Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([CH:11]([O:27][CH3:28])[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2OS(C(F)(F)F)(=O)=O)=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9](=[O:10])[CH:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH3:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OS(=O)(=O)C(F)(F)F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1-c1ccccc1

Procedure:
Using a similar procedure as described in example 57.1 (RS)-trifluoro-methanesulfonic acid 2-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-3-fluoro-phenyl ester (example 279.1) was reacted with phenyl boronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-biphenyl-2-yl)-2-methoxy-acetamide. Solid. MS 375.3 ([M+H]+)
Reaction SMILES: N1C=CN=C1.[CH2:6](O)[CH2:7][O:8][CH2:9][CH2:10][OH:11].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH2:21]>CN(C=O)C>[C:16]([Si:13]([CH3:15])([CH3:14])[O:11][CH2:10][CH2:9][O:8][CH:7]([OH:21])[CH3:6])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O
Reactant: OCCOCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O)OCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of imidazole (2.11 grams, 31 mmol) and diethylene glycol (5 grams, 47 mmol) in dry DMF (11 ml) was cooled to 0° C. and stirred for 30 minutes under argon atmosphere. A solution of tert-butyldimethylsilyl chloride (4.72 grams, 31 mmol) in dry DMF (15 ml) was added dropwise and the resulting mixture was maintained for 2 hours at 0° C. and was then allowed to warm up to room temperature. Water (180 ml) was thereafter added and the resulting solution was extracted with ethyl acetate (4×80 ml). The combined organic extracts were washed with brine, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography, using ethyl acetate as eluent, to give the product (Compound 28a) as a white oil (4.65 grams, 45% yield).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:32](=[O:34])[CH3:33])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Yield: 72 %

Procedure:
To a stirred solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (250 mg, 0.753 mmol) and triethylamine (200 μl. 1.88 mmol) in dichloromethane (2 ml) was added dropwise acetic anhydride (78 μl, 0.828 mmol). Reaction left at ambient temperature until reaction complete. Dichloromethane (10 ml) added to the reaction, the organic phase extracted with saturated NaHCO3 (3×10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as an oil (203 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.94 (d, 2H), 4.95-5.02 (broad, 1H), 4.24-4.38 (m, 1H), 3.79-3.88 (m, 2H), 3.52-3.64 (m, 2H), 3.45 (d, 2H), 2.70-2.88 (m, 3H), 2.36-2.45 (m, 2H), 1.98-2.10 (m, 4H), 1.78-1.90 (m, 7H), 1.05 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)N1CCCCC1
Temperature: 105 °C

Procedure:
4-Fluorophenylacetic acid (280 g, 1.82 mol) was suspended in 1.9 L toluene followed by the careful addition of 185 mL thionyl chloride (303 g, 2.545 mol). The reaction was heated to 105° C. for 16 hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9 L THF, cooled to 0° C., and 0.72 L piperidine (618 g, 7.27 mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18 hr. The mixture was quenched with a saturated solution of aq. NaHCO3 and extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered on a fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtOAc/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCl3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H), 3.54-3.60 (m, 2H), 3.69 (s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.ClCCl>[Br:17][CH2:18][CH2:19][CH2:20][O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1
Reactant: BrCCCBr
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CO)c(=O)c(OCCCBr)c1
Temperature: 80 °C
Yield: 14 %

