Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[CH3:15][N:16]([CH2:18][CH2:19][OH:20])[CH3:17].CN(C)C(=N)N(C)C>>[CH3:15][N:16]([CH3:17])[CH2:18][CH2:19][O:20][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5]
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Reactant: CN(C)CCO
Agent: CN(C)C(=N)N(C)C
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OCCN(C)C
Yield: 32 %

Procedure:
A solution of α-damascone (6.44 g; 33.5 mmol), N,N-dimethylaminoethanol (30.25 ml; 301 mmol) and tetramethylguanidine (TMG) (0.77 g; 6.70 mmol) was heated at 70° C. for 15 h. Afterward, the excess of N,N-dimethylaminoethanol was distilled at ca. 60° C./10 to 2 mbar. The crude product was diluted in diethyl ether (Et2O) and this mixture was extracted with 5% aqueous HCl and washed with water and saturated aqueous NaCl. The combined aqueous phases were basified using aqueous NaOH and extracted twice with ether to recover the crude product in the organic phases. The organic phases were still washed with water and brine, then dried over Na2SO4 and concentrated. Bulb-to-bulb distillation of the crude product (100-125° C./0.05 mbar) afforded 2.94 g of the desired pure product (yield: 32%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[S:35]([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][SH:35])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCS)cc2)cc1
Temperature: 25 °C

Procedure:
4-[4-(6-Mercapto-hexyloxy)-phenylazo]-benzoic acid t-butyl ester was synthesized by modifying a literature procedure [Material Science and Engineering, 1999, 8-9, 385-389; J. Phys. Chem., 1995, 99, 7102]. 0.41 g (0.9 mmol) of 4-[4-(6-bromo-hexyloxy)-phenyazo]-benzoic acid t-butyl ester and 0.25 mg (1.1 mmol) of sodium thiosulfate pentahydrate in 5 mL of water was dissolved in 18 mL of ethanol and refluxed for 3 hours. The mixture was stirred at room temperature for an additional hour. After cooling, the precipitate was filtered off using a fritted funnel. A fine orange solid (bunte salt) was obtained and was used without purification. 10 ml of chloroform and 10 mL of 1M HCl were added to the bunte salt. The reaction mixture was refluxed for 2 hours at 70° C. after which the orange organic phase was extracted from the colorless aqueous layer. The organic layers were further extracted with 10 mL of chloroform (3 times) and combined, washed with saturated NaHCO3 solution, distilled water, and then dried over MgSO4. The solvent was removed by roto-evaporation and the product (compound 1, FIG. 11) was further purified by recrystallization from an ethanol-water mixture. Drying under vacuum produced a fine orange powder (0.22 g, 60% yield) with the following characteristics: 1H NMR (CDCl3) δ 8.11 (d, J=9 Hz, 2H), 7.91 (dd, J=9 Hz, 4H), 7.14 (d, J=9 Hz, 2H), 4.08 (t, J=6 Hz, 2H), 2.48 (m, 2H), 1.85-1.41 (m, 17H), 1.32 (t, 1H). High-resolution mass spectroscopy (HR-MS) yielded a mass of 414.1988 compared to the value 414.1628 calculated for C23H30O3N2S.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:10][CH2:11][CH3:12])(OCC)OCC.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=CC=1O>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[O:10][C:11]2[CH:12]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=2[N:13]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2oc(CCl)nc2c1
Temperature: 120 °C
Yield: 76.8 %

