Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:29]([O:24][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
To a stirred solution of 21 (1.18 g; 2.52 mmol) in anhydrous THF (43 mL) was added 95% NaH powder (128 mg; 5.07 mmol). The suspension was stirred at room temperature for 45 min. Allyl bromide (240 μL, 2.79 mmol) was then added at 0° C. and the reaction was stirred at room temperature for 14 h with exclusion of moisture. Saturated aqueous NaHCO3 (10 mL) was added at 0° C. and stirred for 10 min. Most THF was evaporated and the residue was dissolved in ethyl acetate (150 mL). The solution was washed by saturated aqueous NaHCO3 and NaCl respectively, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using ethyl acetate as the eluent to afford 22 as white solid (537 mg; 42% yield): 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H, 6-H), 6.12 (dd, J=5.6, 8.0 Hz, 1H, 1′-H), 4.17 (m, 1H, 4′-H), 4.14 (m, 1H, 3′-H), 3.98-4.10 (m, 2H, CH2CH═CH2), 3.93 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 3.83 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 2.53-2.60 (ddd, J=1.7, 5.6, 13.6 Hz, 1H, one of 2′-H), 1.94-2.02 (ddd, J=5.9, 8.0, 13.6 Hz, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.17 (s, 3H, one of SiCH3), 0.16 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 165.4, 156.7, 147.7, 135.5, 117.2, 88.2, 87.0, 80.4, 70.9, 64.8, 57.3, 40.1, 26.7, 19.4, −4.7, −4.9; HRMS (FAB+) calcd for C18H31O4N3SiI (M+H+): 508.1129. Found: 508.1123.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O)([O-:8])=[O:7].C(O)C>O>[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[N:2][OH:3])([O-:8])=[O:7]
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCO2
Reaction time: 0.42 h

Procedure:
A solution of 79 g (1.14 mole) of hydroxylamine hydrochloride in 770 ml of H2O, contained in a 2 l. Erlenmeyer flask, was treated with 619 ml of 10% NaOH, 150 g (0.78 mole) of 6-nitro-4-chromanone and enough ethanol (750 ml) to produce a solution at the boiling point. The reaction mixture was boiled for 25 min., cooled to 50° over 2 hrs., and filtered. The filtrate was refrigerated overnight and filtered. The tan crystalline solid was washed with 200 ml of ethanol and dried, m.p. 173°-178°. Yield: 60 g (37%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20](F)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12].O>O1CCCC1>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc(Br)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Br)ncc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To a solution of benzylalcohol (1.5 g) in tetrahydrofuran (30 mL) was added sodium hydride (55%, 0.3 g) under ice cooling, and this mixture was stirred at same temperature for 5 minutes. To this reaction mixture was added a solution of 2-bromo-5-fluoroisonicotinic acid ethyl ester (2.9 g) in tetrahydrofuran (30 mL), and this mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (2.4 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1ccc(F)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3ccc(F)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.95 min; [M+H]+=410.92.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11]1.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:14]1[S:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1ccsc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1csc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetyl bromide (13.52 g, 0.067 mol) in 20 ml of CH2Cl2 was added dropwise to a solution of aluminum chloride (13.4 g, 0.105 mol) in 50 ml of CH2Cl2 at 0° C. The mixture was stirred for 1 h at 0° C., and then a solution of methyl 3-thiophenecarboxylate (9.49 g, 0.067 mol) in CH2Cl2 (50 ml) was added dropwise. The stirring was continued for 12 h and then the mixture was poured over water and ice and extracted with CH2Cl2. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)#[N:2]
Reactant: ClCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Under nitrogen atmosphere, sodium cyanide (540 mg) was added to a solution of 4-chloromethyl-1-tritylpyrazole (3.58 g) in dimethylsulfoxide (30 ml) at 50° C. After stirring for 1 hour, the mixture was poured into water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, to afford 4-cyanomethyl-1-tritylpyrazole (3.41 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](SC)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Na].[CH2:22]([OH:24])[CH3:23]>>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH2:22][CH3:23])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: CCO
Agent: [Na]
Product: CCOc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 72 %

Procedure:
To a solution of the 2-amino-4-methylthio-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine of example 8 (700 mg) in ethanol (20 ml) was added 276 mg sodium. The reaction mixture was refluxed for 5 hours and then cooled down. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of ethanol and dichloromethane, in a volume ratio gradually ranging from 3% to 5% ethanol, thus providing 490 mg of the pure title compound (72% yield), which was characterized by its mass spectrum as follows: MS (m/z): 285 ([M+H]+, 100).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccncc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 78.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and 4-(chloromethyl)pyridine (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.58 g) was obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[C@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])([O-])=O.Cl[Sn]Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-nitrocinnamate (8) (11.03 g, 53.24 mmol) in ethyl acetate (200 ml) was added SnCl2.H2O (60.06 g, 266.19 mmol) at room temperature, and the resulting solution was stirred at 70° C. for 60 minutes. After the reaction was completed, the solution was allowed to cool to room temperature, basified with a saturated aqueous solution of sodium bicarbonate to weak basicity, and filtered with celite. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:5) to give the target compound (8.50 g, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:27](=[O:28])[O:29][CH2:30][CH3:31])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: CCOC(=O)Cl
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCC1(O)CCc2ccccc2C12CCCC2
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of the product from Example 9 (1.05 g, 4.28 mmol) and triethylamine (0.44 g, 4.35 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and ethyl chloroformate (0.47 g, 4.33 mmol) in 5 mL CH2Cl2 was added dropwise. The reaction was warmed to room temperature and washed with water. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate) to give the title compound (1.33 g, 98%) as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Yield: 65.5 %