Procedure:
60% oily sodium hydride (292, mg, 7.3 mmol) in small portions were added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.29 g, 6.64 mmol) in dimethylformamide (5 ml) with stirring. After addition of 1,3-dibromopropane (1.35 ml, 13.3 mmol), the solution was heated at 80° C. for 4 hours. The solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1:1)] to give 293 mg of 2-(3-bromopropoxy)-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow crystal (yield: 14%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[S:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2O)[CH:8]=[CH:7]1.[NH4+].[OH-]>>[Cl:3][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[CH:7][S:6][C:14]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccnc2ccsc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To neat POCl3 (200 mL, 2146 mmol) at 60° C. in a 500 mL round-bottom flask was added thieno[3,2-b]pyridin-7-ol (1 eq., 200 g, 1323 mmol) in small portions over 1.5 h. The reaction mixture was heated at 60° C. for 1 h and at 100° C. for an additional hour. After cooling down to 0° C., the reaction mixture was poured onto crushed ice (1 L) over a period of 30 min. After 15 min, NH4OH (1.5 L) was added to the mixture to form a grey precipitate that was collected by filtration, washed with water (50 mL) and air dried. The dry solid was suspended in EtOAc (1 L). The slurry was stirred at r.t. for 15 min, filtered and the filter was washed with EA (2×100 mL). The organic phase was collected, dried over MgSO4 and concentrated. The residue was passed through a short silica gel pad (300 g, eluent—a gradient hexane/EtOAc, 8/2 to 5/5) and dried in the vacuum oven (35° C.) for 2 h to afford 6 as a off-white solid (214.8 g, 1266 mmol, 96% yield). MS (m/z): 170.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.5 Hz, 1H), 7.54 (d, J=5.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[C:7]3[CH:8]=[C:9]([S:11]([CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:26])([F:25])[F:15])[CH:18]=4)(=[O:13])=[O:12])[S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4cccc(C(F)(F)F)c4)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3-(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.023 g (10% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=6 Hz, 1H), 7.85-7.91 (m, 1H), 7.61-7.72 (m, 2H), 7.50-7.60 (m, 1H), 7.12-7.31 (m, 2H), 4.74 (s, 2H), 3.52-3.71 (m, 8H), 1.50 (s, 9H); MS (ESI+) for C24H26F3N3O4S2 m/z 542 (M+H)+. HPLC 85%, RT 2.13 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3 min).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([SiH2:22][CH2:23]Cl)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>CN(C)C=O.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([SiH2:22][CH2:23][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C([SiH2]CCl)c2ccc(F)cc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C([SiH2]Cn2cncn2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
In this preparation 1.0 g of sodium 1,2,4-triazole is added to a solution of 3.1 g of bis(4-fluorophenyl)methylsilylmethyl chloride in 15 mL of dimethylformamide. The mixture is heated at about 80°-90° C. for two hours and then cooled to room temperature. The mixture is then diluted with 60 ml of water and extracted three times with 50 ml portions of ethyl ether. The extracts are combined, washed twice with 80 ml of water, then with 80 ml of aqueous saturated sodium chloride solution and dried over magnesium sulfate. The ethyl ether solvent is evaporated off affording an oil which is then purified by chromatography over silica gel solution with ethyl acetate, hexane, and mixture thereof.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[NH:26]([C:28]([C:30]1[CH:45]=[CH:44][C:33]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:32][CH:31]=1)=O)[NH2:27].C(OCC)(=O)C>CN(C)C(=O)C>[N:27]1[N:26]=[C:28]([C:30]2[CH:45]=[CH:44][C:33]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:32][CH:31]=2)[N:8]2[C:2]=1[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[N:12]=[CH:11][CH:10]=[CH:9][C:7]2=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)NN)cc1
Reactant: ClC1=Nc2cccnc2Nc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (822 mg, 3.58 mmol) and diisopropylethylamine (2 mL) in N,N-dimethylacetamide (25 mL) was added tert-butyl 4-(hydrazinecarbonyl)phenethylcarbamate (1.0 g, 3.58 mmol). The mixture was stirred at 80° C. for 24 hours then 100° C. for an additional 48 hours. The mixture was poured into ethyl acetate (150 mL) and washed with water (2×700 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to give a brown foam. This residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes (75-80%) to give a brown foam that was crystallized from dichloromethane to yield tert-butyl 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenethylcarbamate as off white crystals (717 mg). M.p.=145-148° C.; 400 MHz 1H NMR (CDCl3) δ: 8.21-8.17 (m, 2H), 7.44-7.37 (m, 3H), 7.24-7.16 (m, 3H), 7.0 (dd, J=1.6, 8.4 Hz, 2H), 6.82-6.79 (m, 1H), 6.38 (s, 1H), 4.55 (br.s, 1H), 3.42-3.37 (m, 2H), 2.84 (t, J=7.2 Hz, 2H), 1.44 (s, 9H). LCMS [M+H]: 455.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[OH:26]>[OH-].[Na+]>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]([NH2:23])=[O:26])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
A solution of 1.60 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile in a mixture of 50 ml of methanol and 50 ml of 1N sodium hydroxide solution is allowed to stand for ca. 10 minutes at 25°. The reaction mixture is then neutralised with 2N hydrochloric acid, and concentrated to about half its volume. The concentrate is extracted in methylene chloride, the organic solution washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from methanol/ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 285°-289°.
Reaction SMILES: [Mg].[Cl-].[CH3:3][CH2:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12](Br)[C:13]#[CH:14].S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[OH:11][C:6]([CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][C:4]#[CH:3]
Reactant: CCCCC(=O)CCC
Reactant: C#CCBr
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C#CCC(O)(CCC)CCCC

Procedure:
14 Grams of powdered (50 mesh) magnesium metal is suspended in 80 ml of ether and activated by addition of 200 mg of mercurie chloride. A solution of 38.4 g of 4-octanone and 36.6 g of propargyl bromide in 120 ml of ether and 50 ml of benzene is added dropwise at a rate which produced a gentle reflux. After the addition is complete, the reaction mixture is stirred for several hours and is then poured into 500 ml of cold 5% sulfuric acid. The organic layer is separated, washed with water twice, dried over sodium sulfate and stripped of solvent. The residue is distilled under vacuum to give the title product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH:20]=O)=[CH:16][CH:15]=1.C1C=CC=CC=1>O>[F:13][C:14]1[CH:23]=[CH:22][C:17](/[CH:18]=[CH:19]/[CH2:20][NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=CC=Cc1ccc(F)cc1
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(/C=C/CNCc2cccc3ccccc23)cc1

