Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[OH:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: OCCCOc1ccc(CO)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the above 3-(4-hydroxymethyl-phenoxy)-propan-1-ol (1.50 g, 8.23 mmol) in acetonitrile (25 mL) is added N-methylmorpholine-N-oxide (1.50 g, 12.38 mmol) followed by tetrapropylammonium perruthenate (140 mg, 0.43 mmol). The dark solution is stirred at rt for 2 h before the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (heptane/EA) to give 4-(3-hydroxy-propoxy)-benzaldehyde. 1H NMR (D6-DMSO): δ 9.83 (s, 1H), 7.85-7.81 (m, 2H), 7.12-7.07 (m, 2H9, 4.56 (t, J=5.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.57-3.51 (m, 2H), 1.88 (p, J=6.4 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.CN1C=CC=C1.C([O-])=O.[NH4+]>O1CCCC1.CO.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CC=Cc2[nH]ccc21
Agent: [Pd]
Agent: Cn1cccc1
Agent: O=C[O-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound CP7-19 of the formula X, where R=trans-CH=CH; Het=N-methylpyrrole; m=1; n=0; A=Butyramido, was prepared. 10% Pd/C(30 mg) and ammonium formate (30 mg) were added to 5-benzyloxy-3-tert-butyloxycarbonyl-1-chloromethyl-8-methyl-1,2-dihydro-3H-pyrrolo 3,2-e!indole (30 mg), which was synthesized using the reported methods (Ref. D. L. Boger and R. S. Coleman, J. Am. Chem. Soc. 1988, 110, 4796-4807), dissolved in a solution of tetrahydrofuran and methanol (0.8 ml, 1/1, v/v) and the reaction mixture was stirred at room temperature for 20 min. The solid was removed by filtration and water (2 ml) was added. The product was extracted with ethyl acetate (10 ml×3) and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo to generate an oil CP7-13. Without further purification, the oil CP7-13 was treated with anhydrous 3N hydrochloric acid in ethyl acetate (3 ml) at room temperature for 40 min. The solvent was removed in vacuo to give an unstable intermediate, CP7-14. Without further purification, CP7-14 was dissolved in dimethylformamide (1 ml) under nitrogen. 4-Butyramido-N-methyl-2-pyrroleacrylic acid (CP7-6) (16.6 mg) and 1- (3-dimethylamino)propyl!-3-ethylcarbodiimide hydrochloride (67.6 mg) were added sequentially. The reaction mixture was stirred in dark at room temperature for 2 days. The mixture was purified on silica plate eluting with a mixture of acetone and ethyl acetate (1:1, v/v) to give an unstable CP7-17. Without further purification, CP7 -17 was dissolved in a mixture of acetonlerile, triethylamine and water (0.6 ml of each) and the reaction mixture was stirred for 30 min under nitrogen. The solvent was removed by a high vacuum pump and the residue was dissolved in acetone. The mixture was then purified on a silica plate eluting with a mixture of acetone and ethyl acetate (1:1, v/v). 9:4 mg (32 % yield) of a yellow powder was obtained. 1H NMR (acetone-d6, ppm): 10.48 (br s, 1H, NH), 8.97 (br s, 1H, NH), 7.63-7.58 (d, 1H, J=15.5 Hz, CHCH), 7.34 (d, 1H, J=2.0 Hz, C5'-H), 6.88 (br m, 1H, C6-H), 6.72 (br s, 1H, C3-H), 6.67 (d, 1H, J=2.0 Hz, C3'-H), 6.58-6.62 (d, 1H, J=15.5 Hz, CHCH), 4.31-4.27 (d, 1H, J=10.5 Hz, NCH), 4.21-416 (dd, 1H, J=4.5, 10.5 Hz, NCHH), 3.76 (s, 3H, NCH3), 3.08-3.03 (m, C8a-H), 2.27-2.21 (t, 2H, J=7.5 Hz, CH3CH2CH2), 1.97-1.93 (dd, 1H, J=4.5, 7.5 Hz, C8-HH), 1.7-1.59 (m, 2H, CH3CH2CH2), 1.28-1.25 (t, 1H, J=4.5 Hz, C8-HH), 0.94-0.89 (t, 3H, J=7.5 Hz, CH3CH2CH2). FABHRMS calcd for C24H26N4O3H 419.2083, found 419.2092 (100%).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>C(O)C>[OH:35][CH2:34][CH2:33][N:32]([CH3:31])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CNCCO
Solvent: CCO
Product: CN(CCO)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 507 mg (6.74 mmol) of 2-(methylamino)ethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 507 mg (6.74 mmol) of 2-(methylamino)ethanol were added and the mixture was stirred in the microwave at 80 for a further 2 h and then at 100° C. for 30 min. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 53.7 mg (33% of theory)
