Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].CO.[CH:7]([CH:9]=O)=O>O>[CH3:1][N:2]([CH3:4])[N:3]=[CH:7][CH:9]=[N:3][N:2]([CH3:4])[CH3:1]
Reactant: CN(C)N
Reactant: O=CC=O
Solvent: O
Solvent: CO
Product: CN(C)N=CC=NN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,1-Dimethylhydrazine (3.20 ml, 41.9 mmol) was added to a mixture of MeOH (14 ml) and a 40 wt % glyoxal solution (2.40 ml, 20.9 mmol) in water at 0° C. The resulting mixture was stirred for 24 h at room temperature. The mixture was then dried over Na2SO4, filtered, and concentrated under vacuum to afford glyoxal bis(N,N-dimethylhydrazone) (abbreviated as bis-hydrazone A) as an orange-brown oil (2.78 g, 94% yield). The 1H NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.13 (singlet, 2 H), 2.89 (singlet, 12 H). The 13C NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 134.9, 43.1. From the 1H NMR and 13C NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1

Procedure:
A solution of 2,2,2-trichloroethyl [3-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (151 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (107 mg, 41.3%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([CH3:16])[C:8]3[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:7]=3[C:6](=[O:24])[C:5]2=1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([CH3:16])[C:8]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:7]=3[C:6](=[O:24])[C:5]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 160 °C
Reaction time: 7 h

Procedure:
Mixture of 2,3-dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound Y3, 16.5 mg, 0.0457 mmol) and pyridinium chloride (0.2 g) was stirred at ambient temperature of 160° C. for 7 hr. The reaction mixture was cooled to room temperature and added with ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was used for the next step without further purification (brown solid, 14.8 mg, 94%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H46N7O3Cl2 [(M+H)+] 694.3034, observed 694.3035.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([C:12]1[N:13]([CH2:26][C:27]#[N:28])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(OCC)C>[F:23][C:22]([F:24])([F:25])[O:21][C:17]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:26][CH2:27][NH:28][CH2:10][C:12]3=[CH:20][C:19]=2[CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1CC#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc2c(c1)cc1n2CCNC1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a suspension of Lithium Aluminium Hydride (0.68 g) in diethylether (70 mL) was added portionwise 1-cyanomethyl-5-trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester (2.28 g). The reaction mixture was then stirred for 16 hours at reflux. The solution was then slowly poured into a saturated solution of sodium-potassium tartrate. The mixture was then extracted with ethyl acetate 3 times. The combined organic phases were then washed with brine, dried with magnesium sulfate, concentrated in vacuo and purified by column chromatography to yield the desired compound (0.83 g, 45%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>ClCCl.CCOCC>[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCC2=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane was added 2M hydrogen chloride in ether (1.78 ml). The reaction mixture was stirred at room temperature for 6 hours. The solvents were removed in vacuo to yield 1-Piperidin-4-ylmethyl-pyrrolidin-2-one hydrochloride salt.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:13])C[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>CCOCC.O>[CH:3]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])=[O:5]
Reactant: O=C1CCCCCC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: O
Product: O=CC1CCCCCC1=O
Reaction time: 20 h
Yield: 99 %

Procedure:
In an argon atmosphere, sodium hydride (60%; 55.2 g, 1.38 mol) was suspended in ether (2 L), and ethanol (2.5 mL) was added thereto at room temperature. Then, a liquid mixture of cycloheptanone (141 g, 1.26 mol) and ethyl formate (152 mL, 1.84 mol) was added dropwise to the mixture over 2 hours, and the resulting mixture was stirred at the same temperature for 20 hours. Ethanol (25 mL) was added to the reaction solution, subsequently water (1.2 L) was added, and the mixture was separated. The resultant was extracted with a 10% (w/v) aqueous solution of sodium hydroxide, and then the aqueous layers were combined and washed with ether. 15% (v/v) hydrochloric acid was added to the aqueous layer under ice cooling to adjust the aqueous layer to pH 3 to 4, and then the mixture was extracted twice with ether, washed with saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and thus the title compound (174 g, 99%) was obtained as a pale orange oil.
Reaction SMILES: [F:1][C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:5]2[C:6](=O)[NH:7][CH2:8][C:9](=O)[NH:10][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1F)NC(=O)CNC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)NCCNC2
Reaction time: 26 h