Procedure:
2-Chloro-1,1,1-triethoxyethane (410 μL, 2.15 mmol) was added to a suspension of 2-amino-4-trifluoromethylphenol (370 mg, 1.79 mmol) in acetic acid (7 mL); during the addition the solution began to clear. The solution was heated at 120° C. (external temperature). After three hours the reaction mixture was cooled and the volatiles were removed under reduced pressure. Purification by silica gel chromatography, eluting with a gradient of 0 to 10% ethyl acetate in heptanes, gave 2-chloromethyl-5-trifluoromethyl-benzoxazole as a yellow oil (324 mg, 77%). (CI, m/z): [M+H]+ 236; 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.66-7.73 (m, 2H), 4.79 (s, 2H); 19F NMR (376 MHz, CDCl3): δ ppm −61.26 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=[CH:29]C([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[S:44]1C=C(CO)[N:46]=[N:45]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[N:46]=[N:45][S:44][CH:29]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OCc1csnn1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)OCc1csnn1

Procedure:
A solution of 0.50 g (0.50 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.128 g (0.99 mmol) of N,N-diisopropylethylamine, 0.030 g (0.25 mmol) of N,N-dimethylaminopyridine and 0.079 g (0.5 mmol) of [1,2,3]thiadiazol-4-ylmethanol (Acta Pharmaceutica Suecica (1973), 10(4), 285-96) in 5 mL of 1,2-dichloroethane is heated in a reactor tube at 80° C. for 12 hours.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].S([O-])([O-])(=O)=O.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][O:20][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Reaction time: 2 h
Yield: 68.1 %

Procedure:
[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (57 mg), toluene (0.3 ml), 50% aqueous NaOH solution and tetrabutylammonim sulfate (32 mg) were stirred at room temperature. tert-Butyl bromoacetate (53 mg) was added dropwise and stirring was continued for 2 hours. Water (3 ml) was added and organic layer was separated. Water layer was extracted with EtOAc (×2). Organic layer was combined and dried over MgSO4. The solvent was evaporated to give dark brown oil. The crude compound was purified by flash column chromatography on silica gel (CHCl3:MeOH=50:1) to give tert-butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (53 mg) as colorless oil
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([NH:12]C(=O)OC)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([C:8]2([NH2:12])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1(c2ncccc2F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1(c2ncccc2F)CCC1
Temperature: 150 °C
Yield: 92.6 %

Procedure:
To a 20 mL microwave reaction vial was added methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0 equiv), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture was heated in the microwave reactor at 150° C. for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g, 93%) as a crude yellow oil that was used without further purification.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[O:7]1C=CC=[C:8]1[C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][N:13]=1.C([OH:26])C>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O.C1C=CC=CC=1>[N:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:16]=[CH:17][C:12]([C:8]([OH:7])=[O:26])=[N:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: c1coc(-c2cnc(-c3ccncc3)cn2)c1
Reactant: CCO
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1cnc(-c2ccncc2)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
At room temperature, potassium permanganate (700 mg) and trioctylmethylammonium chloride (one drop) were dissolved in a mixed solvent of water (20 ml) and benzene (20 ml). To the resulting solution, 2-(furan-2-yl)-5-(pyridin-4-yl)pyrazine (700 mg) was added in portions, followed by stirring at room temperature for 17 hours. After ethanol was added to the reaction mixture to decompose excess potassium permanganate, the solvent was distilled off. To the residue, water (100 ml) was added and the mixture was filtered through Celite. To the filtrate, 1N hydrochloric acid was added to adjust its pH to 6. The solvent was distilled off until the precipitation of colorless crystals. The colorless crystals were collected by filtration, whereby the title compound (491 mg, 79%) was obtained.
Reaction SMILES: NC1C2C(OC)=CC=CC=2SC=1[C:7](OC)=[O:8].C=O.Cl[C:20]1[C:28]2[C:27]([N:29]([CH3:31])[CH3:30])=[C:26]([C:32]([O:34][CH3:35])=[O:33])[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:30][N:29]([CH3:31])[C:27]1[C:28]2[C:20]([O:8][CH3:7])=[CH:21][CH:22]=[CH:23][C:24]=2[S:25][C:26]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Reactant: COC(=O)c1sc2cccc(Cl)c2c1N(C)C
Agent: C=O
Product: COC(=O)c1sc2cccc(OC)c2c1N(C)C

