Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]2[C@H:12]([CH2:13][CH2:14][C:15]=1[CH2:16][OH:17])[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]2=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([C:8]1[N:9]2[C@H:12]([CH2:13][CH2:14][C:15]=1[CH:16]=[O:17])[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]2=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)CC[C@H]12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C=O)CC[C@H]12
Reaction time: 24 h
Yield: 83.2 %

Procedure:
A solution of 194 g (0.52 Mol) of (6R, 7S)-7-tert-butoxycarbonylamino-3-hydroxy-methyl-8-oxo-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid tert-butyl ester (9) in 4.85 l of methylene chloride was stirred with 455 g (0.52 Mol) manganese(IV) oxide at 22-25° C. for 15 h. Another 45.5 g manganese(IV) oxide was added and stirring was continued for 24 h. A further 45.5 g of manganese(IV) oxide was added and stirring was continued for 3.5 h. The solids were removed by filtration over 500 g dicalite and washed with 3 l methylene chloride. The combined filtrates were concentrated under aspirator vacuum and dried at 0.1 torr at 40° C. The residue was dissolved in 182 ml methylene chloride, diluted with 730 ml of pentane and stirred at room temperature for 30 min. The resulting solid was collected by filtration, washed with 140 ml pentane and dried at 0.1 torr at 40° C. to yield 158.5 g (6R, 7S)-7-tert-butoxycarbonylamino-3-formyl-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester (10) as colorless crystals (83% Th.); m.p.: 194-195° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[C:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][CH:4]=[C:3]2[CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:37][CH2:38]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cc2ncc(CN3CCC(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc23)cc1OC
Yield: 100.1 %

Procedure:
A mixture of 5.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 2.49 g of 4-(2-methoxyphenyl)piperidine, and 2.63 g of triethylamine in 50 ml of dimethylsulfoxide was heated at 80° for one hour under argon and then the cooled solution was diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated to give 7.0 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-([4-(2-methoxyphenyl)-1-piperidinyl]methyl)isoquinolin as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:4]([F:19])[CH:3]=1.C1(C)C=CC=CC=1>[Pd].CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:4]([F:19])[CH:3]=1
Reactant: CCCC1CCC(C=Cc2ccc(Br)cc2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCC1CCC(CCc2ccc(Br)cc2F)CC1
Yield: 75.5 %

Procedure:
A mixture of compound (75) (75.0 g, 231.0 mmol) and 5%-palladium on carbon (0.5% sulfur, 50% water-containing article) (2.82 g, 3 wt %) was agitated for 18 hours under a hydrogen atmosphere in a toluene (300 mL)-IPA (100 mL) solvent. The reaction mixture was filtered and a solvent of a filtrate was distilled off by an evaporator. The residue was passed through silica gel column chromatography and recrystallized from heptane-ethanol, and thus 4-bromo-2-fluoro-1-(2-(4-propylcyclohexyl)ethyl)benzene (76) (57.1 g, yield 75.5%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#[N:14])[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1.[C:16]1(C)[CH:21]=CC=[CH:18][CH:17]=1.C#C.Cl>O.C1(C2CCC=CCCC=2)C=CC=C1.[Co]>[CH3:15][N:2]([CH3:1])[C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:21][N:14]=2)[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cc1ccccc1
Agent: [Co]
Agent: C#C
Agent: C1=CC(C2=CCCC=CCC2)C=C1
Solvent: O
Product: CN(C)C1(c2ccccn2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.5 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile, 50 mg of cyclopentadienyl-cycloocta-1,5-diene-cobalt(l) [cpCo(cod)] and 100 ml of toluene was transferred into the reaction vessel in an inert gas/acetylene countercurrent. After saturation with acetylene, the reaction solution was irradiated at a temperature of 25° C. over a period of 6 hours, with vigorous stirring. The reaction was interrupted by switching off the lamp and supplying air and the reaction solution was concentrated. The crude product obtained (5.47 g) was taken up in a mixture of water (8.7 ml) and conc. hydrochloric acid (15 ml) and the mixture was stirred at RT overnight. For working up, the mixture was washed with diethyl ether (3×100 ml), the phases were separated, the aqueous phase was rendered alkaline with 32 per cent strength by weight sodium hydroxide solution and extracted with methylene chloride (3×100 ml) and the combined extracts were dried (Na2SO4), filtered and concentrated. 3.72 g of 4-dimethylamino-4-pyridine-2-ylcyclohexanone (Ket-11) were obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:8]([O:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH3:14])=[O:9])([CH3:7])[C:4]([O-:6])=[O:5].O1CCCC1.CO.[OH-].[Li+]>O>[CH3:1][CH2:2][C:3]([C:8]([O:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH3:14])=[O:9])([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CCC(N)COC(=O)C(C)(CC)C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(N)COC(=O)C(C)(CC)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.8 %

Procedure:
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335 mg, 99%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([NH2:28])[CH3:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>S1(CCCC1)(=O)=O.CCOCC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([NH:28][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:2]=2[I:1])[CH3:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(I)c(OCC2CO2)c1
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(I)c(OCC(O)CNC(C)Cc2ccc(OC)c(OC)c2)c1
Yield: 73.6 %

