Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][C:4]=1F)#[N:2].[NH2:25][CH3:26]>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH:25][CH3:26])#[N:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc(C#N)c(F)c2)CC1
Solvent: CC#N
Product: CNc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Temperature: 120 °C

Procedure:
To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (100 mg, 0.30 mmol) in CH3CN (10 mL) was added aqueous NH2CH3 (10 mL) in a sealed tube, and then heated to 120° C. overnight. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via prep-TLC to afford tert-butyl 4-{2-[4-cyano-3-(methylamino)phenyl]ethyl}piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)(=[O:28])=[O:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)ccc1NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A reaction mixture of 10.0 g (64 mmol) of 5-fluoro-2-aminobenzoic acid, 16.3 g (193 mmol) of sodium hydrogencarbonate and 16.3 g of 8-quinoline-sulfonyl chloride in 325 ml of water and 325 ml of ethyl acetate was stirred overnight at RT. The aqueous phase was separated off and extracted once with 50 ml of ethyl acetate. The aqueous phase was then rendered acidic using conc. hydrochloric acid and stirred for 2 h. The precipitate deposited was filtered off with suction, dried in vacuo and 19.5 g of 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33](Cl)=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O.C(OCC)(=O)C>[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Yield: 82.5 %

Procedure:
A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.9 g, 12.6 mmol) in DMA (25 mL) was heated at 120° C. for 5 hours. The solution was diluted with ethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (3.75 g). 1H NMR δ (CDCl3): 2.13-2.29 (m, 2H), 2.38 (quin, 2H), 3.85-4.04 (m, 4H), 3.90 (s, 3H), 4.19-4.37 (m, 4H), 4.96-5.00 (m, 1H), 6.91 (t, 1H), 7.42-7.45 (m, 2H), 8.14 (d, 1H), 8.25 (d, 1H); m/z 433 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=O)[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:11]1[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cn3ccnc3c(Cl)n2)c(Cl)c1

Procedure:
650 mg (2.3 mmol) of 6-(2,4-dichlorophenyl)imidazo[1,2-a]pyrazin-8(7H)-one (Example 4A) were dissolved in 7 ml of phosphoryl chloride and stirred under reflux for 12 h. The reaction mixture was poured into 100 ml of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. Ethyl acetate was added, and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. Methanol was added to the residue, and the precipitated solid was filtered off and washed with methanol and diethyl ether and dried under high vacuum. This gave 400 mg (58% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11](Br)[CH:12]=[CH2:13].[H-].[Na+]>CN(C=O)C>[CH2:13]([N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH:12]=[CH2:11]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1ccc2ncnc(Cl)c21
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a room temperature solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.2 g, 7.8 mmol,) and allyl bromide in 40 mL of DMF was added 60% sodium hydride (625 mg, 15.6 mmol, 2 equiv.) in several portions. After 20 minutes, the reaction was quenched with water and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide 1.3 g (88%) of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow oil which was used without further purification.
Reaction SMILES: ClCl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:32](=[O:33])[CH2:31][C@@:12]3([CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24]([O:26][C:27](C)(C)C)=[O:25])[CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C(#N)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:32](=[O:33])[CH2:31][C@@:12]3([CH2:16][NH:15][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)OC(C)(C)C
Agent: ClCl
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@]2(CN1)CC(=O)N(c1cccc(Cl)c1)C2
Yield: 105.9 %