Procedure:
To a solution of 8-fluoro-7-methoxy-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (5.1 g, 227 mmol) dissolved in THF (39.8 mL) was added lithium aluminum hydride (1M solution in THF, 102.4 mL, 102.4 mmol) dropwise. The reaction mixture was heated to reflux. After 26 hours, an additional equivalent of lithium aluminum hydride in THF (22.7 mmol) was added. At 30 hours, the reaction was quenched with water, 15% NaOH and an additional portion of water. The precipitate was filtered and washed with ethyl acetate. THF was removed from the filtrate, and then ethyl acetate and water were added to the flask. All the contents in the flask were transferred to the separatory funnel and extracted with ethyl acetate (3×). The combined organic layers were then washed with brine (1×), dried with magnesium sulfate, filtered and concentrated to give a brown oil. Further purification (15% ammonia in 2M solution of ethanol/ethyl acetate) yielded the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[CH:14]=2)[N:7]=[C:6]1[N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1.[C:37]([O-:40])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:36])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:40][CH3:37])=[CH:15][CH:14]=2)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[CH:14]=2)[N:7]=[C:6]1[N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1
Reactant: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(-c2ccc(OC)cc2)c1=O
Yield: 48.3 %

Procedure:
A solution of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-5-chloro-4-(4-cyano-3-fluoro-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid methyl ester (2.2 g, 4.2 mmol), p-methoxyboronic acid (1.9 g, 12.7 mmol), Pd-118 (274 mg, 0.42 mmol) and K2CO3 (1.2 g, 8.4 mmol) in DMF (50 mL) was stirred at 145° C. for 6 h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EA (3×). The combined organics were washed with water, washed brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 600 mg of the title product (24%). [M+H] Calc'd for C31H34FN5O6, 592. Found, 592.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Br>COCCOC>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][CH:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:7]=2[N:6]2[C:2]([CH3:1])=[N:3][N:4]=[C:5]12
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reactant: CN(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2CCN(C)C
Reaction time: 18 h

Procedure:
37.0 g of 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 7.8 g of a 50 percent sodium hydride mineral oil dispersion in 400 ml of dry 1,2-dimethoxyethane are stirred for 2 hours. A solution of 13.7 g of 2-dimethylaminoethyl bromide in 40 ml of dry 1,2-dimethoxyethane is added and the whole is stirred for 18 hours. The solvent is evaporated and the residue is partitioned between methylene chloride and water. The organic phase is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25](I)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=3[C:4]([NH:6][CH3:7])=[O:5])[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1
Reactant: CNC(=O)c1c(N)cccc1OC
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1c(Nc2cc(Nc3cn(C)nc3C)ncc2C(F)(F)F)cccc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
A suspension of 2-amino-6-methoxy-N-methylbenzamide (2.48 g, 13.8 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2.63 g, 6.88 mmol), palladium(II) acetate (0.077 g, 0.34 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.398 g, 0.69 mmol) and cesium carbonate (4.48 g, 13.77 mmol) in dioxane (37 mL) was degassed with argon and stirred at 100° C. for 3 hours. The reaction mixture was concentrated to dryness, diluted with EtOAc (80 ml), washed with water (1×50 ml) and brine, dried over magnesium sulfate and concentrated to afford an oil. The crude product was purified by flash chromatography on silica gel eluting with EtOAc and then 3 to 8% MeOH in EtOAc. The solvent was evaporated to dryness to afford a foam which was dissolved in DCM (12 ml). A solid formed after a few minutes and this was filtered and dried to give the title compound as a white solid (1.570 g, 52.5%). 1H NMR spectrum (500 MHz, CDCl3): 2.15 (s, 3H), 2.97 (d, 3H), 3.79 (s, 3H), 3.91 (s, 3H), 5.99 (s, 1H), 6.32 (s, 1H), 6.56 (d, 1H), 7.05 (d, 1H), 7.20 (dd, 1H), 7.34 (s, 1H), 7.44 (q, 1H), 8.23 (s, 1H), 10.56 (s, 1H); Mass spectrum: ESI+435.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27]O>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCc1ccccc1F
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccccc2F)cc1
Yield: 73.4 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (231 mg, 0.919 mmol) prepared in Example 1 (1a) and 2-(2-fluorophenyl)ethanol (137 μL, 1.02 mmol) to give 214 mg of the title compound (white powder, yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H][H]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: COc1ccc(O)cc1
Reactant: [H][H]
Solvent: CCO
Product: COC1CCC(O)CC1

