Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])C.[CH3:4][C:5]([O-])([CH2:7][CH3:8])[CH3:6].[K+].C1(C)C=CC=CC=1.C1(C(OCC)=O)CC1.Cl.[C:27]1([CH3:35])[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1.Cl>C1COCC1.CCO>[CH:5]1([C:7]2[CH:8]=[C:1]([NH2:3])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:35])=[CH:28][CH:29]=3)[N:34]=2)[CH2:6][CH2:4]1
Reactant: CC#N
Reactant: CCC(C)(C)[O-]
Reactant: Cc1ccc(NN)cc1
Agent: CCOC(=O)C1CC1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nc(C3CC3)cc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonitrile (500 μL, 390 mg, 9.6 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 17.0 mL, 29.0 mmol) followed by the dropwise addition of ethyl cyclopropanecarboxylate (4.56 mL, 4.37 g, 38.0 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of 15 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) was added. The mixture was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 2 hr, then cooled to RT and concentrated in vacuo to a volume of 20 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with isohexane (20 mL) to afford the title compound, Intermediate A15, as a beige solid (1.60 g, 77%); Rt 3.35 min (Method 1 basic); m/z 214 (M+H)+, (ES+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>ClCCl>[NH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][N:17]=[CH:16]3)(=[O:27])=[O:28])[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCNCC1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5.02 g of 4-aminomethylpiperidine and 22 g of triethylamine in 50 ml of dichloromethane. Add dropwise over 30 minutes 5.0 g of 5-isoquinoline sulfonyl chloride dissolved in 50 ml of dichloromethane while cooling the mixture in an ice bath. Stir at room temperature for 72 hours. Filter the reaction mixture and evaporate the filtrate. Chromatograph the residue over 400g of silica gel eluting with dichloromethane/methanol (9/1). Obtain the title compound by evaporating the appropriate fractions, as determined by thin layer chromatography. Dissolve the product in ethanol saturated with HCl and evaporate to obtain the title compound as the dihydrochloride salt. FAB MS (M+1)e =306.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@H:15]([C:20]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:28]>ClCCl.O1CCOCC1>[ClH:28].[ClH:28].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@H:15]([C:20]([O:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1
Reactant: CC(C)C[C@H](NC1CCCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@H](NC1CCCNC1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a solution of 3-((S)-1-cyclopentyloxycarbonyl-3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.840 g, 2.20 mmol) in dichloromethane (5 mL) was added 4M hydrogen chloride in dioxane (10 mL). The reaction was stirred at room temperature for 90 minutes and then concentrated to give the product (184 mg, 24% yield). LC/MS: m/z 283 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[C:12]([CH3:18])=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([Cl:10])[C:12]=1[CH3:18]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: Cc1c(Cl)cccc1N=Cc1ccccc1Cl
Reaction time: 0.25 h

Procedure:
o-Chlorobenzaldehyde (0.20 mole) was treated with 3-chloro-2-methylaniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 mins. The reaction mixture was left standing at room temperature for 10 mins., then it was placed in an ice-bath for 0.5 hr. The crystals which formed were collected, washed with 95% ethanol and air dried. Recrystallization from 85% ethanol gave N-(o-chlorobenzylidene)-3-chloro-2-methylaniline. m.p. 83°-85° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[C:9](=O)[NH:8][C:7](=O)/[C:6]/2=[CH:17]/OC.Cl.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].Cl.[CH3:33][O:34]N>>[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:34][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:25][NH:26]/[CH:17]=[C:6]1\[CH2:7][N:8]=[CH:9][C:10]2[C:5]\1=[CH:4][C:3]([C:3]1[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1)=[CH:12][CH:11]=2
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(OC)cc21
Reactant: COc1ccc(CN)cc1O
Reactant: CON
Agent: Cl
Product: COc1cc(CN/C=C2\CN=Cc3ccc(-c4ccccc4)cc32)cc(O)c1OC

