Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:7]=1[F:24])[CH3:2].[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:7]=1[F:24])[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Yield: 94 %

Procedure:
steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.
Reaction SMILES: [N+]([O-])([O-])=O.[Ca+2:5].[N+]([O-])([O-])=O.[P:10]([O-:14])([O-:13])([OH:12])=[O:11].[NH4+].[NH4+].N>>[P:10]([O-:14])([O-:13])([O-:12])=[O:11].[Ca+2:5].[Ca+2:5].[Ca+2:5].[P:10]([O-:14])([O-:13])([O-:12])=[O:11]
Reactant: O=P([O-])([O-])O
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
The reaction of 3 l of 0.5 mol/l aqueous solution of calcium nitrate [Ca(NO3)2 ] with 2 l of 0.5 mol/l aqueous solution of ammonium hydrogen phosphate [(NH4)2HPO4 ] was carried out by mixing them under nitrogen gas stream at a temperature equal to or less than 5° C., while adjusting pH to 11 by the addition of aqueous ammonia to the solution.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])[CH3:36])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:39]1([C:37]([N:35]([CH2:34][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH3:36])=[O:38])[CH2:41][CH2:40]1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R*,4R*)-3-[(cyclopropanecarbonyl-methyl-amino)-methyl]-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (154 mg, 0.267 mmol) in 3 mL CH2Cl2, TFA (309 μL, 4.01 mmol) is added. The mixture is stirred 4 h at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 95:5) to give the title product. TLC, Rf (SiO2—NH2, CH2Cl2/MeOH 95:5)=0.1. MS (LC-MS): 476.1 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.10 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:21][N:20]([CH3:22])[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: OB(O)c1cncnc1
Reactant: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidine-4-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 267. NMR (CDCl3): 1.71-1.4 (m, 2H, CH2), 1.9-1.99 (m, 2H, CH2), 2.14-2.20 (m, 2H, CH2), 2.52-2.57 (m, H, CH), 2.97 (s, H, CH3), 3.04-3.07 (m, 5H, CH3+CH2), 3.80 (s, 2H, CH2), 3.91-3.93 (m, 4H, 2×CH2), 3.98-4.02 (m, 4H, 2×CH2), 7.19 (s, H, ArH), 9.29 (s, H, ArH), 9.70 (s, 2H, 2×ArH). MS: (ESI+): MH+=468.26
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CO
Product: Cc1c(SCCN2CCOCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (20 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine (2 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.1 g of 2-chloromethyl-3-methyl-4-(2-morpholinoethylthio)pyridine as an oily substance. The oily substance was added to ethanol (50 ml) containing a solution of 2-mercaptobenzimidazole (1.0 g) and sodium hydroxide (0.6 g) in water (10 ml) and the mixture was refluxed under heating for 5 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from a mixed solvent of ethanol-acetone to give 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as white crystals, melting point 201°-203° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[OH:24])#[N:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:12]#[N:13])=[C:15]([O:24][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:16]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Bromoethyl)carbamic acid tert-butyl ester (700 mg, 3.12 mmol) from step 1 and 4-cyano-3-hydroxybenzoic acid methyl ester (Example 34 Step 3, 550 mg, 3.12 mmol) was dissolved in DMF (4.5 ml). Cs2CO3 (2.03 g, 6.24 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and washed with DMF (3×10 mL). The DMF was removed in vacuo. The residue was purified by flash chromatography (12% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42](=O)[CH3:43])[CH:37]=3)=[O:34])[C:14]1=[O:45])=[O:11])[CH2:2]2.Cl.[NH2:47][OH:48].C(N(CC)CC)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH:5]12[CH2:6][CH2:7][CH:1]([CH2:9][CH2:8]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42](=[N:47][OH:48])[CH3:43])[CH:37]=3)=[O:34])[C:14]1=[O:45])=[O:11])[CH2:4]2
Reactant: NO
Reactant: CC(=O)c1cccc(NC(=O)NC2N=C(c3ccccc3F)c3cccc(C)c3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=NO)c1cccc(NC(=O)NC2N=C(c3ccccc3F)c3cccc(C)c3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
A mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-acetylphenyl)urea (217 mg) and hydroxylamine-hydrochloride (124 mg), triethylamine (180 mg) in tetrahydrofuran (4 ml) was stirred at room temperature overnight. Ethyl acetate and 1N aqueous hydrochloric acid solution were added the reaction mixture. The separated organic layer was washed with 1N aqueous hydrochloric acid twice, saturated aqueous sodium bicarbonate and brine successively and then dried over magnesium sulfate. The solvent was evaporated in vacuo to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(1-hydroxyiminoethyl)phenyl]urea (235.0 mg) as a crystalline powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:23][C:22]4[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=4[F:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Cc1ccc(F)c(N)c1
Product: Cc1ccc(F)c(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-fluoro-5-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7 Hz), 7.08–6.84 (m, 4H), 6.74–6.67 (m, 1H), 6.64–6.59 (m, 1H), 4.27 (s, 4H), 2.28 (s, 3H); 19F NMR (282 MHz, CDCl3): −38659, −47267; LCMS: purity: 100%; MS (m/e): 371(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][OH:19])[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1.FC(F)(F)C(O)=O.N1C=CC=CC=1.C(O)(=O)C(O)=O>O.CO.CCOCC>[CH3:1][C:2]1([CH2:16][CH2:17][CH:18]=[O:19])[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1
Reactant: Cc1c2n(c3ccccc13)CCOC2(C)CCCO
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1c2n(c3ccccc13)CCOC2(C)CCC=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Dicyclohexylcarbodiimide (2.87 g.) is added to a cooled, stirred solution of the primary alcohol, 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propanol (1.0 g.), described in Example 462, in 10 ml. of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid (0.18 ml.) and pyridine (0.38 ml.). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 100 ml. of ether, followed by the dropwise addition of a solution of oxalic acid (1.26 g.) in 6 ml. of methanol. After thirty minutes, water (100 ml.) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO4) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as an oil, δCHCl3Max 1720 cm-1.
Reaction SMILES: CN(CC[C:6]1[N:10]2[C:11]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=3[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[O:14][CH2:15][C:9]2=[N:8][N:7]=1)C>C(O)(=O)C>[CH3:9][N:10]([CH2:11][CH2:12][CH2:13][C:6]1[N:10]2[C:11]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=3[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[O:14][CH2:15][C:9]2=[N:8][N:7]=1)[CH3:6]
Reactant: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Solvent: CC(=O)O
Product: CN(C)CCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2