Procedure:
A mixture of 100 g 4-methoxyphenol and Nishimura's catalyst in 750 ml ethanol were hydrogenated (50 psi hydrogen) at room temperature for 4.5 hours. The mixture was filtered and the filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (88 mg, 0.28 mmol), N,N-diisopropyl ethyl amine (214 μL, 1.25 mmol) and 4-aminotetrahydropyran (28 mg, 0.28 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (68 mg, 66%) as a white solid. MS: m/e=415.3 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:6]2[CH2:10][O:9][C:8](=[O:11])[N:7]2[C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29](COCC[Si](C)(C)C)[N:28]=5)=[C:23]([F:40])[CH:22]=4)=[C:14]3[N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1([C@H]2COC(=O)N2C2C=CN3N=CC(C4C=CC(C5N(COCC[Si](C)(C)C)N=CN=5)=C(F)C=4)=C3N=2)CCCC1>>[CH:1]1([C@H:6]2[CH2:10][O:9][C:8](=[O:11])[N:7]2[C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][NH:29][N:28]=5)=[C:23]([F:40])[CH:22]=4)=[C:14]3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5C5CCCC5)nc34)cc2F)n1
Agent: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C4CCCC4)nc23)cc1F
Product: O=C1OC[C@H](C2CCCC2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 50 %

Procedure:
(S)-4-cyclopentyl-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (10 mg, 50%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-4-cyclopentyl-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl) oxazolidin-2-one and (S)-4-cyclopentyl-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one. LCMS (APCI+) m/z 434.6 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:21][CH:22]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
In pyridine was dissolved 5 g of dodecyl p-hydroxybenzoate, and a solution of 5 g of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the solution and the mixture was stirred at room temperature for 4 hours. Water was added to the thus-obtained solution, the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 3.18 g dodecyl 4-(4-acetoxybenzoyloxy)benzoate. The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol at a volume ratio of 10/1, 7 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, and the obtained mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dried on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from a liquid mixture of n-hexane and ethyl acetate to obtain 2.22 g of dodecyl 4-(4-hydroxybenzoyloxy)benzoate.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O>>[S:9]1[C:10]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1cc2ccccc2s1
Product: O=C1C=C(c2cc3ccccc3s2)CCC1
Yield: 89 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and benzothiophene-2-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (134 mg, 89%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.73-7.82 (m, 2H), 7.58 (s, 1H), 7.31-7.39 (m, 2H), 6.46 (s, 1H), 2.87 (td, J=5.9, 1.2 Hz, 2H), 2.51 (t, J=6.3 Hz, 2H), 2.18 (quintet, J=6.3 Hz, 2H). 13C (75 MHz, CDCl3): 199.3, 152.5, 142.6, 140.2, 139.8, 126.3, 125.04, 125.0, 124.9, 124.6, 122.5, 37.6, 27.9, 22.8. HRMS (LCT Electrospray): mass calcd for (C14H12OS+Na) m/z 251.0507; measured [M+Na]+: m/z 251.0501.
Reaction SMILES: N#N.BrCCBr.C[Si](Cl)(C)C.I[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>CN(C=O)C.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:22][CH:23]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)CCI
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: N#N
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Br)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A solution of Zn metal (18 g, 0.27 mol) in DMF (5 mL) was purged with N2. BrCH2CH2Br (2.0 g, 10 mmol) was added, followed by TMSCl (0.92 g, 8.5 mmol). The resulting mixture was stirred at 90° C. for 30 min, and allowed to cool to rt. A solution of compound 57a (50 g, 0.22 mol) in DMF (150 mL) was added, and the resulting mixture was stirred overnight at rt. Pd(PPh3)2Cl2 (7.4 g, 10 mmol) was added, followed by 2,5-dibromopyridine (50 g, 0.21 mol). The resulting mixture was stirred at 68° C. for 2 h. The reaction was quenched by the addition of saturated NaHCO3 solution (300 mL). The resulting solution was extracted with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 57b as a yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C10H12BrNO2: 258.0 (M+H). Found: 258.2.