Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.I[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][C@@H:16]2[NH:23]C(=O)OC(C)(C)C>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]>[CH2:1]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][C@@H:16]2[NH2:23])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C[Zn]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](N)CCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
To a suspension of the 0.3 M neopentyl zinc reagent in THF (60 ml, 15 mmol) was added the tert-butyl (4S)-6-iodo-3,4-dihydro-2H-chromen-4-ylcarbamate (1.8 g, 5.0 mmol) and Pd(dppf)Cl2 (0.2 g, 0.25 mmol) as solids in one portion. The mixture was stirred at r.t. under nitrogen for 48 hours (progress monitored by LC/MS and HPLC). The mixture was quenched with aqueous NH4Cl (20 ml) and extracted with EtOAc (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in MeOH(25 ml) and treated with DOWEX® 50WX2-400 ion exchange resin. The mixture was heated to 50° C. for six hours and then the resing was collected by filtration. The resin was washed successively with MeOH and CH2Cl2 these washings were discarded. The resin was then treated with 7 N NH3/MeOH to elute the free amine from the resin. The elutions were concentrated in vacuo to yield a light brown oil (0.63 g, 57%) of (4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine. This material was consistent with previous preparations and was used as obtained for the subsequent opening of the di-fluoroPhe epoxide. S)-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine was previously characterized as the mono.HCl salt. 1H NMR (300 MHz, DMSO-d6) δ); 7.25 (s, 1H), 7.02 (m, 1H,), 6.76 (m, 1H), 4.47 (bs, 1H), 4.21 (m, 2H), 2.38 (s, 2H), 2.24 (m, 1H), 2.10 (m, 1H), 0.87 (s, 9H). HRMS (ESI+) calculated for C14H21N1O1 220.1701; found m/z 220.1698 (M+H)+. Anal. Calcd for C14H21NO.HCl: C, 65.74; H, 8.67; N, 5.48. Found: C, 65.62; H, 8.53; N, 5.42. [α]23D=15.6, c=1.17 in CH3OH.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]([O:25][C:26](=[O:45])[C:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:28])([CH3:24])([CH3:23])[CH3:22].Cl>O1CCCC1>[C:21]([O:25][C:26](=[O:45])[CH:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: O=C(O)C1CCCC1
Reactant: C=C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a stirred solution of diisopropylamine (14.98 g, 20.75 ml, 148 mmole) in dry tetrahydrofuran (250 ml) cooled to -30° C. under nitrogen, was added dropwise, n-butyl lithium (59.3 ml of a 2.5M solution, 148 mmole), keeping the temperature below -20° C. The reaction was stirred at -20° C. for 1 hour, then cooled to -30° C. and cyclopentanecarboxylic acid (8.05 g, 7.65 ml, 70.6 mmole) added dropwise in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at 0° C. for two hours, during which time a white precipitate formed. The solution was then cooled to -70° C., and a solution of 2-(dibenzylaminomethyl)-propenoic acid t-butyl ester (23.8 g, 70.6 mmol) in dry tetrahydrofuran (35 ml) was added dropwise. The reaction was left overnight (below -40° C.), and then poured into iced hydrochloric acid (4.2 eq, final pH=2) and the product extracted into diethyl ether. The ether layer was washed with hydrochloric acid, water (2x), dried (Na2SO4) and evaporated to yield the crude product (40 g). This was chromatographed over silica gel (500 g) eluting with dichloromethane containing methanol (0 to 5%) to yield, on evaporation of the pure fractions, 3-(1-carboxycyclopentyl)-2-(dibenzylaminomethyl)propanoic acid t-butyl ester as an oil (18.3 g, 57%). Found: C,74.38; H,8.41; N,2.91. C28H37NO4 requires C,74.47; H,8.26; N,3.10%.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)C(O)C>[ClH:1].[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: NC1CCCCNC1=O
Yield: 73.9 %

Procedure:
A stirred mixture of L-lysine hydrochloride 1 (55 g, 300 mmol) and NaOH (12 g, 300 mmol) in 1,2-propanediol (1.2 L) is heated to reflux. A Dean-Stark trap is used to withdraw the first 120 mL of condensed solvent. The reaction solution is refluxed for an additional 2 hours until all starting material is consumed (which maybe determined by 1 H NMR). The solution is cooled and is concentrated under vacuum. Ethanol is used to completely dissolve the α-amino-ε-caprolactam 2. Byproduct NaCl is removed by filtrat is concentrated and the resulting crude α-amino-εcaprolactam 2 is dissolved in water. After acidification to pH 6 with addition of concentrated HCl and subsequent partial concentration, crystals maybe formed at room temperature to afford α-amino-ε-caprolactam hydrochloride (36.5 g) in 74% yield.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>C(OC)(C)(C)C>[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: COC(C)(C)C
