Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[O:11][C:10]([CH3:13])([CH3:12])[O:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH2:17]([SiH](CC)CC)[CH3:18].OS(O)(=O)=O>C(Cl)Cl.CCO.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([O:9][C:8](=[O:14])[CH:7]([O:11][CH:10]([CH3:13])[CH3:12])[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC1(C)OC(=O)C(Cc2ccc(O)cc2)O1
Reactant: CC[SiH](CC)CC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 0° C. solution of 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (0.20 g, 0.900 mmol) and triethylsilane (1.05 g, 9.0 mmol) in dry CH2Cl2 (10 mL) was treated dropwise with a 1 molar solution of TiCl4 in CH2Cl2 (0.90 mL, 0.900 mmol) under N2. The resultant red slurry was stirred at 0° C. for 15 minutes and then warmed to room temperature for 45 minutes. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.320 g of crude acid that was carried on as is. The oil was dissolved in EtOH (25 mL) and treated with conc. H2SO4 (1 mL) and then stirred at room temperature for 17 h under N2. The solvent was removed in vacuo and the oil extracted with EtOAc and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to give 0.158 g (70%) 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester. Rf=0.48 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.10 (d, 2H, J=8.80 Hz), 6.73 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H) 4.20-4.12 (m, 2H), 3.99 (dd, 1H, J=8.31 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=5.87 Hz), 2.95-2.83 (m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.97 (d, 3H, J=6.36 Hz); MS (ES−) Calc'd for C14H19O4 (M−1) 251. Found m/z 251 (100%). 97.6% ee by chiral HPLC assay (Chiralcel OJ, 4.6×250 mm, 90/10 heptane/IPA eluent, 1 mL/min, 266 nm).
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:31])[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:31][N:8]([CH3:7])[C:9]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccccc2)CC1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 18 h

Procedure:
Chlorotrimethylsilane (0.124 ml) and water (9 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-phenyl-acetamide (300 mg, 0.9 mmol) in ethyl methyl ketone (2 ml). After 18 h it was possible to isolate the hydrochloride as a colourless solid in a yield of 64% (210 mg) (Example 55).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1S(C)(=O)=O.Cl>CC(N(C)C)=O.C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1[O:9][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: OC1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)n1nc(-c2nc(OC3CCCCC3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added cyclohexanol (0.081 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane (60:40 v/v) to give 6-[5-amino-6-(cyclohexyloxy)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (55 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a well stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 50.7 mmol) in dry THF (100 mL) was added NaH (60% oil suspension; 3.0 g, 75 mmol) at 0° C. and stirred for 30 min. Phenylsulfonyl chloride (10.7 g, 60 mmol) was added slowly and the mixture was stirred at ambient temperature for 16 h (TLC monitoring: 60% ethyl acetate in hexanes). Solvent was removed under reduced pressure, water (25 mL) was added to the residue, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue thus obtained was crystallized from dichloromethane to yield the title compound (13.0 g, 76%). 1H NMR (CDCl3, 300 MHz): δ=6.55 (d, J=4.2 Hz, 1H), 7.46-7.62 (m, 3H), 7.74 (d, J=4.0 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 8.15-8.18 (m, 2H), 8.44 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:24][CH2:21][CH2:22][CH3:23])#[N:20]
Reactant: CCCN
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Product: CCCN=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Yield: 23 %

Procedure:
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and n-propylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:3) to give the title compound (60 mg, 23%) as white crystals. Mp 141-143° C.; 1H-NMR (CDCl3): δ 0.92 (d, 6H), 1.58 (sextet, 2H), 3.25 (q, 1H), 5.1 (br, 1H), 7.19 (m, 2H), 7.25 (m, 1H), 7.95 ppm (br, 1H); MA calc for C11H12Cl2N4 : C, 48.73%; H, 4.46%; N, 20.66%. Found: C, 49.02%; H, 4.55%; N 20.27%.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1>O1CCCC1.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(Br)cc1
Yield: 63.7 %

Procedure:
To a suspension of copper(I) iodide (63.4 mg, 333 μmol) in tetrahydrofuran (10 ml) was added at 0° C. o-tolylmagnesium bromide solution (2 M in diethyl ether, 3.66 ml, 7.33 mmol) to give a light brown suspension. The reaction mixture was stirred at this temperature for 1½ h, then a solution of (E)-3-(4-bromophenyl)-1-(pyridazin-4-yl)prop-2-en-1-one (963 mg, 3.33 mmol) in THF (5.0 ml) was added, then after 1¾ h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; ethyl acetate/heptane 1:1) afforded the title compound (809 mg, 64%). Light yellow foam; MS: 381.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=4)[CH2:18][CH2:17][NH:16]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1.CC([O-])=O.[Na+].C([BH3-])#N.[Na+]>CO>[N:26]1([C:31]2[CH:38]=[CH:37][C:34]([CH2:35][N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=4)[CH:15]3[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Oc1ccc2c(c1)CCNC2c1ccc(OCCN2CCCC2)cc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Oc1ccc2c(c1)CCN(Cc1ccc(-n3ccnc3)cc1)C2c1ccc(OCCN2CCCC2)cc1
Yield: 112.3 %

