Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[Si:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A 10 mL round bottom flask fitted with magnetic stirrer and pressure-equalizing dropping funnel was charged with 3 mL of DMF which had been dried by vacuum distillation from CaH2. Methyl 6-hydroxy-2-naphthoate (1.01 g, 5 mmol) and t-butyldimethyl silyl chloride (0.83 g, 5.5 mmol) were added and the atmosphere replaced with nitrogen. A solution of imidazole (0.75 g, 11 mmol) in 3 mL of dry DMF was added via the dropping funnel over 15 minutes, and stirring continued for 4 hours. TLC analysis (SiO2, 5% ethyl acetate/hexane) showed clean conversion to a new material. The solution was poured into 50 mL of 1% aq. Na2CO3 solution and extracted with 3-35 mL portions of pentane. The combined pentane solutions were washed with 25 mL of water, 25 mL of brine and dried over MgSO4. Evaporation of the pentane yielded 1.45 g of slightly yellow solid. Purification by column chromatography on silica using 5% (V/V) ethyl acetate/hexane as eluent afforded 1.4 g (88%) of white solid after recrystallization from pentane: mp 72°-72.5° C.; 1H NMR delta 0.266 (s, 6H), 1.022 (s, 9H), 3.958 (s, 3H), 7.19-8.53 (m, 6H); 13C NMR delta -4.35, 18.23, 25.64, 52,03, 114.74, 122.87, 125.38, 125.62, 126.75, 128.16, 130.87, 130.95, 137.10, 155.69, 167.36; IR (KBr) 2950, 2860, 1715, 1635, 1605, 1480, 1290, 1210 cm-1 ; MS m/e (rel. intensity) 316 (33, 285(7), 260 (33), 259 (100), 200 (11), 185 (13), 141 (8) . ##STR26##
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:21][Si](C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:21])=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)(=O)C(C(=O)OC(C)(C)C)=C1Br
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(C(=O)OC(C)(C)C)=C1N

Procedure:
To 3-ethoxy-4-bromo-5-t-butyloxycarbonylisothiazole-1,1-dioxide (340 mg, 1.0 mmol) in 5 ml of dry acetonitrile was added hexamethyldisilazane (242 mg, 1.5 mmol) and the solution was stirred at reflux for 7 hours. The reaction mixture was evaporated in vacuo and the residue was refluxed in 10 ml of ethanol for 3/4 hr. Removal of the ethanol in vacuo gave a crude oil which was chromatographed on silica gel. The product was recovered as a viscous yellow oil (210 mg). Trituration in petroleum ether gave a yellow solid, m.p. 128°-130° C. Mass spectral analysis confirmed the structure.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[S:27][C:26]([C:28]([N:30]([CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH3:31])=[O:29])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[S:27][C:26]([C:28]([N:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:31])=[O:29])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:11][CH:12]=1
Reactant: CC(=NNC(=O)c1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Solvent: O=C(O)C(F)(F)F
Product: CC(=NNC(=O)c1ccc(C(=O)N(C)CCC(=O)O)s1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 56 %

