Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[C:23]([F:26])([F:25])[F:24].Cl>CN(C=O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:7][C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C#N)cc2C(F)(F)F)n[nH]1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
Potassium carbonate (2.8 g, 20.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 4-fluoro-3-trifluoromethylbenzonitrile (2.8 g, 15.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 80° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (70 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellowish solid of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (1.7 g, yield: 42.4%). mp: 123-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (d, J=0.5 Hz, 3H), 5.75 (d, J=0.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.75 (dd, J=2.0 and 8.8 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 9.60-11.60 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13]>CCO.[Pd].C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13]
Reactant: CC1c2ncn(-c3ccc(F)cn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC1c2ncn(-c3ccc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 48 h
Yield: 62.3 %

Procedure:
To a solution of (2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (0.80 g, 1.83 mmol) in degassed EtOH (25 mL) was added 10% palladium on carbon (0.20 mg, 0.19 mmol). The reaction was placed under an atmosphere of hydrogen and let stir for 48 h. The reaction was diluted with DCM and filtered through a pad of Celite®. The solvent was concentrated and chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (500 mg, 62%). 1H NMR (500 MHz, CDCl3) δ 8.45-8.30 (m, 1H), 7.94 (dd, J=18.2, 10.7 Hz, 1H), 7.76 (d, J=5.7 Hz, 1H), 7.67-7.43 (m, 3H), 7.43-7.30 (m, 1H), 5.81 (dd, J=13.3, 6.7 Hz, 1H), 5.07 (d, J=5.6 Hz, 1H), 4.52 (d, J=6.7 Hz, 1H), 3.61-3.31 (m, 1H), 3.08-2.69 (m, 1H), 1.63-145 (m, 3H). MS (ESI): mass calculated for C20H15ClF4N4O, 438.08. m/z found 439.1 [M+H]+.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]([Cl:18])[CH:8]=1)(=O)(=O)C.[C-:19]#[N:20].[Na+]>CS(C)=O>[Cl:18][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=1)[CH2:6][C:19]#[N:20]
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCc1cc(Cl)cc(OC(F)(F)F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl mesylate (8.2 g, 26.8 mmol; see step (i) above) in DMSO (50 mL) was added sodium cyanide (2.6 g, 53.6 mmol). The resulting heterogeneous solution was warmed to 50° C. and sonicated for 1 hour. The reaction was cooled and partitioned between Et2O and H2O. The organics were washed with H2O (2×) and brine (2×). The combined aqueous phases were extracted with Et2O (1×). The combined organics were dried (Na2SO4), filtered and concentrated under a low heat and partial vacuum to afford the sub-title compound (6.3 g, 100%) as a reddish volatile oil which was used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[CH:39]=2)[CH:35]=[CH:34]1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][C:55]([S:58]([F:63])([F:62])([F:61])([F:60])[F:59])=[CH:54][C:50]=1[C:51](O)=[O:52]>CN(C=O)C>[CH3:47][O:48][C:49]1[CH:57]=[CH:56][C:55]([S:58]([F:63])([F:59])([F:60])([F:61])[F:62])=[CH:54][C:50]=1[C:51]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([CH3:25])=[C:27]([N:33]2[C:40]3[N:36]([N:37]=[C:38]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:39]=3)[CH:35]=[CH:34]2)[CH:28]=1)=[O:52]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: COc1ccc(S(F)(F)(F)(F)F)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(S(F)(F)(F)(F)F)cc1C(=O)Nc1ccc(C)c(-n2ccn3nc(-c4cccnc4)cc23)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
394 mg (1.04 mmol) of HATU and 127 mg (1.04 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added to a solution of 200 mg (0.69 mmol) of the compound of Example 6A and 288 mg (1.04 mmol) of 2-methoxy-5-(pentafluoro-λ6-sulphanyl)benzoic acid in 2.2 ml of DMF. The reaction was stirred at 50° C. for 16 h. The reaction mixture was then purified directly by preparative HPLC (Method 16). This gave 222 mg (53% of theory) of the title compound.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>O>[Br:1][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:18][C:12]1[C:11]2[C:16](=[CH:17][C:8]([Cl:7])=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Br
Reactant: OCCOCCNc1ccnc2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(NCCOCCBr)ccnc2c1
Temperature: 155 °C
Yield: 31 %