Procedure:
The arylated lactam (3S,5S)-di-tert-butyl-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (A7a) (45.7 mg, 101 μmol) was taken up in 1M HCl in ethyl acetate (1.0 ml, 10 eq). The reaction was aged at room temperature overnight. The reaction was purged by bubbling N2 gas through it, until dry. The product was then taken up in a saturated solution of hydrochloric acid in methanol (2 ml), and aged at room temperature overnight. The reaction was blown dry with nitrogen gas and dried in-vacuo to give (3S,5R) methyl-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (B7a) (35.2 mg, 102 μmol). LCMS for C15H17N2O3Cl 308.09 [M], found ES+ 309.2 [M+H]+ and 311.1 [M+H]+ (for the chlorine isotope) at 2.0 minutes retention time, using 5-45% acetonitrile/water (with 0.1% formic acid buffer) gradient over 7 minutes. The minor diastereomer (3S,5R)-di-tert-butyl 7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (A7b) (15.2 mg, 34 μmol) was treated similarly to give (3S,5S)-methyl 7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (B7b) (12.4 mg, 36 μmol). LCMS for C15H17N2O3Cl 308.09 [M], found ES+ 309.2 [M+H]+ and 311.1 [M+H]+ (for the chlorine isotope) at 2.2 minutes retention time, using 5-45% acetonitrile/water (with 0.1% formic acid buffer) gradient over 7 minutes.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].Cl.[CH3:16][N:17]=[C:18](SC)[S:19][CH3:20]>C(O)C>[CH3:16][NH:17][C:18](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:19][CH3:20]
Reactant: CN=C(SC)SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: Cl
Solvent: CCO
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
Two g. of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole, 25 ml. of denatured ethanol, 0.72 ml. of concentrated hydrochloric acid and 1.16 g. of methylcarbonimidodithioic acid, dimethyl ester, were added to a flask and heated under reflux for 16 hours. The reaction mixture was then evaporated to an oily residue under vacuum, and the residue was taken up in 25 ml. of water and extracted with two 15 ml. portions of diethyl ether. The aqueous layer was cooled and 3 ml. of 50% aqueous sodium hydroxide was added. The aqueous solution was then extracted with two 20 ml. portions of diethyl ether, and the extract was evaporated to dryness under vacuum to obtain 2.0 g. of crude product, which was identified by its mass spectrum, showing a molecular ion of weight 318, and by its nuclear magnetic resonance spectrum; 'H NMR (CDCl3) δ7.07 (s, 1H), 3.87 (s, 2H), 3.75 (s, 2H), 3.42 (t, 2H), 2.75 (m, 2H) and 2.33 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 11c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:25]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 500 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (312 mg, 1.67 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (183 mg, 1.12 mmol) and N-methyl morpholine (484 mg, 4.79 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl) (390. mg, 2.15 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction mixture was quenched with dilute hydrochloric acid (2N, 30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate 400 mg (57%) as thick oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([OH:19])[C@H:16]([OH:20])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>O1CCCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][C@@H:16]([O:20][CH3:23])[C@H:17]([OH:19])[CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 1 h