Product: OC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Phenylmagnesium bromide (100 mL, 0.1 mol) was added dropwise to a stirring solution of 4,4′-difluorobenzophenone (20 g, 0.092 mol) in t-butylmethyl ether (150 mL) at rt. After the addition was complete the reaction was heated at reflux for 3 h. The solution was cooled to rt and was poured in to ice cold aqueous 1.0 M HCl (100 mL). The organics were extracted with EtOAc (2×50 mL) and dried (Na2SO4). Concentration under reduced pressure gave bis(4-fluorophenyl)phenylmethanol as a pale brown oil. After drying in vacuo for 2 h the crude material was used in the next reaction without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=2)[CH:19]=1)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(hydroxyl-methyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.6 g, 5.84 mmol) in DCM (50 mL), triphenyl phosphine (6.1 g, 23.23 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (7.7 g, 23.23 mmol) was added portion-wise to it and resulting solution was stirred at room temperature for overnight. After completion of reaction, solid was filtered and dried to obtain the desired compound (1 g, 34.5%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])#[N:2].C(NCC)C.C(=O)=O.[SH2:23]>>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[CH2:4][CH2:3][C:1]([NH2:2])=[S:23])[CH3:14]
Reactant: S
Reactant: CCO[Si](CCC#N)(OCC)OCC
Agent: O=C=O
Solvent: CCNCC
Product: CCO[Si](CCC(N)=S)(OCC)OCC
Temperature: 60 °C

Procedure:
Into a clean, dry 300 milliliter high pressure reaction vessel was added 200 grams (0.92 moles) of beta-cyanoethyltriethoxysilane and 10 grams of diethylamine. The reactor was cooled to the temperature of solid carbon dioxide, and 42.0 grams (1.3 moles) of hydrogen sulfide was added via a calibrated metering system. The reactor was placed in a rocker and with agitation was heated to 60° C. for 5 hours. The pressure of the system increased to a maximum of 140 psig and decreased to 70 psig when the reaction was terminated. The final pressure at ambient temperature was 30 psig. The yield of crude beta-triethoxysilylthiopropionamide product was 258.4 grams. Analysis of the product mixture indicated 19 mg/g or 16% unreacted beta-cyanoethyltriethoxysilane.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=S)=[N:6][CH:7]=1.CI.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])=[NH:11])=[N:6][CH:7]=1
Reactant: COc1ccccc1CN
Reactant: NC(=S)Nc1ccc(I)cn1
Solvent: CI
Solvent: CO
Product: COc1ccccc1CNC(=N)Nc1ccc(I)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
0.970 g (3.475 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 30 mL methanol, 0.30 mL (4.777 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated at 60° C. (oil bath temperature) for 20 min and subsequently stirred at room temperature for 18 hr. The solvent was removed under vacuum, and the intermediate product was redissolved in 30 mL ethanol. 1.50 mL (11.262 mmol) 2-methoxybenzylamine was added dropwise and heated for 1.5 hr at 85° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was redissolved in dichloromethane and extracted with water (2×50 mL). The organic phase was then extracted again with 2 N sodium hydroxide solution (1×50 mL) and washed with water (1×50 mL) to remove iodide salt from the product. After drying over magnesium sulfate and overlayering with pentane the product was crystallized. 1.252 g (3.080 mmol, 89%) N-(5-iodopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine was obtained. For additional purification, a portion of the first crystallizate was again recrystallized from dichloromethane/water.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 76.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.0237 g, 0.84 mmol) gives the title compound (0.0545 g, 77.0%): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C2)H28N3O4 386.2080 (M+H)+, found 386.2076, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.3 min, 100% purity.