Procedure:
t-Butyl 3-(5-{1-[4-Hydroxy-5-(4-trifluoromethylphenyl)thiophen-3-yl]ethylidenehydrazinocarbonyl}-N-methylthiophene-2-carboxamido)propionate (30 mg, 0.05 mmol) was stirred with trifluoroacetic acid (300 μL) at room temperature for 15 minutes. The reaction solution was concentrated, and after addition of ether the resulting solid was collected by filtration to give the desired product (yield 56%).
Reaction SMILES: C([O:3][C:4](=[O:26])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=[N:11][CH:12]=1)C.[OH-].[Na+]>CO.C1COCC1>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C@@H:14]([NH:13][C:10]2[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:26])=[O:3])=[CH:8][CH:9]=2)[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)O)cn2)C1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A mixture of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (600 mg) and 1N NaOH solution (3.3 ml) in MeOH (10 ml) and THF (10 ml) was stirred at 70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and H2O. The aqueous solution was adjusted to PH4.5 and extracted with AcOEt and THF. The organic layer was washed with brine and dried over MgSO4. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give (2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (0.45 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)[OH:6])[CH3:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([NH:36][C@@H:34]([C:31]1[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=1)[CH3:35])=[O:12])[OH:6])[CH3:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: CCN(CC)CC(O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CC(O)c1cc(C(=O)N[C@H](C)c2ccc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.075 mmol) in N,N-dimethylformamide (5 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (100 mg, 0.48 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (300 μL, 1.7 mmol). The reaction mixture was stirred for 16 hours at 25° C. and purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:24][CH2:23][N:22]3[C:15](=[CH:16][C:17]4[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]=43)[C:14]2=[O:27])=[N:8][CH:9]=[CH:10][C:11]=1Cl)(=[O:3])[CH3:2].[B:28]1(B2OC(C)(C)C(C)(C)O2)[O:32]C(C)(C)C(C)(C)[O:29]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:24][CH2:23][N:22]3[C:15](=[CH:16][C:17]4[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]=43)[C:14]2=[O:27])=[N:8][CH:9]=[CH:10][C:11]=1[B:28]([OH:32])[OH:29])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 65 °C
Yield: 86.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 199d (4.5 g, 1.0 eq., 11.6 mmol), Pin2B2 (7.38 g, 2.5 eq., 29.0 mmol), PdCl2(dppf) (473 mg, 0.05 eq., 0.58 mmol), x-phos (470 mg, 0.1 eq., 1.16 mmol), potassium acetate (3.41 g, 3.0 eq., 34.8 mmol), and dioxane (100 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford crude 199e as a brown-red liquid (4.0 g, purity: 65%). MS-ESI: [M+H]+ 398.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Cl:16])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Cl)cc21
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10 g) in THF (dry) (192 mL) was added N-chlorosuccinimide (6.41 g) portionwise at 0° C. The mixture was stirred at room temperature over weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (10.12 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1CCNCC1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and piperidine (0.31 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (52 mg, 51%) as an off-white powder. ES-HRMS m/e calcd for C20H31N4O (M+H+) 343.2493, found 343.2489.
Reaction SMILES: O.[N:2]1[C:9]([Cl:10])=[N:8][C:6](Cl)=[N:5][C:3]=1[Cl:4].[CH3:11][C:12]([NH2:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[OH-]>C1(C)C(C)=CC=CC=1>[Cl:10][C:9]1[N:2]=[C:3]([Cl:4])[N:5]=[C:6]([NH:19][C:12]([CH3:18])([CH3:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
Into a flask, 20 grams of water, 50.0 grams (0.271 mole) of cyanuric chloride and 125 grams of a mixed xylene were charged and 35.9 grams (0.278 mole) of 1,1,3,3-tetramethylbutylamine was slowly and dropwise added into the mixture while keeping the temperature at 8-10° C. Then, 55.5 grams of a 20% aqueous hydroxide solution was slowly and dropwise added into the mixture while keeping the temperature at 8-10C. After the reaction was complete, the oil (organic) and water phases were separated and the water phase was separated off to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23](=[O:25])[NH2:24])=[CH:14][CH:13]=1)(C)(C)C.[ClH:27]>C1COCC1.O1CCOCC1>[ClH:27].[ClH:27].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]([NH2:24])=[O:25])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNCC(N)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NCCCCc1ccc(OCCNCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 3 (0.25 g, 0.68 mmol) was dissolved in THF (3 mL), treated with 4 N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hours. After this time, TLC analysis indicated a complete reaction. The reaction mixture was concentrated under vacuum, and methanol (2 mL) was added to the resulting residue. The resulting precipitate was collected by vacuum filtration and further dried in a vacuum oven to provide 4 (0.154 g, 67% overall yield for two steps) as a light brown solid. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.65 (m, 2H), 2.95 (m, 2H), 3.27 (m, 2H), 3.52 (t, 2H), 3.90 (s, 2H), 4.30 (t, 2H), 6.92 (d, 2H), 7.18 (d, 2H). m/z (ESI) 266.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]#[N:15]>C(O)C.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[NH:12][C:14]([NH2:15])=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]c(N)nc2c1
Temperature: 25 °C

Procedure:
3.4 g (20.5 mmol) of methyl 3,4-diaminobenzoate was dissolved in a mixture of 50 mL of ethanol and 10 mL of H2O. To this stirring solution 2.6 g (24.5 mmol) of BrCN was added in one portion, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 10 mL, then washed with ethyl acetate (20 mL). The EtOAc layer was extracted with water (20 mL). The combined water extracts were neutralized with saturated NaHCO3 solution to ˜pH 8, and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water and brine solution, dried with Na2SO4, and evaporated to give 2-amino-1H-benzoimidazole-5-carboxylic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:28]=[CH:27][C:16]4=[N:17][O:18][C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=5)=[C:15]4[CH:14]=3)OCC[O:9]2)=[CH:4][CH:3]=1>O1CCCC1.C(Cl)Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:17][CH:16]1[CH:15]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=2)=[O:18])[CH:14]=[C:13]([C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:28]=[CH:27]1
Reactant: Clc1ccc(C2(c3ccc4noc(-c5cccc(I)c5)c4c3)OCCO2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
5-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazole (65.4 g, 130 mMol) was dissolved in a solution of tetrahydrofuran (THF) (500 mL) and DCM (100 mL). To this solution, was added 500 mL of titanium(III) chloride (10 wt. % solution in 20-30 wt. % hydrochloric acid (HCl)) and the reaction mixture was stirred for 1 hour. An additional 100 mL of titanium(III) chloride (10 wt. % solution in 20-30 wt. % HCl) was added to the reaction mixture and the reaction mixture was stirred for 2.5 hours. The reaction mixture was then poured into ice water and the resulting heterogeneous solution was extracted with DCM. The DCM layer was successively washed with aqueous saturated NaHCO3 and brine. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give titled compound as an orange oil (60 g). The oil was used without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:8]=1)(=O)=O.[NH4+:27].[OH-]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:8]=[C:7]([CH2:6][NH2:27])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Yield: 39.8 %