Procedure:
Using the procedure described for the preparation of example 46, 50 mg of orange solid (40% yield) is obtained from 80 mg (0.29 mmol) of 4-methoxymethylene-6-phenyl-3-yl-isoquinolin-(4H)-1,3-dione and 3-hydroxy-4,5-dimethoxybenzylamine 115 mg (0.29 mmol), (prepared similarly to (4E)-6,7-dimethoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 3-hydroxy-4-methoxy-benzylamine hydrogen chloride, except methoxy amine hydrogen chloride is used instead of hydroxylamine hydrogen chloride); mp 250-251° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][N:13]([CH3:40])[CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][N:17]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][N:23]=1)[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CN(C)CCCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of 6.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane is added to a solution of 2 mmol of 10-[[6-[3-(dimethylamino)propylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H -pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane. The solution is stirred 16 hours at room temperature, washed with water, dried (MgSO4) and the solvent removed. The residue is purified by column chromatography over silica gel with 30% methanol in chloroform as eluent to give 0.75 g of solid; mass spectrum (CI) 525 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.Cl.[CH:14]1([NH:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[CH:14]1([N:20]2[C:2]3=[C:3]4[CH:12]=[CH:11][NH:10][C:4]4=[N:5][CH:6]=[C:7]3[CH:8]=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: c1cc2c(ncc3cnn(C4CCCCC4)c32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A solution containing 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.100 g, 0.554 mmol, Adesis), cyclohexylhydrazine hydrochloride (0.125 g, 0.831 mmol) and DIEA (0.19 mL, 1.1 mmol) in t-BuOH (5 mL) was stirred at ambient temperature for about 1 h, then heated at about 70° C. for about 1 h, followed by heating in a Biotage microwave at about 200° C. for about 1 h. The insoluble residue was removed by filtration and the filtrate was subjected to purification by preparative RP-HPLC (Table 2, Method p) to yield 1-cyclohexyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.045 g, 0.187 mmol, 34%) as an off-white solid: LC/MS (Table 2, Method d,) Rt 2.13 min; m/z: 241 (M+H)+, 239 (M−H)−.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[Cl:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([Cl:20])=[C:13]([CH2:12][C:11]2[S:31][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][CH:10]=2)[CH:18]=1
Reactant: O=C(CNC(=O)c1ccccc1)Cc1cc(Br)ccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(Br)cc1Cc1cnc(-c2ccccc2)s1
Yield: 72.5 %

Procedure:
To a solution of the above 1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) in toluene (20 ml) was added Lawesson reagent (2.35 g), and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to give the desired 5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene (512 mg) as a colorless solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2)=[CH2:28]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OC[C@@H]2CCCO2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-5-[(S)-1-(tetrahydrofuran-2-yl)methoxy]pyridine-2-carboxamide (1.70 g), tributylvinyltin (1.55 g), triphenylphosphine (85.5 mg), palladium(II) acetate (18.3 mg) and DMF (20 ml) was admixed under argon with triethylamine (7.4 ml) and heated to reflux for 4 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was filtered through silica gel. This afforded the product with the molecular weight of 364.45 (C22H24N2O3); MS (ESI): 365 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH:22](Br)[C:21]2=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH:22]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:21]2=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1cccnc1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1cccnc1
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
To a solution of 3-hydroxypyridine (8.56 g, 0.090 mol) in 300 ml of dimethylformamide was added NaH (60% in oil, 3.6 g, 0.090 mol). After stirring 0.5 hour, 6-benzyloxy-3-bromo-4-chromanone (30.0 g., 0.090 mol) was added in one portion. After stirring for 1 hour, the reaction mixture was poured into 1 liter of water and extracted 3×250 ml of ethyl acetate. The organic layers were combined, washed 1×100 ml H2O, 1×100 ml 10% LiCl and 1×100 ml brine, dried (Na2SO4) and stripped to yield 40 g of crude title product, which was chromatographed on silica gel using 1:4 ethyl acetate:CH2Cl2 as eluant to yield 1.13 g of purified title product as an off-white powder; mp 133°-134° C. A portion (290 mg) was recrystallized from isopropyl ether to yield 240 mg of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C([Li])(CC)C.CN(C)[CH:22]=[O:23].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:6]([CH:22]=[O:23])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CC1(C)COC(c2ccc(Cl)cc2)=N1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC1(C)COC(c2ccc(Cl)cc2C=O)=N1
Reaction time: 2 h