Procedure:
A solution of 1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol (0.023 g, 0.067 mmol), 4-imidazol-1-yl-benzaldehyde (0.011 g, 0.063 mmol), NaOAc (0.011 g, 0.14 mmol), and sodium cyanoborohydride (0.004 g, 0.063 mmol) in MeOH (2.0 ml) was stirred at rt for 18 hr. The reaction mixture was evaporated in vacuo to a yellow residue that was dissolved in EtOAc (5 ml) and washed first with sat. NaHCO3 solution (5 ml) and then with H2O (5 ml). The organic solution was dried over MgSO4 and evaporated to give 0.035 g of yellow residue. Purification by preparative TLC, eluting with EtOAc:MeOH (7:3), gave 0.007 g (23% yield) of white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7]Br)=[N:4][S:5][CH:6]=1.[NH2:9][CH2:10][CH2:11][SH:12].Cl.NCCS>>[BrH:1].[Br:1][C:2]1[C:3]([CH2:7][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][CH:6]=1
Reactant: BrCc1nscc1Br
Reactant: NCCS
Agent: Cl
Product: Br
Product: NCCSCc1nscc1Br

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g) was performed under conditions similar to those described in Example 57, From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.) m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium bydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.) The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methylN'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:33][CH2:34][C:35](=N)OCC.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:25]([O:24][CH2:23][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:35]1[CH2:34][Cl:33])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 61 %

Procedure:
tert-Butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (4.51 g, 10.1 mmol) was dissolved in 80 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (2.39 g, 15.1 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated sodium bicarbonate (NaHCO3) solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 50% ethyl acetate/hexanes) gave tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (3.11 g) as a golden foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[CH:5]=O.[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:24][C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])[N:19]=2)[CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1
Reactant: Cc1cc(C=O)cc(C)c1OC[C@@H]1CCC(=O)N1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC[C@@H]4CCC(=O)N4)c(C)c3)nc2c1
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (0.200 g, 0.81 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.81 mmol), NaHSO3 (0.093 g, 0.89 mmol), and p-TsOH (0.015 g, 0.08 mmol) in DMA (10 mL) was heated at 150° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound as an off-white solid (0.108 g, 31%). 1H NMR (300 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.79-7.91 (m, 3H), 6.74 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.88-3.94 (m, 4H), 3.84 (s, 3H), 3.63-3.75 (m, 2H), 2.30 (s, 6H), 2.09-2.27 (m, 3H), 1.91-2.00 (m, 1H). APCI MS m/z 424 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)c(F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.71-0.75 (2H, m), 0.96-1.02 (2H, m), 2.06-2.10 (1H, m), 5.17 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.88-6.92 (1H, m), 7.07-7.10 (2H, m), 7.40 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.55 (1H, d, J=2.0 Hz), 8.02 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H15FN4O, 335; Found, 335.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14].N12CCCN=C1CCCCC2.O>CN(C=O)C>[O:12]=[C:5]1[N:6]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.4 %

Procedure:
To a stirred mixture of isatoic anhydride (2.0 g) and 4-cyano-benzyl bromide (2.40 g) in DMF (20 ml) was added drop-wise 1,8-diazabicyclo[5,4,0]-undec-7-ene (2.20 ml). The reaction mixture was stirred at room temperature for 22 hours, cooled in an ice-bath and water (75 ml) was added. The resulting precipitated material was isolated by filtration and re-crystallised from hot toluene and gave the title compound (1.65 g) as an off-white solid. 13C-NMR (DMSO-d6) δ 158.7, 148.2, 141.2, 141.1, 136.9, 132.4, 129.5, 128.8, 128.1, 127.5, 123.7, 118.6, 114.8, 112.2, 110.2, 47.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].[H-].[Na+].[H][H].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: [H][H]
Reactant: Oc1ccc2c(-c3ccccn3)noc2c1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(-c3ccccn3)noc2c1Cl
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole (10.0 g) is dissolved in 80 ml of DMF and added to an ice cold suspension of NaH (1.1 g) in 50 ml of DMF. When hydrogen evolution ceases, ethyl bromoacetate (7.5 g) in 20 ml of DMF is added. After an additional 90 minutes, 200 ml of H2O and 10 ml of 50% NaOH are added and the reaction warmed at 65° C. for 45 minutes. The mixture is poured into H2O, acidified to pH 1-2, and a solid product filtered and dried to give {[7-chloro-3-(2-pyridyl)-1,2-benzisoxazole-6-yl]oxy}acetic acid, mp 255°-256° C.
Reaction SMILES: [C:1]1([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:17][O:18][S:19]([O:22]C)(=[O:21])=[O:20]>O>[CH3:17][O:18][S:19]([OH:22])(=[O:21])=[O:20].[CH3:17][N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]1[CH2:10][O:9][C:1]1[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1cccc(C)c1OCc1ccccn1
Reactant: COS(=O)(=O)OC
Solvent: O
Product: COS(=O)(=O)O
Product: Cc1cccc(C)c1OCC1C=CC=CN1C