Reaction SMILES: C[OH:2].O.[Si]([O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([F:52])=[C:17]([CH:23]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:50]=[C:49]([CH3:51])[O:48][N:47]=3)=[CH:42][CH:41]=2)[C:24]2[NH:25][C:26](=[O:38])[N:27]([C:29]3[C:34]([N+:35]([O-])=O)=[CH:33][CH:32]=[CH:31][N:30]=3)[N:28]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)(C(C)(C)C)(C)C>[Fe].C(O)(=O)C>[C:49]([OH:2])(=[O:48])[CH3:51].[NH2:35][C:34]1[C:29]([N:27]2[C:26](=[O:38])[NH:25][C:24]([CH:23]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([NH2:50])=[NH:47])=[CH:44][CH:45]=3)[C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH2:13][CH2:12][OH:11])[C:16]=3[F:52])=[N:28]2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CO
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 55 mg of 5-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (21 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.[Cl-].[Na+].O.CO>[CH:6]1[C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:9][CH2:10][C:5]=1[CH2:3][OH:2]
Reactant: COC(=O)C1=CC2(CCCCC2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1=CC2(CCCCC2)CCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of spiro[5.5]undec-1-ene-2-carboxylic acid methyl ester (2.07 g) obtained in Step 4 in tetrahydrofuran (30 mL) was added dropwise a 1M toluene solution of diisobutylaluminum hydride (30 mL) at −70° C. under argon atmosphere over 15 minutes, followed by stirring the reaction mixture at −70° C. for 1 hour. Then after careful addition of methanol (2 mL) and 6N aqueous hydrochloric acid solution (5 mL) to the reaction mixture, the temperature was raised to room temperature. The reaction mixture was poured into saturated brine, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5) to give spiro[5.5]undec-1-ene-2-methanol (1.685 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[CH:5][N:4]=1>CO.[Ni]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: COc1ncncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1ncncc1N
Yield: 99.2 %

Procedure:
10 g 4-methoxy-5-nitropyrimidine in 500 ml methanol are hydrated for 2.5 hours at 2 bar in the presence of 4.5 g Raney nickel. After filtration, the solution is concentrated. 8.0 g 5-amino-4-methoxypyrimidine having a melting point of 71° to 74° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:13]I.[OH-].[K+].S(=O)(O)[O-].[Na+].Cl>CN(C=O)C.O>[I:13][C:3]1[C:4]2=[N:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: II
Reactant: O=C(O)c1ccc2[nH]ccc2n1
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]cc(I)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.400 g, 2.467 mmol, Adesis, New Castle, Del.) in DMF (4.9 mL) was added I2 (0.626 g, 2.467 mmol) and KOH (0.346 g, 6.17 mmol). The mixture was stirred at RT for 1 h. The mixture was poured into ice and H2O (30 mL) containing sodium bisulfite (0.257 g, 2.467 mmol). The reaction was acidified with 5 M HCl. A yellow solid precipitated out and was collected by filtration, washed with H2O and dried overnight in a vacuum oven to give 3-iodo-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.516 g, 1.791 mmol, 72.6%). MS (ESI, pos. ion) m/z: 289.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (2H, s), 8.01 (1H, d, J=2.74 Hz), 12.03-12.11 (1H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:23][CH2:22][CH2:21][C:15]21[C:19](=O)[NH:18][CH2:17][CH2:16]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[H][H]>C1COCC1>[CH2:7]([N:14]1[C:15]2([CH2:16][CH2:17][NH:18][CH2:19]2)[CH2:21][CH2:22][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCC12CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC23CCNC3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (1.98 g, 52.2 mmol) was added in portions, under argon, to a ice bath cooled solution of 6-benzyl-2,6-diazaspiro[4.4]nonan-1-one (4.00 g, 17.4 mmol) in dry THF (100 mL). The addition funnel was replaced with a reflux condenser, and the mixture was heated at reflux for 24 h. The mixture was cooled to 0° C. and treated drop-wise (caution: exothermic reaction) with 10 M aqueous sodium hydroxide until hydrogen evolution ceased and the aluminate salts were granular. The mixture was stirred 1 h at 0° C. and filtered through Celite. The filtrate was dried (K2CO3) and concentrated, leaving 3.60 g (95.7%) of viscous, colorless liquid.