Procedure:
A solution of 5.6 g (0.018 mole) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane, the product of Example 5b. and 3.25 g (0.016 mole) of 2-(3,4-dimethoxyphenyl)-alphamethylethylamine in 15 ml of sulfolane was heated at 80° C. for one hour and at 110° for six hours. The mixture was dissolved in ether and the ether washed with water and brine. The ether layer was dried (K2CO3) and the solvent evaporated in vacuo. The residue was flash chromatographed on SiO2 using MeOH:CHCl3, 1:30 as the eluant. The major compound bearing fractions were pooled and the solvent evaporated in vacuo. There was obtained 5.9 g (71% yield) of 1-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-3-(2-iodo-5-methoxyphenoxy)-2-propanol as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:16]([N:23]1[CH2:27][CH2:26][C@@H:25](O)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:25]1[CH2:26][CH2:27][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a cold (0° C.) mixture of ethyl-5-hydroxyindole-2-carboxylate (purchased at Biosynth, H-6350, 20.5 g, 1.0 eq.), (R)-1-benzyl-3-pyrrolidinol (23 g, 1.3 eq.) and tri-n-butylphosphine (58 mL, 2.0 eq.) was slowly added 1,1′-(azodicarbonyl)dipiperidine (50.4 g, 2.0 eq.) in several portions. The reaction mixture was stirred at room temperature overnight and then filtered off. The filtrate was concentrated in vacuo and diethylether was added. The precipitate was filtered off and the filtrate was concentrated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 18 mg (49%) of the desired product as light yellow foam. MS (m/e): 365.5 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]([C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C)#N.[OH-].[K+].C1CCCCC1>C(O)CO.O>[C:5]1([CH:3]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C#N)(c1ccccc1)c1cccnn1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1CCCCC1
Solvent: O
Product: CC(c1ccccc1)c1cccnn1
Yield: 56.8 %

Procedure:
A solution of 3-(1-cyano-1-phenylethyl)-pyridazine (1 g.) in ethylene glycol (10 ml.) and water (1 ml.) containing potassium hydroxide (0.3 g.) was heated at reflux for 6 hours. The yellow solution was diluted with water (40 ml.) and extracted with chloroform (3 × 25 ml.), dried over magnesium sulphate, filtered and evaporated to give a cream-coloured solid (0.8 g.). 3-(1-Phenylethyl)pyridazine (0.5 g.), m.p. 44°-45° C., was obtained from the cream-coloured solid in the form of colourless crystals by recrystallisation from cyclohexane.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4].C1(=O)[NH:30]C(=O)C2=CC=CC=C12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:30][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NCC(=O)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
7.1 g of 2-(2-chloroacetamidopropyl)-4-phenyl-1(2H)-isoquinolone, 3.7 g of phthalimide and 3.7 g of potassium carbonate were added to 50 ml of dimethylformamide, and the mixture was stirred at 80° C. for 5 hours. The resulting reaction mixture was poured into water and the precipitated crystals were collected by filtration, washed with water and dried in air. The resulting crystals and 2 g of hydrazine hydrate were added to 100 ml of ethanol and the mixture was heated at reflux for 3 hours. After allowing the mixture to cool, 5 ml of concentrated hydrochloric acid was added to the resulting reaction mixture and the mixture was stirred for 5 hours. The solvent was then distilled off, and water was added to the residue, followed by thoroughly stirring. The mixture was filtered and the filtrate was rendered neutral with a 10% aqueous solution of sodium hydroxide. The precipitated was extracted with dichloromethane, and the extract was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 2.3 g (34% yield) of 2-(2-aminoacetamidopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 141° C. as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)[CH3:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]([NH:5][CH2:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])=[O:13])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CC(C)(CCO)C(=O)NCc1ccccc1Cl
Reactant: CCc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide (400 mg, 1.6 mmol) in THF (25 mL) were added 4-ethylphenylisocyanate (276 μL, 1.92 mmol, 1.2 equiv.) and DMAP (293 mg, 2.4 mmol, 1.5 equiv.). The reaction mixture was stirred overnight. The reaction mixture was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O, and further purified by flash column chromatography using a mixture of hexanes and EtOAc to give 4-(2-chlorobenzylamino)-3,3-dimethyl-4-oxobutyl 4-ethylphenylcarbamate (160 mg, 25%). LRMS (M+H+) m/z 403.1.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (136 mg, 0.56 mmol) according to general procedure II. Obtained as an orange solid (236 mg, 84%). MS (ISN) 497.1 [(M−H)−]; mp 223° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (42.7 mg, 0.10 mmol) in DCM (3 mL) was added 4-fluorophenylboronic acid (17 mg, 0.12 mmol), TEA (21 mg, 0.2 mmol) and Cu(OAc)2 (22 mg, 0.12 mmol). After stirring at RT for 16 hr, the mixture was purified by Pre-TLC (DCM/CH3OH=20/1) to afford 30 mg (57%) of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.90-7.77 (m, 3H), 7.52-7.37 (m, 3H), 7.34-7.27 (m, 2H), 7.22-7.14 (m, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=6.4 Hz, 1H), 5.80-5.75 (m, 1H), 3.37-3.28 (m, 1H), 3.09-2.95 (m, 1H), 2.50-2.37 (m, 1H), 2.10-1.95 (m, 1H). MS (ESI) m/e [M+1]+ 521.8.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].O>ClCCl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:10]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(Cc2csc3ccc([N+](=O)[O-])cc23)c(OC)c1

