Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:18][N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Reaction time: 72 h

Procedure:
A mixture of 300 g of 3,4-dichlorocinnamic acid methyl ester, 400 g of nitromethane and 26 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with ethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([C@@H:15]2[C@@H:18]([CH2:19][CH:20]=[O:21])[NH:17][C:16]2=[O:22])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.C(O)(=O)C>[OH:21][CH2:20][CH2:19][C@H:18]1[NH:17][C:16](=[O:22])[C@@H:15]1[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][CH:23]=1)=[O:11])[CH3:14]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CCO
Yield: 62.1 %

Procedure:
(3S,4R)-3-[(1RS)-1-(p-Nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(2-oxoethyl)azetidine (8 mg) was dissolved in methanol (0.8 ml) and sodium borohydride (2 mg) was added at 0° C. The mixture was then stirred for 30 minutes at the same temperature and acetic acid (3 drops) was added. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (silica gel) developing with benzene: acetone (1:1) to give (3S,4R)-4-(2-hydroxyethyl)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidine (5 mg).
Reaction SMILES: NC1C=[C:6]([O:8]C)[CH:5]=CC=1CCO.ClC1C=C[C:17]([O:20]C)=[CH:16]C=1[N+]([O-])=O.NC1C=C(OC)C=CC=1C(CO)CO.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([CH2:50][OH:51])[CH2:48][OH:49])=[C:43]([N+:52]([O-:54])=[O:53])[CH:42]=1>>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([C:48]([O:20][CH2:17][CH3:16])=[O:49])[C:50]([O:8][CH2:6][CH3:5])=[O:51])=[C:43]([N+:52]([O-:54])=[O:53])[CH:42]=1
Reactant: COc1ccc(CCO)c(N)c1
Reactant: COc1ccc(C(CO)CO)c([N+](=O)[O-])c1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: COc1ccc(C(CO)CO)c(N)c1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1[N+](=O)[O-]

Procedure:
In particular, 2-(2-amino-4-methoxyphenyl)ethanol may be prepared from 1-chloro-4-methoxy-2-nitrobenzene using conventional procedures, known by one skilled in the art and described in the literature (Bioorg. Med. Chem, 2004). Similarly, 2-(2-amino-4-methoxyphenyl)propane-1,3-diol may be prepared by hydrogenation of 2-(4-methoxy-2-nitrophenyl)propane-1,3-diol obtained by reduction of diethyl (4-methoxy-2-nitrophenyl)malonate. Also, 5-methoxy-2-(2-methoxyethyl)aniline may be prepared by reduction of the product resulting from the methylation of 2-(4-methoxy-2-nitrophenyl)ethanol. 5-Methoxy-2-[2-(methylsulfonyl)ethyl]aniline may be prepared by hydrogenation of the product resulting from the oxidation of 4-methoxy-1-[2-(methylthio)ethyl]-2-nitrobenzene. The latter may be prepared by reaction between sodium thiomethoxide and the intermediate obtained by bromo-de-hydroxylation of 2-(4-methoxy-2-nitrophenyl)ethanol as described in the scheme below.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 2-(4-chlorophenyl)ethylamine (0.55 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was further crystallized from methanol-diethyl ether to give the title compound (0.71 g, 2.5 mmol, yield: 79%) as colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:21])[CH:9]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH2:32][CH2:33]/[CH:34]=[C:35](\[C:37]([F:40])([F:39])[F:38])/[CH3:36])(=O)=O)=CC=1.C(=O)([O-])[O-:43].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)C>[F:38][C:37]([F:40])([F:39])/[C:35](/[CH3:36])=[CH:34]\[CH2:33][CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:21])[C:9]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)([OH:43])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CCNCC1)C(c1ccccc1)C1CCCC1
Reactant: C/C(=C/CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C/C(=C/CCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCCC2)CC1)C(F)(F)F
Reaction time: 3 h
Yield: 25.7 %