Procedure:
Hydrobromic acid (5.9 ml, 109.1 mmol) and then sulphuric acid (2.0 ml, 37.0 mmol) are added dropwise to 4.7 g of compound 21 (17.6 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 155° C. for 2 h 30 min, and then poured into 70 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9), and the medium is then extracted at the reflux of toluene (70 ml) for 20 min. The organic phase is then collected and the compound 22 is obtained after crystallization at −18° C. overnight, filtration, washing with hexane, and then drying under vacuum: 1.77 g (yield=31%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@@H:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)P(N(C)C)(N(C)C)=O.CCCCCC.C(OCC)(=O)C.O1CCCC1>[CH2:21]([C@@H:15]([C@@H:14]([OH:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C[C@H](C)O
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)[C@@H](Cc1ccccc1)[C@H](C)O
Temperature: -40 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Subsequently, in a 50 ml flask were charged 3.3 g (30.0 mmol) of diisopropylamine and 10 ml of tetrahydrofuran, and 16.6 ml (24.9 mmol) of n-butyllithium 1.5M hexane solution was added thereto dropwise on an ice bath in a nitrogen stream. The mixture was then stirred for 1 hour at that temperature. The reaction mixture was further cooled to −40° C., and 1.40 g (11.9 mmol) of methyl (S)-3-hydroxybutyrate prepared as above was added thereto dropwise. After the mixture was stirred for 0.5 hour, 3.00 g (17.5 mmol) of benzyl bromide dissolved in 6 ml of hexamethylphosphoramide was added thereto dropwise at −10° C. or lower temperature. After the addition, the temperature was heated up to 0° C., and the mixture was stirred for 15 min. The resulting mixture was then poured into an ice water, and was extracted with ethyl acetate. The ethyl acetate layer was concentrated to give 3.90 g of a crude product. The crude product was subjected to column chromatography (hexane/ethyl acetate=4/1 by volume) to obtain 1.50 g (61%) of the title compound (anti/syn=98/2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (259 mg, 0.930 mM), morpholine (162 μL, 1.86 mM) was added to the resulting solution and then the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (274 mg, yield: 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN)cc3)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNC(=O)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{4′-[4-(2-Amino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.031 g, 0.08 mmol), benzoyl chloride (0.01 mL, 0.09 mmol), and triethylamine (0.03 mL, 0.24 mmol) were combined in CH2Cl2 (0.5 mL) and stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]#[N:35])[CH:30]=3)[C:25]2=[O:36])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[I-].[Li+].N1C=CC=CC=1>O>[C:34]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:36])[N:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:37])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=1)[C:32]2=[O:33])#[N:35]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)OC)CCCC1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a mixture of 4-(5-cyano-1,3-dioxo-2H-isoindol-2-yl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.3 mmol, 151 mg) and lithium iodide (3.0 mmol, 397 mg) was added pyridine (6 mL) at room temperature. The solution was refluxed for 15 h at which time TLC analysis of the mixutre indicated the absence of starting material. Then, it was cooled to room temperature and diluted with water (15 mL) and the bulk of the pyridine was removed by concentration under reduced pressure. The residue was extracted with ether (2×15 mL) to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air-drying, the crude product was purified by reverse phase HPLC to afford 50 mg (34%) of a white solid, mp 143-146° C. HR MS (C27H27N3O6): Obs mass, 490.1990. Calcd mass, 490.1978 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](B(O)O)=[C:28]2[CH2:33][CH2:32][CH2:31][N:29]2[N:30]=1>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:27]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][N:29]4[CH2:31][CH2:32][CH2:33][C:28]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Product: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2cccnc21

Procedure:
Using Preparation 3A, 1-benzene-sulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine (Preparation 5) is reacted with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 2) to provide the titled product. MS (ES) m/z=442 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[Cl:23])[CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl.O1CCOCC1>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][C@H:9]([CH2:8][NH2:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of [(R)-1-(2-chloro-4-nitrophenyl)pyrrolidin-3-yl]methylcarbamic acid tert-butyl ester (560 mg) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (2 mL; alternatively a solution of HCl in dioxane or propanole-2 can be used) and stirred at room temperature for 5 hours. The reaction mixture was partitioned between dichloromethane and sodium carbonate solution. The organic phase was dried and concentrated. The product with the molecular weight of 255.71 (C11H14ClN3O2) was obtained in this way; MS (ESI): 256 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCCCc1ccccc1
Yield: 34.6 %