Procedure:
Stannic chloride (0.41 g.) was added to a stirred solution of 5-nitrobenzo[b]thiophene (0.28 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.61 g.) in dichloromethane (5 ml.). The mixture was heated under reflux for 18 hours. The cooled mixture was poured into water (10 ml.) and extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil was purified by flash chromatography on silica gel (100 ml.) eluting with 1:9 v/v ethyl acetate:hexane. The solid obtained was crystallized from hexane to give methyl 3-methoxy-4-(5-nitrobenzo[b]thien-3-ylmethyl)benzoate (I) as a solid (0.16 g., 30%); NMR: (250 MHz, CDCl3): 3.92(s, 3H, OCH3), 3.98(s,3H, OCH3), 4.28(s,2H, CH2 --Ar), 7.15 (d,1H), 7.22(s,1H), 7.56(m,2H), 7.93(d,1H), 8.19(dd, 1H); 8.73(d,1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:11][CH:10]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reaction time: 60 h
Yield: 114.8 %

Procedure:
4-(t-butoxycarbonyl)amino-2′-methylsulfonyl-[1,1′]biphenyl (4.6 g, 13 mmol), was suspended in 100 mL of 4M HCl in dioxane and stirred 2.5 days. The resulting mixture was filtered and the cake rinsed with Et2O to yield a tan solid (3.69 g, 98%). 1H NMR (DMSO-d6) δ: 8.04 (d, 1H), 7.71 (t, 1H), 7.61 (t, 1H), 7.31 (m, 3H), 7.06 (m, 2H), 2.79 (s, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CC(C)O
Product: O=C(O)CCc1oc(N2CCOCC2)nc1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), morpholine (2.2 ml) and 2-propanol (20 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated, and water was added to the residue. The pH was then adjusted 3 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-morpholino-5-oxazolepropionic acid (1.64 g, 98%). This was recrystallized from ethanol to give colorless needles. mp 180-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].I[CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:18](=[O:19])[CH2:17][CH2:16][O:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(OC)CCOCC1I
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1CCOCC1c1ccc(F)c(F)c1

Procedure:
3,4-difluorophenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Y(2)).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>O1CCCC1.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>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:6]=3[CH:7]=2)=[N:15][N:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc3occ(-c4ccccn4)c3c2)o1
Yield: 40.8 %

Procedure:
A solution of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (279 mg, 1.00 mmol), 2-(tri-n-butylstannyl)pyridine (0.384 mL, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.0300 mmol) in tetrahydrofuran (5 mL) was heated under reflux under an argon atmosphere for 85 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (113 mg, yield 41%) as colorless crystals.
Reaction SMILES: NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1.C(N=C=O)C.ClC[CH2:42][CH2:43][NH:44][C:45]([NH:47][C:48]1[N:80]=[C:51]2[C:52]([C:70]3[CH:75]=[CH:74][CH:73]=[C:72]([C:76]([F:79])([F:78])[F:77])[CH:71]=3)=[C:53]([CH3:69])[C:54]([C:56]3[N:57]([C:61]4[CH:66]=[CH:65][C:64]([C:67]#[N:68])=[CH:63][CH:62]=4)[N:58]=[CH:59][CH:60]=3)=[CH:55][N:50]2[N:49]=1)=[O:46]>>[C:67]([C:64]1[CH:63]=[CH:62][C:61]([N:57]2[C:56]([C:54]3[C:53]([CH3:69])=[C:52]([C:70]4[CH:75]=[CH:74][CH:73]=[C:72]([C:76]([F:79])([F:78])[F:77])[CH:71]=4)[C:51]4[N:50]([N:49]=[C:48]([NH:47][C:45]([NH:44][CH2:43][CH3:42])=[O:46])[N:80]=4)[CH:55]=3)=[CH:60][CH:59]=[N:58]2)=[CH:66][CH:65]=1)#[N:68]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Agent: CCN=C=O
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: CCNC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and ethyl isocyanate (90 μL, 1.089 mmol) using a similar method to that employed in Intermediate 21 (27 mg).
Reaction SMILES: C=C[CH2:3][CH:4]([C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)[CH2:5][CH:6]=[CH2:7]>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:4]1([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH2:3][CH:7]=[CH:6][CH2:5]1
Reactant: C=CCC(CC=C)c1ccc2c(c1)OCO2
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: C1=CCC(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of Grubbs I (0.345 mmol, 0.284 g) in CH2Cl2 was added diene 97 (6.91 mmol, 1.49 g). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was purified by flash chromatography (hexanes) to afford compound 98 (0.42 g, 32%).