Procedure:
To a solution of 77 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-phenylacetamide in 3 ml of N,N-dimethylformamide, 74 mg of (3Z)-4-trifluoromethyl-3-pentenyl p-toluenesulfonate, 102 mg of potassium carbonate and 43 mg of potassium iodide were added by the order stated, followed by 3 hours' heating under reflux. The reaction liquid was diluted with diethyl ether, washed with water and saturated saline solution by the order stated, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck) chloroform/methanol=9/1) to provide 27 mg of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5cccc(Cl)c5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (1.1 g, 2.81 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.903 g, 3.65 mmol), Na2CO3 (0.745 g, 7.03 mmol) and Pd(PPh3)4 (0.325 g, 0.281 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 mL) and concentrated to afford the crude title compound (310 mg) as a yellow solid. LC-MS (ES) m/z=476 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CO.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>CCOC(C)=O>[F:20][C:21]([F:28])([F:27])[C:22]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of p-aminobenzoic acid in MeOH (500 mg, 3.65 mmol) was treated with 1.0 eq triethylamine (3.65 mmol, 509 μl) followed by 1.1 eq trifluoroacetic acid, ethyl ester (4.015 mmol, 478 μl). The solution was stirred overnight. The solution was diluted with EtOAc, washed with 5% KHSO4, followed by brine. The solution was dried over MgSO4 and solvent was removed by evaporation. The residue was purified by recrystallization in EtOAc/Hexane to afford eggshell-colored glossy plates (265 mg (31%), C9H6F3NO3).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1.C(Cl)Cl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(B(O)O)cc1
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp. This solution was filtered and cooled to −100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between −105 and −93° C. To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to −72° C. The reaction mixture was recooled to −100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2×200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid. This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2×200 mL). The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder. 1H NMR (d6-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])(C)[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[CH:18]=[C:17]([OH:22])[CH2:16]1.[C:23]([OH:27])(=O)[CH2:24][CH3:25].[C:28]1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:12])[CH:7]([CH3:28])[C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[C:18]([C:23](=[O:27])[CH2:24][CH3:25])=[C:17]([OH:22])[CH2:16]1
Reactant: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(Cl)c2c1CC(C)(C)O2
Reactant: Cc1ccccc1
Reactant: CCC(=O)O
Agent: CN(C)c1ccncc1
Product: CCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2Cl)OC(C)C3C)CC1=O
Temperature: 25 °C

Procedure:
To a solution of 5.9 g of the 5-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one in 70 ml of absolute toluene was added 9.5 ml of anhydrous propionic acid and refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford an oily residue. To the solution of residue in 70 ml of absolute toluene was added 0.67 g of 4-dimethylaminopyridine, refluxed for 15 hours and cooled to room temperature and then concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 3.25 g of 5-(7-chloro-2,3-dihydro-2,3,4,5-tetramethylbenzofuran-6-yl)-2-propionyl-3-hydroxycy-clohex-2-en-1-one as a yellow solid.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[O:23][C:24]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=4[CH:26]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[N:1]1([C:8]2[C:9]([C:22]3[O:23][C:24]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=4[CH:26]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(6-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylate (73 mg, 0.17 mmol) in methanol (25 mL) and chloroform (5 mL) was added sodium hydroxide (13.6 mg, 0.34 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (15 mL), adjusted pH to 5 with HCl (3 N) to give the precipitate, which was collected by filtration to afford 3-(azepan-1-yl)-2-(6-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylic acid (39 mg, 55%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:14][CH:13]=3)=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:45]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:14][CH:13]=3)=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:35][CH:36]=3)[S:8][C:7]=2[CH:45]=1
Reactant: COc1ccc2c(Cc3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: Oc1ccc2c(Cc3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of 1.150 g (1.84 mmol) (±)-6-methoxy-3-[4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part A) in 20.0 mL of anhydrous dichloroethane at 0° C. was added 1.10 mL (14.7 mmol) of ethanethiol, followed by the addition of aluminum chloride (982 mg, 7.36 mmol). The yellow biphasic reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched at 0° C. with 20 mL of saturated aqueous NaHCO3. The aqueous layer was separated and extracted with EtOAc (3×200 mL). The combined organic layers were washed with 150 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by using flash chromatography (silica gel, 60:37:3 THF-hexanes-TEA) to afford 1.067 g (1.75 mmol, 95%) of a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:21]1[CH2:22][CH2:23][CH:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][C:13]=2[O:24][CH3:25])[N:10]=[CH:9][N:8]=[C:7]3[NH:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=2[F:29])[CH2:20]1)(=[O:32])[CH3:31]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(C(C)=O)C1
Yield: 63 %