Procedure:
To a solution of 16 g (76 mM) of 2-(4-chlorophenyl- 4,4-dimethyl-4,5-dihydrooxazole in 60 ml of dry tetrahydrofuran at -78° C. under an inert atmosphere was added dropwise 75 ml of 1.4M sec-butyllithium in hexane. After 1 hour 9.7 ml of freshly distilled dimethylformamide in 20 ml of tetrahydrofuran was added and stirring was continued for 2 hours at room temperature. The mixture was poured into water (200 ml) and extracted with diethylether (2×100 ml), dried and evaporated to yield the crude product. Vacuum distillation, bp 140°-150° C./0.4 mm gave the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2C)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (220 mg), 2,4-difluoro-3-methylbenzonitrile (290 mg) and lithium carbonate (210 mg), the title compound was obtained as pale-yellow oil (yield: 97.3 mg, yield: 29%).
Reaction SMILES: [N+:1]([CH2:4][CH:5](O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.C(N(CC)CC)C.O>C(Cl)Cl>[N+:1]([CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCC(O)C[N+](=O)[O-])cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCC=C[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of 4.89 g (18.1 mmol) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol in 24 mL of dry methylene chloride at 0° C. was added 2.1 g (18.1 mmol) of methanesulfonyl chloride followed by addition of 3.66 g (36.2 mmol) of triethylamine. The mixture was stirred at 0° C. for 20 minutes, poured into 40 mL of water, extracted with 50 mL of methylene chloride, dried over anhydrous, and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:9 ethyl acetate:hexanes, to afford 4.1 g (90%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-1-butene as a light yellow solid: IR (KBr) 3112, 2982, 1713, 1647, 1610, 1519, 1424, 1417, 1353, 1277, 1178, 1104, 1021, 954, 935, 857, 766, 706 cm-1. 1H NMR (CDCl3) δ 8.02 (2H, d, J=8.5 Hz), 7.28 (1H, dt, J=14.0 and 7.5 Hz), 7.27 (2H, d, J=8.5 Hz), 6.98 (1H, d, J=14.0 Hz), 4.39 (2H, q, J=7.0 Hz), 2.92 (2H, t, J=7.5 Hz), 2.64 (2H, q, J=8.0 Hz), 1.42 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) δ 166.55, 144.90, 140.91, 140.39, 130.23, 129.27, 128.49, 61.16, 34.12, 29.89, 14.52; EIMS m/z 249 (M+), 204, 202, 163, 135, 129, 118, 107, 90, 77; HRMS calc'd for C13H15NO4 249.1001 found 249.1029.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>>[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: OB(O)c1cccnc1
Product: c1ccc(-c2ccc(Cc3cccnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (100 mg, 0.40 mmol) and 3-pyridineboronic acid (74 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 32 mg, 32%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.80 (s, 2H), 6.99-7.06 (m, 1H), 7.15-7.20 (m, 1H), 7.21-7.35 (m, 4H), 7.45 (d, J=8.2 Hz, 1H), 7.72-7.77 (m, 2H), 8.28 (dd, J=4.7, 1.3 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=35.9, 120.4, 123.6, 126.8, 128.7, 128.9, 133.6, 135.4, 136.2, 137.0, 139.0, 148.1, 149.9, 150.1, 155.9; (ESI): m/z=246.98 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=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>[C:1]([C:5]1[N:10]=[C:9]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1-c1cccnc1
Yield: 28.3 %

Procedure:
Using a procedure analogous to Example B41, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1.24 mmol) and pyridin-3-ylboronic acid (1.8 g, 1.48 mmol) in presence of tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.062 mmol) were combined to afford ethyl 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylate (0.10 g, 28% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].I[CH2:14][CH2:15][CH3:16]>>[CH2:14]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10])[CH2:15][CH3:16]
Reactant: CCCI
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Product: CCCn1cc([N+](=O)[O-])cc1C(=O)OC
Yield: 63.7 %

Procedure:
Following the basic procedure of Example 25(d), by reacting 1.79 g (10.5 mmol) of methyl 4-nitro-2-pyrrolecarboxylate with 1.23 ml (12.6 mmol) of 3-iodopropane, 1.42 g (64%) of the expected compound was obtained.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15]Cl)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH:22]=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CO>[OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][N:26]2[CH2:27][CH2:28][C:23](=[CH:22][C:21]3[CH:29]=[CH:30][CH:31]=[C:19]([F:18])[CH:20]=3)[CH2:24][CH2:25]2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Fc1cccc(C=C2CCNCC2)c1
Reactant: Oc1nc(-c2ccc(F)cc2)c(CCCl)s1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 21.4 %

Procedure:
In 2 ml of methanol were stirred 773 mg of 2-hydroxy-5-(2-chloroethyl)-4-(4-fluorophenyl)thiazole, 683 mg of 4-(3-fluorobenzylidene)piperidine hydrochloride and 1.04 ml of N,N-diisopropylethylamine at 80° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was separated with ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (silica gel; ChromatorexNH NHDM1020 (manufactured by Fuji-Davison Chemical Co.), eluent; hexane-ethyl acetate =1:1), and recrystallized from hexane-ethyl acetate to give 265 mg of 2-hydroxy-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,4-dichlorophenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0494.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]2=[O:27])([O-:16])=[O:15].FC1C=C2C(=CC=1)NC(=O)C2=O>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]1[C:21](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:20]2=[O:27])([O-:16])=[O:15]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc([N+](=O)[O-])ccc2-n2c1nc1ccccc1c2=O
Yield: 18 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-nitroisatin for 5-fluoroisatin gave the title compound in 18% yield: mp 302.2°-303° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (d, 1H) 8.77 (d, 1H) 8.66-8.74 (m, 1H) 8.46-8.52 (m, 1H) 8.09 (d, 1H) 7.88-7.98 (m, 1H) 7.72-7.80 (m, 1H); MS (M+H)+ 293.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:13].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1.O>O1CCCC1>[C:3]1([CH2:9][CH2:10]/[CH:11]=[CH:15]/[C:16]([O:17][CH2:18][CH3:14])=[O:13])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: C1CCOC1
Reactant: O=CCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% wt., 181 mg) was suspended in dry tetrahydrofuran (5 ml) and cooled to 0° C. Triethyl phosphonoacetate (896 μl) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min. After cooling to −78° C. 3-phenylpropionaldehyde (500 μl) was added dropwise. The reaction mixture was stirred at this temperature for 1 h. The reaction mixture was allowed to warm-up to room temperature, hydrolyzed with water/THF, poured into water and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude was purified by flash column chromatography.