Procedure:
To a solution of title compound 381 (0.83 g, 5.84 mmol) and diisopropylethylamine (1.02 mL, 0.74 mmol) in THF (50 mL) was added a solution of 2-chloronicotinoyl chloride (1.03 g, 5.84 mmol) in THF at 0° C. The reaction mixture was stirred over night and concentrated. To the residue was added a saturated solution of bicarbonate (3 mL) and this aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The solid was triturated in DCM (3 mL) and filtered. The filtrate was evaporated and purified by flash chromatography (0% to 80% ethyl acetate in hexanes). The 2 solids were mixed to afford title compound 382 (1.1 g, 65%) as a white solid. MS (m/z): 288.0 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:9](=[O:11])[CH3:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][CH2:13][OH:14])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCC1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(CCO)CCC1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of N-(2-(1,3-dioxolan-2-yl)ethyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)acetamide (0.65 g, 2.04 mmol) in THF (5 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.24 mL). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 100% ethyl acetate/iso-hexane to afford the title compound (0.287 g, 69%) which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCOCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), morpholine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 101 (5), 100 (bp), 98 (4), 56 (5).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>>[NH2:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(N)CN
Product: CC(C)(N)CNc1ccc(C#N)cn1
Temperature: 120 °C

Procedure:
A mixture of 1,2-diamino-2-methylpropane (3.14 ml, 30 mmol), and 6-chloronicotinonitrile (2.77 g, 20 mmol) were heated to 120° C. for 2 days. The reaction mixture was filtered, and the inorganic salt was rinsed with EtOAc. The filterate was concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 191 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C(OCC)(=O)C>[CH3:12][O:11][P:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:15])[O:13][CH3:14]
Reactant: Fc1ccc(CBr)cc1
Reactant: COP(OC)OC
Solvent: CCOC(C)=O
Product: COP(=O)(Cc1ccc(F)cc1)OC
Temperature: 110 °C
Yield: 67.5 %

Procedure:
4-fluorobenzyl bromide (25 mL, 0.20 mol) was added to a stirred solution of trimethyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was heated at 110° C. for six hours, and then at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotatry evaporation. The resulting crude product was purified by flash silica chromatrography using 0-35% acetonitrile in ethyl acetate as eluant to yield (4-fluoro-benzyl)-phosphonic acid dimethyl ester (29.44 g, 135 mmol, 66% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 2H); 7.17-7.12 (dd, 2H); 3.61-3.58 (d, 6H); 3.31-3.24 (d, 2H); ESMS (m/z): (M+1)+ found, 219.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-(methylthio)benzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 11.2 (s, 1H), 8.82 (s, 1H), 7.76 (d, 2H), 7.76 (d, 2H), 7.61 (s, 2H), 7.51 (m, 2H), 7.35 d, 2H), 7.22 (d, 1H), 6.50 (s, 1H), 2.49 (s, 3H), M.P. 163-178° C.; LC-MS 389 (MH+); HPLC RT: 4.73 minutes.
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH2:14][C:15]([O-:17])=[O:16])[CH:13]=1)(OC)OC.[C:26](=O)([O-:28])[OH:27].[Na+].C(O)C>O>[C:26]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:28])=[O:27]
Reactant: O=C([O-])O
Reactant: COC(OC)(c1ccc(Sc2ccccc2)c(CC(=O)[O-])c1)C(C)Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 5 h
Yield: 13.6 %

Procedure:
A mixture of 4.39 g (10 mol.) of 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 4.20 g (50 mmol.) of sodium hydrogen carbonate, 50 ml of ethanol and 35 ml of water was heated under reflux and stirring for 5 hours. The reaction mixture was distilled to remove distillates having a boiling point of below 100° C. The residue was then heated under reflux for 4 hours. The mixture was treated in the same manner as in Example 6-(1) to obtain 2.15 g of the desired product as white crystals (yield 68%), m.p. 145°-146° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:26](Br)[C:27]#[CH:28]>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:27]#[CH:26]
Reactant: C#CCBr
Reactant: COc1ccc(-c2cc(C=O)ccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C=O)cc1-c1ccc(OC)cc1
Yield: 5.9 %

Procedure:
A solution of 4-hydroxy-3-(4-methoxyphenyl)benzaldehyde (1.14 g, 5 mmol) in DMF (10 mL) was treated with potassium carbonate (2.48 g, 18 mmol), potassium iodide (10 mg) and propargyl bromide (0.67 mL, 6 mmol). The mixture was heated at 80 C for 3 days, then cooled and the solvent removed under reduced pressure. The residue was redissolved in ethyl acetate and washed water then brine. The organic layer was dried over sodium sulphate then the solvent removed under reduced pressure and the residue purified by column chromatography (3/1 hexane/ethyl acetate) to afford 0.078 g of title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].I[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Reactant: ICCOCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCC(=C(c1ccccc1)c1ccc(OCCOCCOC2CCCCO2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.33 g, 0.001 mol) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Sodium hydride (0.036 g, 0.0015 mol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-[2-(2-iodo-ethoxy)-ethoxy)-tetrahydropyran (0.6 g, 0.002 mol) was added and the mixture was refluxed for 3 hours. After cooling and adding water the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated to dryness. The residue was used in the next reaction step without further purification.
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[Cl:20]C1C=C(C=CC=1)C(Cl)=O>>[Cl:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:4]=1)[C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:9]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1CCCCCN1C(=O)c1cccc(Cl)c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3-chlorobenzoyl chloride (Aldrich) in place of 4-nitrobenzoyl chloride.