Procedure:
Using a procedure similar to that described in Example 38, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazoline hydrochloride (300 mg; prepared as described in Example 33-starting material) was reacted with acetic anhydride to give the title product (194 mg, 63%); 1H NMR Spectrum (DMSO d6+CD3COOD) 1.71-1.90 (m, 1H); 1.93-1.94 (m, 3H); 2.00-2.20 (m, 1H); 2.66-2.86 (m, 1H); 3.18-3.31 (m, 1H); 3.43-3.72 (m, 3H); 3.93 (m, 3H); 4.04-4.18 (m, 2H); 7.15-7.32 (m, 2H); 7.42-7.53 (m, 2H); 7.78-7.80 (m, 1H); 8.35-8.37 (m, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[CH:14][C:13]=2Cl)[O:9][N:8]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:13]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][N:15]=[CH:16][C:17]=2[O:18][CH3:19])[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1
Yield: 4.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-chloro-5-methoxy-pyrid-4-yl)-1,2,4-oxadiazole (75 mg, 0.260 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% ethyl acetate in hexane and 100% ethyl, acetate afforded 3.5 mg (4.1%) 3-(2-pyridyl)-5-[3-methoxy-5-(3-pyridyl)-pyrid-4-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.39 (s, 1H), 8.91 (d, 1H), 8.72 (d, 1H), 8.42 (d, 1H), 8.25 (d, 1H), 8.20 (s, 1H), 7.92 (dt, 1H), 7.63 (dd, 1H), 7.50 (m, 2H), 4.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[Si:24]([O:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:12][CH:13]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccc(CO)cc2)c1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cc([N+](=O)[O-])ccc2F)cc1
Yield: 98 %

Procedure:
6.0 g (98% yield was prepared by the method of Example 19E from 4.2 g 4-(2-fluoro-5-nitrophenyl)benzyl alcohol, 2.5 g imidazole and 3.5 g t-butyldimethylsilyl chloride. The oil was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:25].[Na+].C(O)(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:13]([CH2:12][O:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@H:5]([O:4][CH2:1][CH:2]=[O:25])[CH2:6]2)[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCO[C@H]1CCC[C@@H](OCc2cccc(C)c2C(=O)OC)C1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCC=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.0 g of methyl 2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate is dissolved in 30 ml of diethyl ether, and 2.0 g of sodium periodate, dissolved in 30 ml of water, are added. At 0° C., 2 ml of a solution of 2.5% by weight of osmium tetroxide and tert-butanol are added. The reaction mixture is stirred vigorously for three hours. The mixture is then cooled to 0° C., and 50 ml of a saturated sodium thiosulfate solution are added. The organic phase is removed. The aqueous phase is extracted three times with in each case 20 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of methyl 2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate as a yellow oil C18H24O5 (320.39), MS(ESI): 321 (M+H+), Rf=0 23 (n-heptane:ethyl acetate=1:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].[O:12]1[CH2:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C1COCC1>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:15][CH2:14][CH2:13][OH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1COC1
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
(3-Bromopropyl)benzene (20 g) in THF (75 ml) was added dropwise to magnesium (2.43 g) at a rate to maintain gentle reflux. The mixture was stirred for 2 h at RT and oxetane (10 g) was added dropwise. The resulting suspension was stirred at RT for 2h and at reflux for 16 h and poured into saturated aqueous NH4Cl (100 ml). The mixture was extracted with ER (3×75 ml) and the dried extract was evaporated to leave a yellow oil. Distillation of the oil gave the title compound as a colourless liquid (6.05 g) b.p. 100-105°/0.4 mmHg. T.l.c. [O] 0.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:3]1[C:2](=[O:10])[N:1]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2)[CH3:12]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1=c2ccccc2=NC1=O
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyl lithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was poured into aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the crude product (24.5 g, 51%). A sample (3 g) was recrystallized from EtOAc/hexane to obtain 3-ethyl-indol-2-one (1.4 g), m.p. 100-101° C.; 1H-NMR (DMSO-d6) δ0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69, 0.45 Hz), 6.93 (dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].