Procedure:
A mixture of 10 g of 1-aminomethylnaphthalene, 9.55 g of p-fluorocinnamaldehyde and 150 ml of benzene is heated in a reaction vessel equipped with a water separator, at reflux, until the theoretical amount of water has been separated. The mixture is cooled and evaporated to dryness. 5.78 g of the resulting Schiff's base in 60 ml of methanol, after warming to 50°, is mixed, with vigorous stirring, with 1.51 g of solid NaBH4, portionwise, and the mixture is refluxed for 20 minutes. The resulting mixture may be used as such in the next stage. The title compound can be isolated as an oil, however, by evaporation and dividing the residue between aqueous NaHCO3 solution and chloroform, drying the organic phase and evaporation.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4].[C:23]([OH:28])(=[O:27])[C:24]([CH3:26])=[CH2:25].C(N(CC)CC)C.O>CN(C)C=O.[I-].[Na+]>[C:23]([O:28][CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Yield: 91.3 %

Procedure:
In 800 ml of dimethylformamide were dissolved 199 g of the 2-chloroacetate obtained in Example 1-6-1, 64.8 g of methacrylic acid, and 4.50 g of sodium iodide. To the solution below 30° C., 73.1 g of triethylamine was added dropwise. The reaction solution was stirred at the temperature overnight, whereupon 500 ml of deionized water below 30° C. was added, followed by ordinary workup. Recrystallization from hexane yielded 209 g of the title compound. Yield 91%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[Sn](CCCC)(CCCC)CCCC>CN(C)C(=O)C>[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnccn5)cc43)n2)CC1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
A solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (40 mg, 0.096 mmol) and palladium(0)tetrakis(triphenylphosphine) (11 mg, 0.0095 mmol) in N,N-dimethylacetamide 1 mL was added (2-pyrazinyl)tributyltin (0.064 mL, 0.19 mmol). The reaction mixture heated at 150° C. for 45 min in biotage microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 20% EtOAc) to give tert-butyl 4-[6-(6-pyrazin-2-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate 30 mg 67% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)[OH:23]>>[C:13]([CH:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:23])[NH2:14]
Reactant: O=S(=O)(O)O
Reactant: N#CC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Product: NC(=O)C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
At 23° C., 6.0 g of 3-chloro-2-[1-(4-chlorophenyl)-1-cyanomethyl]-5-trifluoromethylpyridine (prepared by the method of Example 1) were stirred in 30 ml of 96% strength sulfuric acid for 16 hours. The reaction mixture was then carefully stirred into 200 ml of ice water during which the product crystallized out. The solid was separated off, washed successively with water and n-hexane and dried. Yield: 5.5 g (87%) of colorless crystals; mp.: 135-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[F:21].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].CCOC(C)=O>C(Cl)Cl>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:3]([F:21])[CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F)Oc1ccccc1
Temperature: 2.5 °C
Yield: 102.5 %

Procedure:
Mix N-[4-(4-amino-3-fluoro-phenoxy)-2-pyridyl]cyclopropanecarboxamide (500 mg, 1.7 mmol), DCM (8 mL) and pyridine (345 mg) and cool to 0-5° C. Add a solution of phenyl chloroformate (350 mg, 2.2 mmol) in DCM (1 mL). Stir the reaction at room temperature for 1.5 hrs. TLC (EtOAc:PE=1;1) shows the reaction is complete. Quench the reaction with water (5 mL). Wash the organic layer with 1N HCl solution, saturated NaHCO3 solution and brine respectively. Dry the organic layer with anhydrous Na2SO4. Filter and concentrate to give the crude product (710 mg) which is used without further purification. MS: (M+1): 408.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[CH3:1][N:2]([O:24][C:27](=[O:28])[NH:26][CH3:25])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CN=C=O
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CNC(=O)ON(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (700 mg, 1.93 mmol) in anhydrous THF (10 ml) is added methylisocyanate (220 mg, 2 eq.). The mixture is stirred at RT for 4 hours. The solvent and excess methlisocyanate are removed to yield N-methyl-N[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl](N-methyl)carbamoyloxyamine.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)OCc2ccccc2)cc(OC)c1C
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A suspension of compound 1g (382 mg, 1.0 mmol), benzyl 2-bromoacetate (0.224 mL, 1.4 mmol), and potassium carbonate (276 mg, 2.0 mmol) in DMF (3 mL) was sealed in a pressure tube and heated at 80° C. for 5 h and at rt for two days. The reaction mixture was diluted with water, and the resulting solid precipitate was recovered by filtration and washed with MeOH and hexane to give compound 14a (252 mg, 48%) as a yellow solid. ESI-MS m/e 531.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1([CH2:10][OH:11])[CH2:9][O:8][CH2:7]1.O[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:11][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)[CH2:7][O:8][CH2:9]1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: OCC1(COc2ccc(C(F)(F)F)cc2Cl)COC1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccc(C(F)(F)F)cc3Cl)COC2)cc1

Procedure:
Analogously to example 1, [3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]-methanol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-ylmethoxy]phenyl}hex-4-ynoic acid.