Procedure:
To a mixture of 5.35 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]pyridine and 40 ml of tetrahydrofuran was added dropwise 800 mg of oily (60%) sodium hydride gradually under stirring, and the mixture was stirred as it was for 1 hour. Then, 1.24 ml of methyl iodide was added thereto and the resultant mixture was stirred overnight as it was. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 2.18 g of the title compound.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.[CH2:37](O)[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].BrCCCCBr>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: CCCCO
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: O
Product: CC(C)N1CC2N(C(=O)C(N3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 μl of 1,4-dibromobutane were added to this mixture. The reaction mixture was stirred at 90° C. for 16 hours and evaporated. The residue was suspended in 5% Et3N/ethyl acetate, filtered and evaporated. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=612.11 (calculated, monoisotopic); measured value (M+H)+: 613.4.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCCCCCC>C1COCC1>[CH3:5][C:4]([CH3:6])([CH:3]=[CH2:2])[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=CCCl
Solvent: CCCCCCCCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
4-Chloro-2-methyl-2-butene (2.00 mmol) was weighed into a vial and sealed with a septum. Using a freeze-pump-thaw technique, air was removed and replaced with argon. THF (4 ml) was added to the vial and then cooled to -78° C. The allyl chloride was then cannulated to the active coppersolution (8.00 mmol) at -108° C. The solution was stirred at -108° C. for 10 minutes and then warmed to -95° C. Benzoyl chloride (8.80 mmol) and decane (2.00 mmol) were admixed with 4 ml of THF in a vial, cooled to -78° C. and then cannulated to the organocopper solution at -95° C. The reaction mixture was allowed to warm to -78° C. and stirred for 30 minutes. The solution was then quenched with saturated NH4Cl(aq), extracted with ether (3×20 ml), washed with brine (3×50 ml), and the organic layer dried over MgSO4. Flash silica gel chromatography using hexanes afforded 2,2-dimethyl-1-phenyl-3-butene-1-one (1.12 mmol), for a 56% yield: IR (neat) 3085, 3059, 2975, 2934, 2872, 1679, 1635, 1597, 1578, 1466, 1412, 1380, 1363, 1259, 1173, 1157, 1001, 971, 918, 796,719,694, 667. 1H NMR (300 MHz) 7.85-7.89 (m, 2H), 7.32-7.46 (m, 3H), 6.11-6.26 (dd, J1 =17.52 Hz, J2 =10.63 Hz, 1H), 5.17-5.27 (m, 2H), 1.39 (s, 6H). 13C NMR (300 MHz) 204.5, 143.8, 137.1, 131.5, 129.1, 127.8, 113.9, 50.1, 25.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[CH:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottom flask 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (2.124 g), 4-trifluoromethoxyphenylboronic acid (2.466 g), and sodium carbonate (0.635 g) were suspended in a mixture of DMF (81 mL) and deionized water (9 mL) that was degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (0.462 g) was added and the reaction mixture stirred at 90° C. overnight, concentrated, the residue dissolved in ethyl acetate, and washed with water (2×) and concentrated NaHCO3. The combined organic phase dried over MgSO4 and concentrated, then subjected to gradient chromatography (ethyl acetate/hexane) to produce dark grey solid. The solid was recrystallized from ethyl acetate/hexanes mixture to produce off-white material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([SH:12])[N:3]=1.[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>C(O)C.O>[F:10][C:8]([F:9])([F:11])[C:6]1[N:5]=[C:4]([S:12][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CSc2nc(O)cc(C(F)(F)F)n2)cc1

Procedure:
4-hydroxy-6-trifluoromethyl-2-pyrimidinethiol (Cpd #264; 4.90 g, 25.0 mmol) in ethanol (8 ml) is treated with 3.25 N NaOH (8 ml, 26.0 mmol) followed by 4-methoxybenzyl chloride (3.5 ml, 25.7 mmol). After refluxing for 1 hr, the reaction is diluted with water and filtered. The solid is recrystallized from ethanol: 4.63 g (14.6 mmol, 58%), mp 169-170° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21].CCN(CC)CC>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[C:9]#[N:10]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccc(F)cc1F)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of 2.0 g Et3N in 25 ml of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives β-oxo-α-(2,4-difluorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 169°-171°.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[O:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CN(C=O)C.Cl>[CH:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[C:4]([O:3][CH:23]([CH3:25])[CH3:24])=[O:15])=[O:1]
Reactant: O=C1OC(O)c2cccc(C(F)(F)F)c21
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1c(C=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
To a solution of (±)-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one (2.2 g, 10.1 mmol) in 20 mL of DMF was added potassium carbonate (2.8 g, 20.2 mmol) followed by 2-iodopropane (1.11 mL, 11.1 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with 1N HCl to pH ˜4 and extracted with EtOAc. The organics were washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 2.3 g (87%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 10.08 (s, 1H), 8.12 (d, 1H, J=7.7 Hz), 7.95 (d, 1H, J=8.2 Hz), 7.73 (t, 1H, J=7.7 Hz), 5.44-5.36 (m, 1H), 1.40 (d, 1H, J=6.6 Hz).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.34-7.52 (m, 3H), 6.83-6.91 (m, 2H), 5.21 (s, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.368 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO3S, 474.1 (M−H). found 474.1.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=O)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1.C(O)(=O)C>C(O)C>[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1
Reactant: Cc1cc2cccc(C=O)c2o1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2cccc(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (25 mg, 0.081 mM) in absolute ethanol (2.0 mL), there were added 2-methyl-7-formyl-benzofuran (19 mg, 0.12 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and washed with ethanol to thus give the title compound (28 mg, yield: 78%).