Procedure:
Following a procedure similar to that described in Example 5(a), 1.69 g of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 1.72 g of 1-t-butoxycarbonyl-2-(2-hydroxyethyl)piperidine, 5.9 g of triphenylphosphine and 3.92 g of diethyl azodicarboxylate were reacted in 75 ml of methylene chloride. The crude oily product, extracted as described in Example 5(a), was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.13 g (yield 34%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[N:9]2[CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[CH3:12][C:11]1([CH3:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[N:9]([CH:15]2[CH:16]3[CH2:24][CH:20]4[CH2:19][CH:18]([CH2:23][CH:22]2[CH2:21]4)[CH2:17]3)[C:10]1=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(NS(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
Under an argon atmosphere, a solution of 1-(4-aminophenyl)-4,4-dimethyl-2-(adamantan-2-yl)-1,2-diazetidin-3-one (30.0 mg, 0.0920 mmol) prepared in Example 183 in dichloromethane (1 mL) was added with triethylamine (18.6 mg, 0.184 mmol) and methanesulfonyl chloride (15.8 mg, 0.138 mmol) at room temperature, and the resultant was stirred at the same temperature for 3 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:1), and the title compound (6.80 mg, 18.3%) was obtained as a brown amorphous solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[C:9]([C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].CCCCCC>CN(C)C=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:4][CH3:1])=[C:15]([CH3:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(C(C)(C)C)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCCCCC
Product: COc1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
Potassium carbonate (8.4 g) and methyl iodide (2.9 mL) were added to a solution of 4-tert-butyl-2-methylphenol (CAS #98-27-1, 5.0 g) in N,N-dimethylformamide (25 mL), and the mixture was stirred at room temperature for three days. Ice water and hexane were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.16 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].O.C1C[O:15][CH2:14]C1>>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[NH:10][C:14](=[O:15])[NH:1][C:2]=2[CH:7]=1
Reactant: C1CCOC1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.49 g (33.9 mmol) of 1,1″-carbonyldiimidazole were added in portions to a stirred solution of 5.00 g (28.2 mmol) of 1,2-diamino-4,5-dichlorobenzene in THF (100 ml) at room temperature. The reaction solution was then stirred at room temperature overnight. The reaction mixture was mixed with water (60 ml) and cooled in an ice bath. The precipitate which separated out was filtered, washed with water and dried in vacuo.
Reaction SMILES: N1C=CN=C1.[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7].Cl[Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15]>C(Cl)Cl>[CH2:6]([NH:8][CH2:9][CH2:10][O:11][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCNCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCNCCO[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
Imidazole (18.15 g) was added to the solution of 2-(ethylamino)ethanol (9.14 g) in CH2Cl2 (200 mL) at room temperature. The mixture was stirred for 10 minutes until all imidazole were dissolved. The solution was cooled in ice bath for 20 minutes. Chlorotriethylsilane (15.46 g) was added to the solution via a syringe. The solution was stirred under nitrogen for overnight, while it was warmed up to room temperature. The reaction solution was washed by H2O (150 mL×3), brine (150 mL×1), dried by Na2SO4 and concentrated to give crude ethyl-(2-triethylsilanyloxy-ethyl)-amine (21.94 g), which was used in next step without further purification. 1H NMR (300 MHz, DMSO-d6) □ 3.58 (t, 2H, J=6.0 Hz), 2.53 (m, 4H), 1.41 (s, 1H), 0.93 (m, 12H), 0.54 (q, 6H, J=8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: BrCCBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=c1ccc2cc(OCCBr)ccc2o1
Yield: 26 %

Procedure:
A mixture of 6-hydroxy-chromene-2-one, which can be synthesized in accordance with the procedure set forth by T. Harayama, K. Katsuno, H. Nishioka, M. Fujii, Y. Nishita, H. Ishii, and Y. Kaneko, Heterocycles, 1994;39:613, (3.2 g, 19.7 mmol), 1,2-dibromoethane (6.7 mL, 14.6 g, 78 mmol), and potassium carbonate (5.4 g, 39 mmol) in 150 mL of acetone is stirred at reflux for 48 hours. The cooled reaction mixture is added to 1.0 L of water and 250 mL of ethyl acetate. The mixture is filtered, and the insoluble material is washed with a small amount of additional ethyl acetate. The combined filtrates are separated, and the aqueous layer is washed several times with fresh ethyl acetate. The combined organic layers are washed with 5% aqueous sodium carbonate solution and brine, then dried (sodium sulfate), and evaporated. The residue is purified by flash chromatography (1% methanol in dichloromethane elution) to give 1.4 g (26%) of product. A sample recrystallized from ethyl acetate-hexane had melting point (mp) 101-102° C.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1.[C:15](=[O:17])=[O:16].O>C1COCC1>[F:6][C:7]1[N:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][C:12]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(F)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(F)c(C(=O)O)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL, 385 mmol) at −60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385 mmol) over 5 minutes such that the internal temperature was maintained below −60° C. After stirring for 45 minutes at −65° C. a solution of 2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of THF was added over the course of 2 minutes maintaining an internal temperature <−65° C. The reaction was stirred at −70° C. for 1.5 hours then reaction was poured into a 3 L flask containing 1200 g of crushed dry ice. The reaction was allowed to warm to 0° C. and then poured into 1000 mL of water. The organics were removed under reduced pressure and the aqueuous layer was acidified with 1100 mL of 2 N HCl. The resulting thick white slurry was stirred for 1 hour then filtered to provide 2-fluoro-5-methoxynicotinic acid as a white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]=[CH:8][C:7]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(-c2ncc(Br)cn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 1 h

Procedure:
n-BuLi 2.0M (ALDRICH, 0.18 ml) was added dropwise, with vigorous stirring, to a solution of 5-bromo-2-(4-trifluoromethylphenyl)pyrimidine (60 mg) in THF (2 ml) at −78° C. After stirring for 1 hour, tributyltin chloride (97 μl) was added dropwise at −78° C., under argon atmosphere. After 1 hour 30 minutes at −78° C., the reaction was quenched with 1 N NH4Cl (5 ml), diluted, extracted with ethyl acetate (3×10 ml), washed with brine, dried over MgSO4, concentrated under vacuum and purified by chromatography column using CH2Cl2-hexane 1:8 as eluent to give 75 mg of the desired product as a colorless oil.