acetic acid, 1.8 g of ethyl 4-aminoacetoacetate hydrochloride and 1.64 g of sodium acetate is heated for 3 hours at a temperature close to 95° C. The reaction mixture is filtered and the insoluble matter is rinsed with 3×5 ml of acetic acid. The filtrate is evaporated in a rotary evaporator and the evaporation residue is supplemented with 75 ml of dichloromethane. The organic solution is dried over sodium sulphate, filtered and evaporated in a rotary evaporator. The evaporation residue (1.86 g) is purified by chromatography on a silica column, eluting with ethyl acetate. 1.5 g of ethyl 4-(ethoxycarbonylmethyl)imidazole-2-carboxylate are obtained in the form of a red-yellow solid melting at 88° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:17][C:11]1[N:12]=[CH:13][C:14]([C:23]2[CH:24]=[C:19]([OH:18])[CH:20]=[CH:21][CH:22]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccc(O)c2)cc1-c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (100 mg, 0.330 mmol), 3-hydroxyphenylboronic acid (68 mg, 0.49 mmol) and potassium carbonate (140 mg, 0.980 mmol) in 1,4-dioxane (4.5 mL) and H2O (1.5 mL) was degassed and refilled with argon (3×) prior to the addition of Pd(dppf)Cl2 (10 mg, 0.020 mmol). The reaction mixture was degassed and refilled with argon (2×) and left to stir at 100° C. for 30 min in the microwave reactor. Then, the mixture was passed through a pad of Celite and to the filtrate was partitioned between EtOAc and NaHCO3 aq. soln. (3×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification via silica gel chromatography (5% MeOH in DCM) afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=6.75-6.77 (m, 1H), 7.04-7.04 (m, 1H), 7.10-7.12 (m, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.46-7.50 (m, 1H), 7.55-7.58 (m, 1H), 8.02 (br.s, 2H), 8.10-8.16 (m, 3H), 8.46 (d, J=4.0 Hz, 1H), 9.54 (s, 1H). MS (ES+): m/z=320.09 (100) [MH+]. HPLC: tR=3.44 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:15][CH2:14][CH2:13]1)[CH2:5][C:6](=O)[NH:7]2>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:15][CH2:14][CH2:13]1)[CH2:5][CH2:6][NH:7]2
Reactant: O=C1CC2(CCC2)c2c(F)cccc2N1
Solvent: C1CCOC1
Product: Fc1cccc2c1C1(CCC1)CCN2

Procedure:
A solution of 50 mg (0.244 mmol) of 5′-fluoro-1′H-spiro[cyclobutane-1,4′-quinolin]-2′(3′H)-one obtained in step 31.2 in 1 mL of tetrahydrofuran was treated with 0.73 mL of 1 M solution of borohydride-tetrahydrofuran complex in tetrahydrofuran. The mixture was stirred at reflux for 2 h, quenched with water and evaporated till dryness. The crude compound was used in the subsequent step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[I:21]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: II
Reactant: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
Silver trifluoroacetate (0.52 g, 2.35 mmol) was added to a solution of (5R)-3-(3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 14) (0.50 g, 1.81 mmol) in dichloromethane (15 ml). Iodine (0.55 g, 2.17 mmol) was added over 1.5 hours, and it was stirred overnight. After 16 hours, the solids were removed by filtration and additional silver trifluoroacetate (0.38 g, 1.72 mmol) and iodine (0.27 g, 1.06 mmol) were added. After and additional 24 hours, the reaction mixture was filtered. The filter cake was washed with methanol. The methanol filtrate was concentrated under vacuum to give 0.31 g of the title product.