Procedure:
Two hundred (200) g of 2-[(2,6-xyloxy)methyl]-pyridine are mixed with 300 g of dimethylsulphate whereupon 500 g of water are added at 100° C. during 3 hours. The excess of dimethylsulfate is removed by extraction using ether. The remaining solution is purified using active carbon and the resultant solution filtered. N-methyl-2-[(2,6-xyloxy)methyl]pyridine methylsulfate is isolated as a salt by evaporation of the water in vacuo.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 15 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.12 l of N,N-dimethylformamide were added 13.8 g of tert-butyl-dimethylchlorosilane and 12.0 g of triethylamine. The mixture was stirred for 3 h at room temperature and then evaporated in vacuo. The residue was taken up in 0.4 l of ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated in vacuo and the solid residue was recrystallized from hexane to give 20.5 g of 2-formyl-3-(tert-butyl-dimethylsilanyloxy)-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 94°-95° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenylacetyl chloride (62 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white oil. MS (ESI, positive ion) m/z: 414 (M+H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]([OH:35])=O)[CH:28]=[N:29][CH:30]=1.[CH:36]1([O:41][C:42]2[CH:43]=[C:44]([CH:50]3[N:54]([CH3:55])[NH:53][C:52](=[O:56])[CH2:51]3)[CH:45]=[CH:46][C:47]=2[O:48][CH3:49])[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([N:53]2[C:52](=[O:56])[CH2:51][CH:50]([C:44]3[CH:45]=[CH:46][C:47]([O:48][CH3:49])=[C:42]([O:41][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)[CH:43]=3)[N:54]2[CH3:55])=[O:35])[CH:28]=[N:29][CH:30]=1
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Reactant: O=C(O)C=Cc1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(C(=O)/C=C/c3cncc(Br)c3)N2C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 mmol, 0.230 g), 1-hydroxybenzotriazole hydrate (1.20 mmol, 0.162 g) and 3-(5-bromo-3-pyridyl)propenoic acid (1.20 mmol, 0.274 g [see Nishikawa, et al, J Med Chem, 32, 583 (1989)] is suspended in dry methylene chloride (20 mL) at room temperature and stirred for 2 hours. To the suspension is added a solution of 5-[3(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (1.20 mmol, 0.340 g) in dry methylene chloride (10 mL) and the resulting mixture is stirred at room temperature overnight followed by reflux for 24 hours. The homogenous solution is cooled to room temperature and the volatiles are removed in vacuo. The residue is partitioned between ethyl acetate (50 mL) and 1N NaOH (50 mL), the aqueous phase extracted with ethyl acetate (50 mL) and the combined organics are washed with water (50 mL) and dried (Na2SO4). Concentration in vacuo affords a white foam, which is purified via flash chromatography (SiO2 : concentration gradient ranging from 5% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) to give the title compound as a white solid which is triturated with ether and hexane and dried in vacuo at 50° C. to provide analytically-pure material (0.52 mmol, 0.260 g, 52%). H-NMR (DMSO-d6, 400 MHz) δ8.82 (d, 1H, J=1.7 Hz); 8.66 (d, 1H, J=1.7 Hz); 8.41 (t, 1H); 7.71 (d, 2H, J=2.4 Hz,); 6.98 (d, 1H, J=1.5 Hz); 6.89 (m, 2H); 4.70 (m, 1H); 4.47 (dd, 1H, J=0.6, 1.7 Hz); 3.70 (s, 3H); 3.65 (m, 1H); 2.84 (s, 3H); 2.77 (m, 1H); 1.80 (m, 2H); 1.62 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3460, 2940, 2860, 1748, 1660, 1623, 1515, 1445, 1435, 1425, 1326, 1260, 1235, 1208, 1150, 1130, 1015, 990, 962, 848, 680.