Procedure:
A solution of [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl methanesulfonate (58 g, 0.134 mol) in THF (200 mL) and NH4OH aq. (25%, 412 mL, 2.68 mol) was stirred at room temperature for 15 hours. The excess ammonia was removed in vacuo and EtOAc (200 mL) and sat. aq. NaHCO3 (150 mL) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc, the combined organic layers were washed with sat. aq. NaHCO3 (2×150 mL), brine (200 mL) and water (1×200 mL), dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to afford the crude material (89.85 g). This material was purified by column chromatography using dichloromethane, methanol and ammonium hydroxide (97:3:1) in silica gel to yield the [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl amine (18.90 g, 40%, two steps) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18].C1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4]
Reactant: CNC(=O)Nc1cc(C(C)(C)C)no1
Reactant: CCCCSCl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a solution of 1-methyl-3-(3-t-butyl-5-isoxazolyl)-urea (0.99 g) in pyridine (8 ml), butylsulfenyl chloride (0.67 g) is added dropwise at -30° to -40° C., and the resultant mixture is stirred at the same temperature for 6 hours. The reaction mixture is allowed to stand at room temperature overnight, poured into ice water and shaken with benzene. The organic layer is washed with 3% hydrochloric acid, 5% aqueous sodium bicarbonate solution and water in that order, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(3-t-butyl-5-isoxazolyl)urea (0.031 g) is obtained as an oil. IR: 1712, 1617 cm-1 (CC14).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][Si](C)(C)C)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:20]C(F)(F)C(F)(F)Br.[F-].[Cs+]>CN(C=O)C>[Br:20][CH2:15][C:10]1[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[N:9]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Cc1cc(C[Si](C)(C)C)nc(-n2c(C)ccc2C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(CBr)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 9 (5.6 g, 21 mmol) in DMF (100 mL) was added 1,2-dibromotetrafluoroethane (10 g, 42 mmol) and CsF (6.4 g, 42 mmol). The reaction was allowed to stir at room temperature for 3 h, and the resulting purple solution was concentrated and loaded directly on flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 6 (5.7 g, 20.8 mmol, 99%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.19 (s, 6H), 2.47 (s, 3H), 4.56 (s, 2H), 5.93 (s, 2H), 7.01 (s, 1H), 7.30 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 21.1, 33.5, 107.1, 121.8, 122.9, 128.5, 150.7, 151.7, 156.3; LCQ-MS (M+H+) calcd for C13H16BrN2 279. found 279; LC-TOF-MS (M+H+) calcd for C13H16BrN2 279.04969. found 279.04963.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)c1ccc(Cl)c(CC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Cl)c(CC(=O)O)c1
Yield: 99.4 %

Procedure:
Dissolve tert-butyl 2-(2-chloro-5-isopropyl-phenyl)acetate (483 mg, 1.80 mmol) in dichloromethane (5.1 mL). Add trifluoroacetic acid (1.09 mL, 14.4 mmol) slowly and stir the reaction mixture 3 hours at ambient temperature. Concentrate under reduced pressure to give the title compound (380 mg, 1.79 mmol). MS (m/z): 229.8 (M+18). The following compound is prepared essentially by the method of Preparation 49.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[N:14]1[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]=12.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Li:30].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Li:30].[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@:18]12[CH2:19][O:20][CH2:21][CH2:22][C@H:17]1[CH2:16][O:15][NH:14]2
Reactant: Fc1ccccc1Br
Reactant: C1CC2CON=C2CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1ccccc1F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccccc1[C@]12COCC[C@H]1CON2
Reaction time: 1 h

Procedure:
2-Bromofluorobenzene (1.85 g) was dissolved in toluene (30 ml), and tetrahydrofuran (10 ml) was added. n-Butyllithium (2.73 M; 3.68 ml) was added dropwise at −78° C. 2-Fluorophenyllithium was prepared by stirring at the same temperature for one hour. A boron trifluoride-ether complex (1.26 ml) was added to a solution of 3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole (630 mg) in toluene (70 ml) at −78° C. After stirring at the same temperature for 10 minutes, 2-fluorophenyllithium prepared above was added to the reaction mixture through a cannula. After stirring at the same temperature for one hour, an ammonium chloride solution was added. The reaction mixture was returned to room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.26 g).