Reaction SMILES: CN1C(=O)CCC1.Br[CH2:9][CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]#[N:13].[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:9][CH2:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]#[N:13])[CH2:33]1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(COC2CCNC2)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#CC(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
To 20 ml of NMP was added 2,54 g of 4-bromo-2,2-diphenylbutyronitrile, 1.79 g of 3-(3-chlorobenzyloxy)pyrrolidine and 1.29 g of triethylamine, and the mixture was stirred for 20 hours at 140° C. The reaction mixture was concentrated under reduced pressure and water was added to the residue, and then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.81 g of the aimed compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[Br:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#Cc1ccc(N)c(Br)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(C#N)cc1Br)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 5.00 g (25.4 mmol) 4-amino-3-bromobenzonitrile in 30 mL of toluene was added 8.23 g (38.1 mmol) of diethyl ethoxymethylenemalonate (2a). The mixture was then heated to reflux for overnight with a condenser open to the air. The resulting solution was cooled down to room temperature and poured into 100 mL of hexanes. The white precipitate was collected and washed with hexanes (30 mL×3) to yield 11.9 g of an off-while solid as the desired product. MS ESI (m/z) 367 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:27])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:2])[CH3:3]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.300 g, 0.000894 mol) was dissolved in THF (20 mL) and H20 (10 mL). Osmium tetroxide (0.550 mL, 0.0716 mmol, 4% wt in water) was added followed by Sodium metaperiodate (0.383 g, 0.00179 mol). The reaction was stirred overnight at room temperature. The reaction was quenched using saturated sodium thiosulfate. 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde (0.302 g, 95.1% yield) was isolated using an aqueous workup and carried on without further purification
Reaction SMILES: N1C=CC=C(C)C=1.[CH2:8]([O:10][N:11]=[C:12]([C:16]1[C:17](=[O:35])[CH2:18][CH:19]([C:23]2[C:24]([O:33][CH3:34])=[N:25][C:26]([S:31][CH3:32])=[N:27][C:28]=2[O:29][CH3:30])[CH2:20][C:21]=1[OH:22])[CH2:13][CH2:14][CH3:15])[CH3:9].[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:22][C:21]1[CH2:20][CH:19]([C:23]2[C:28]([O:29][CH3:30])=[N:27][C:26]([S:31][CH3:32])=[N:25][C:24]=2[O:33][CH3:34])[CH2:18][C:17](=[O:35])[C:16]=1[C:12](=[N:11][O:10][CH2:8][CH3:9])[CH2:13][CH2:14][CH3:15])=[O:39]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccnc1
Product: CCCC(=NOCC)C1=C(OC(=O)C(C)(C)C)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Temperature: 25 °C

Procedure:
A solution of 3-picoline (40 mg) and 2-[1-ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (2) (80 mg) in dichloromethane (10 ml) was treated with trimethylacetyl chloride with stirring at room temperature. After 2 hours the solution was washed with dilute hydrochloric acid (1M, 20 ml), separated, dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give 3-trimethylacetyloxy-2-[1-(ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (7) as a pale brown oil (100 mg) which was characterized by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: CCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.04 g, 0.11 mmol) was dissolved in 1,4-dioxan (0.5 mL) and ethyl isocyanate (0.013 mL, 0.16 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30:70→100:0 as the eluent. This afforded the title compound as an amorphous compound. 13C NMR (DMSO-d6) δ 195.6, 159.0 (dd), 156.0 (dd), 155.3, 149.2, 139.3, 138.3, 133.7, 133.5, 131.5, 129.2, 127.5, 126.4 (dd), 124.5 (dd), 120.2, 118.4, 115.1, 112.1 (dd), 112.0, 105.1 (dd), 34.0, 19.1, 15.4
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20].O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Reactant: CCN(CC)CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNC(=O)/C(=C/C=C/c1cc2ccccc2o1)OC
Yield: 18 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 3-diethylaminopropylamine (65 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was chromatographed on silicagel (preparative TLC, EtOAc/MeOH/aq.NH3 8/2/1). The fraction collected was dried to give pure title compound (32 mg, O90 mmol, yield 18.0%) as pale brown crystals, m.p.=79°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH2:5][CH:6]([OH:9])[CH2:7][N:8]=1.[N+](C1C=CC=CC=1)([O-])=O.C[O-].[Na+]>CO>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[CH:5][C:6]([OH:9])=[CH:7][N:8]=1
Reactant: OC1CN=C(C(F)(F)F)NC1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: Oc1cnc(C(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
A mixture of 2-(trifluoromethyl)-1,4,5,6-tetrahydro-5-pyrimidinol (6.50 g, 38.7 mmol) and nitrobenzene (30 mL) was heated to 90° C. to form a homogeneous solution. At this temperature, a solution of sodium methoxide (8.5 g, 157 mmol) in methanol (30 mL) was added portionwise, allowing the methanol to distill off before next addition (the whole process took about 3 h). Then the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was cooled to room temperature, and then partitioned between ethyl acetate and water. The organic phase was separated off. The aqueous phase adjusted to pH 4.0 with 6M aqueous HCl and then extracted with EA. The organic phase was dried over sodium sulfate, and filtered. Concentrated in vacuo then afforded the title compound (533 mg, 3.25 mmol, 8.4% yield). LCMS: rt=1.78 min, [M+H+]=165
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH:20][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1
Reactant: Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CC1

Procedure:
20 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was dissolved in 3 mL of toluene, and added with 20 μl of triethylamine and 10 μl of cyclopropanecarbonyl chloride at room temperature and stirred all day and night. The reaction solution was added with saturated aqueous sodium hydrogen carbonate, extracted with sodium acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 20 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3N)n2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-aminophenyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.54 g, 1.22 mmol), copper acetate (0.33 g, 1.83 mmol, Aldrich, St. Louis, Mo.), 6-methoxypyridin-3-ylboronic acid (0.56 g mg, 3.67 mmol, Boron Molecular, Research Triangle Park, N.C.) and diisopropylethylamine (0.85 mL, 4.89 mmol) in DCM (15 mL) was stirred at room temperature for 16 h, filtered through a pad of Celite® (diatomaceous earth), and the solvent was removed in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 0% to 2% 2 M NH3-MeOH in CH2Cl2, to give the title compound as a dark yellow oil. m/z (ESI, +ve ion) 548.8 (M+H)+.