Procedure:
Compound 28 is dissolved in acetic acid (10 ml), refluxed under heating for 3 hours, and concentrated under reduced pressure. The residue is neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer is washed with water, dried, and concentrated. The residue is treated on column chromatography (silica gel/methanol) to give crystalline Compound 29 (0.55 g), which is recrystallized from ethyl acetate.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)(=[O:4])=[O:3]
Reactant: N#Cc1ccc(CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (2.32 mL, 30 mmol) was added to a cooled (0° C.), stirred solution of 4-(4-hydroxybutyl)benzonitrile (from step (ii) above, 5.2 g, 29.7 mmol) and triethylamine (4.35 mL) in dichloromethane (50 mL). The resulting mixture was stirred for 4 h before water (150 mL) was added, and the organic layer separated, dried and concentrated to give the sub-title compound. This product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[N:12][N:11]=[C:10]2S)=[CH:5][CH:4]=1.[OH-].[NH4+]>[Ni].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:10]=[N:11][N:12]=[C:13]2[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(C)nnc2S)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2cnnc2C)cc1

Procedure:
A mixture of 10.5 parts of 4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol, 10 parts of Raney-nickel catalyst, 18 parts of ammonium hydroxide and 200 parts of methanol is stirred and refluxed for 4 hours. The reaction mixture is decanted while hot and the Raney-nickel catalyst is boiled in 160 parts of methanol. The latter is decanted and the combined methanol-phases are evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 4.2 parts of 4-(4-methoxyphenyl)-3-methyl-4H-1,2,4-triazole; mp. 111.9° C.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Reactant: OB(O)c1cccc(Cl)c1
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4cccc(Cl)c4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 3-chlorophenyl boronic acid according to the procedure of Example 2, m.p. 170-171° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26]COCC)=[O:25])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.COC1C=CC(O)=CC=1>C(O)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCOCC)cc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C

Procedure:
98.5g (0.2 mole) of ethoxymethyl 4-(4-(6-acryloyloxyhexyloxy)-benzoyloxy)-benzoate (12) were dissolved in 400 ml of ethanol and 5 g (0.02 mole) of pyridinium 4-toluenesulfonate and 20 mg of 4-methoxyphenol were added. The mixture was heated at 60° C. for 15 h. After cooling down to room temperature the product crystallized. It was collected, washed with 300 ml of ethanol, and dried in the desiccator after which 55.3 g of a white powder (67%) were obtained.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])=[O:2].[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC.C(N(CC)CC)C>C(Cl)Cl>[OH:2][CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])[CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)c1noc(C=O)c1C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(O)c1onc(C(=O)OCC)c1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (350 mg, 1.911 mmol) in DCM (19 mL) was added allyltrimethylsilane (276 μl, 1.911 mmol) and the mixture was cooled to −78° C. A solution of boron trifluoride etherate (278 μl, 2.198 mmol) in DCM (5 mL) was cooled to −78° C. and added to the reaction mixture over 5 min. The reaction mixture was stirred for 15 mins and triethylamine (266 μl, 1.911 mmol) was added. The reaction mixture was maintained at −78° C. for 15 minutes and allowed to warm to room temperature. The resulting mixture was quenched by the addition of a saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were passed through a phase separating cartridge and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-40% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]([CH3:25])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:38][Si:39](Cl)([CH3:41])[CH3:40]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:25])[CH:8]2[Si:39]([Cl:38])([CH3:41])[CH3:40])=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc(C(C)(C)C)c(OCC(C)C)c(-c3ccccc3)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=Cc2c(cc(C(C)(C)C)c(OCC(C)C)c2-c2ccccc2)C1[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 100.3 %

Procedure:
To a solution of 16.8 g (50.2 mmol) of 5-tert-butyl-6-isobutoxy-2-methyl-7-phenyl-1H-indene in 200 ml of toluene 20.1 ml (50.5 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The formed viscous solution was stirred for 10 h, and then 10 ml of THF was added. The resulting mixture was stirred for 1 h at 65° C., then cooled to −20° C., and 32.5 g (252 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. This mixture was warmed to room temperature, refluxed for 0.5 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 21.5 g (99%) of (6-tert-butyl-5-isobutoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)dimethylsilane which was further used without an additional purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[N:8][NH:9][C:10](=O)[C:4]2=[CH:3][CH:2]=1.C(#N)C.O=P(Cl)(Cl)[Cl:17].[ClH:20]>O1CCOCC1>[ClH:17].[Cl:20][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Clc1nncc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 50 g (342 mmol) phthalazone, 1370 ml acetonitrile, 66 ml (0.72 mol) POCl3 and 85 ml 4 N HCl in dioxane is stirred for 8 h at 50° C. The resulting solution is cooled to RT, evaporated to a volume of about 0.8 l and diluted with 1.2 I DIPE. Filtration and washing with DIPE yield the title compound: FAB-MS (M+H)+=165/167.