Reaction SMILES: CO[C:3](=[O:9])[CH:4]=[C:5]([NH2:8])OC.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:8][C:5]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:11]([Cl:10])[CH:12]=2)[C:3](=[O:9])[CH:4]=1
Reactant: COC(=O)C=C(N)OC
Reactant: NNCc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
144 g (10% excess) of β-amino-β-methoxyacrylic acid methyl ester are introduced into 500 ml of dioxane. 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture while flushing with nitrogen. The mixture is stirred for 2 hours at 60°, the solvent is driven off on a rotary evaporator, the residue is worked with 600 ml of 2 N NaOH and extracted with ether, and the aqueous phase is stirred with animal charcoal of one-half hour. After filtration, the mixture is adjusted to pH 5 with dilute acetic acid. The product which initially is obtained as an oil becomes crystalline on rubbing and is finally purified by recrystallising it again from alcohol. 139 g, corresponding to about 54% of theory, of the compound identified above, as felted colorless needles of melting point 159° are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9](C1NC=CN=1)(C1NC=CN=1)=[S:10]>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:9]=[S:10])=[N:3][CH:4]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Product: S=C=Nc1ccc(Cl)cn1
Yield: 36.6 %

Procedure:
2-Amino-5-chloropyridine (10.28 g) was added in portions, with stirring, over a period of 25 minutes to a solution of thiocarbonyl diimidazole (14.26 g) in acetonitrile (100 ml) at ambient temperature. The stirring was continued and the solution/suspension was left at ambient temperature for a few hours. The precipitate was filtered and washed with acetonitrile (3×25 ml). The solid residue was dissolved in hot acetone and filtered. The acetone solution was evaporated in vacuo, the residue was dissolved in hot ethyl acetate and filtered through a pad of silica (diam. 7×3 cm). The silica was washed with another portion of hot ethyl acetate. The combined solutions were evaporated in vacuo to yield a crude product (5 g) of the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:6]=1
Reactant: ClCCn1cc(Br)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1cc(Br)cn1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (for a preparation see Intermediate 29) (120 mg, 0.573 mmol) was mixed with potassium phthalimide (159 mg, 0.859 mmol), dissolved in N,N-Dimethylformamide (DMF) (4 mL) and stirred under nitrogen at 120° C. for 20 hours. The reaction was left to cool to room temperature and the product was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine, 30 mL), dried (MgSO4), filtered and evaporated to dryness to give a white solid. The product was purified on a 25+S Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 7:3). Product-containing fractions were evaporated to dryness to give a white solid (85 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:14].[Na+].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N#Cc1ccc(C(=O)O)c(N)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(C(=O)O)c(N)c1
Temperature: 45 °C
Yield: 89 %

Procedure:
2-amino-4Cyanobenzoic acid (3.01 g, 18.3 mmol), prepared by the method of Chan and Bruice, J. Am. Chem. Soc., 99: 6721 (1977), was dissolved in 60 mL of 97% H2SO4 and heated to 45° C. for 12 h. The mixture was added to ice, and saturated Na2CO3 solution was added to adjust the pH=3. The mixture was then filtered, and the yellow solid lyophilized to yield the title compound (2.94 g, 89%): mp 276°-278° C. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (br s, 3H), 7.90 (br s, 1H), 7.71 (d, 1H), 7.37 (br s, 1H), 7.21 (d, 1H), 6.92 (dd, 1H), 6.75 (br s, 2H); MS (DCI/NH3) m/z 181 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:27][CH2:28][CH2:29]Cl)=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:27][CH2:28][CH2:29][N:9]2[CH2:10][CH2:11][C:6]3([O:5][C:4](=[O:12])[N:3]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:2]3=[CH2:1])[CH2:7][CH2:8]2)=[CH:24][CH:25]=1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=C1N(c2ccccc2)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 12 h
Yield: 83.5 %

Procedure:
A mixture containing 8.4 g of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane, 18.4 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride, 0.3 g of potassium iodide, 9.2 g of anhydrous potassium carbonate and 81 ml of methyl isobutyl ketone is mildly refluxed under argon while stirring for 12 hours. After cooling down and filtering off the inorganic salts, the precipitate is washed with methyl isobutyl ketone, the filtrate is washed with water to neutral, dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. After triturating the evaporation residue with n-hexane, the precipitate is filtered and recrystallized from ethanol to give the title compound in 83.5% yield, m.p.: 136.5°-137.5° C.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]12[CH2:26][CH:25]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:27])[C:17](=[O:28])[CH:16]1[CH:12]([CH2:13][CH:14]([O:29][C:30]3[C:39]4[C:34](=[C:35]([CH3:42])[C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[C:32]([N:43]4[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[N:44]4)[N:31]=3)[CH2:15]1)[C:11](=[O:51])[NH:10]2)=[O:8])C>O.C1COCC1>[CH:48]([C:45]1[CH:46]=[CH:47][N:43]([C:32]2[N:31]=[C:30]([O:29][CH:14]3[CH2:13][CH:12]4[CH:16]([C:17](=[O:28])[N:18]([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:9]([C:7]([OH:8])=[O:6])([NH:10][C:11]4=[O:51])[CH2:26]5)[CH2:15]3)[C:39]3[C:34](=[C:35]([CH3:42])[C:36]([O:40][CH3:41])=[CH:37][CH:38]=3)[N:33]=2)[N:44]=1)([CH3:50])[CH3:49]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-n4ccc(C(C)C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Reaction time: 120 h

Procedure:
A solution of lithium hydroxide hydrate (796 mg, 18.6 mmol) in water (10 mL) was added to a stirred solution of the ester (145) (346 mg, 0.526 mmol) in THF (30 mL). After 5 days at room temperature, the reaction mixture was concentrated under vacuum. The pH was adjusted to 4 with 1N HCl and the resulting solution was successively extracted with AcOEt, washed with brine, dried (Na2SO4) and evaporated.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(O)C.[F:18][C:19]1[CH:20]=[C:21]([O:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=O)[CH:22]=[CH:23][CH:24]=1>O>[F:18][C:19]1[CH:24]=[CH:23][C:22]2[C:29](=[O:31])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[CH2:26][O:25][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccccc1COc1cccc(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To 250 g of phosphorus pentoxide is slowly added 160 ml of ethanol at room temperature. The mixture is further stirred with heating at 100° C. for 1 hour. Thereto 42 g of 2-[(3-fluorophenyloxy)methyl]benzoic acid is added and the mixture is stirred with heating at 100° C. for 1 hour. After cooling to room temperature, 500 ml of water is added. After extraction with toluene, washing successively with saturated sodium hydrogen carbonate, water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 31 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 228(M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[N:5][C:6]([S:17][CH3:18])=[N:7][C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)C1=C(N)c2c(nc(SC)nc2-c2cccc(OC)c2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc(OC)c3)c2c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-7,8-dihydroquinazoline-6-carboxylate (example 25c, 22 mg) was dissolved in CH2Cl2 (1 ml). A 0.06M solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in CH2Cl2 (1.2 ml) was added and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with toluene/EtOAc=95/5 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:31])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.CC([O-])(C)C.[K+].[CH2:46]([OH:49])[C:47]#[CH:48]>O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:49][CH2:46][C:47]#[CH:48])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:31])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)C(F)(F)CO1
Reactant: C#CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(NC(=O)OC(C)(C)C)OCC3(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
((R)-4-{5-[(5-Chloro-pyrazine-2-carbonyl)-amino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (400 mg, 800 μmol) was combined with DMF (1.2 ml) to give a colorless solution. KOtBu (180 mg, 1.6 mmol) and propargyl alcohol (449 mg, 477 μl, 8.00 mmol) were added and the reaction mixture was stirred 2 h at RT. Water was carefully added and the product was extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 20 g, 0 to 50% EtOAc in heptane). Light yellow solid (350 mg, 84%). MS (ISP): m/z=520.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:6]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[ClH:18]>O>[CH2:8]1[CH2:7][C@@H:6]([C@@H:5]([C:3]([OH:4])=[O:2])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:11][CH2:10][CH2:9]1.[ClH:18]
Reactant: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H](c1ccccc1)[C@@H]1CCCCN1

Procedure:
A solution of dl-threo-methylphenidate (1 g) in water (25 ml) and conc. HCl (5 ml) was heated under reflux for 3 h. The clear solution was evaporated to dryness, to give a dl-threo-ritalinic acid hydrochloride as a white solid.