Procedure:
Alkylation of methyl 3-amino-4-methoxybenzo[b]thiophene-2-carboxylate (1.4 g, 5.9 mmol) [Beck J. R., supra] with paraformaldehyde as described for the preparation of methyl 4-chloro-3-(dimethylamino)benzo[b]thiophene-2-carboxylate provides methyl 3-(dimethylamino)-4-methoxybenzo[b]thiophene-2-carboxylate as a crude solid suitable for further synthesis; mp=69°-73° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]2[CH:18]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:31][C:29]([CH3:32])([CH3:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:19]1[CH:18]=[C:17]([CH:16]=[CH:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(O)CCCCCCc1cccc(C=Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCCc1cccc(C=Cc2cccc(O)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 207 mg (0.46 mmol) of 8-(3-{2-[3-(tert-butyldimethylsilanyloxy)phenyl]vinyl}phenyl)-2-methyloctan-2-ol with 0.5 ml of tetrabutylammonium fluoride 1M/THF, after purification on a silica column (ethyl acetate 30-heptane 70), a white powder (m=203 mg; Y=32%) is obtained. m.p.=142-3° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](Cl)=[O:15])[CH3:12]>N1C=CC=CC=1.ClCCl>[CH2:11]([O:13][C:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15])[CH3:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To the solution of 2-nitroaniline (6.9 g, 50.0 mmol) in pyridine (6 mL) and dichloromethane (25 mL) at 0° C. under argon was added ethylchloroformate (7.3 mL, 75.0 mmol) through an addition funnel. After the addition was finished, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to yield the title compound as a yellow solid (7.7 g, 73.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:27][CH:28]([CH2:31][CH3:32])[CH2:29][SH:30].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:27][CH:28]([CH2:31][CH3:32])[CH2:29][S:30][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(C)CS
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(C)CSc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C

Procedure:
A mixture of (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (53 mg, 0.130 mmol), 2-methylbutane-1-thiol (14.21 mg, 0.130 mmol), tris(dibenzylideneacetone)dipalladium (5.93 mg, 6.48 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.75 mg, 6.48 μmol), N,N-diethyl-N-isopropylpropan-2-amine (45.1 μL, 0.259 mmol), and dry 1,4-dioxane (0.5 mL) was irradiated in microwave glass vessel at 160° C. for 35 minutes. The whole was cooled to rt and the resulting solid was filtered off and washed with MeOH (3 mL). The filtrates were combined, concentrated, and purified with reverse phase HPLC. Fractions containing the product were combined, and concentrated. TFA was removed using catch and release with strong cation exchange with 2 g SCX columns. First, the material was loaded in the column with MeOH. The column washed with MeOH to remove the TFA, then with 2M NH3 in MeOH to collect the product. The basic wash was collected and dried to afford (4′S)-3-(2-methylbutylthio)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][C:21](=[O:27])[C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].N1C=CN=C1>>[Br:19][CH2:20][C:21](=[O:27])[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)C(=O)CBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CBr
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
tert-Butyldiphenylsilyl chloride (50.8 g, 184.6 mmol) is added at 0° C. to a solution of 1-bromo-4-hydroxy-3,3-dimethyl-butan-2-one (30.0 g, 153.8 mmol) and imidazole (26.0 g, 384.5 mmol). The reaction mixture is warmed to room temperature and stirred for 14 h. After adding ice water, the mixture is extracted with diethyl ether and the organic layer is dried over anhydrous Na2SO4. After filtration, removal of the solvent under reduced pressure affords the crude product that is purified by silica gel chromatography to afford 40.0 g of 1-bromo-4-(tert-butyl-diphenyl-silanyloxy)-3,3-dimethyl-butan-2-one as a light yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (9H, s), 1.16 (6H, s), 3.61 (2H, s), 4.80 (s, 2H), 7.38-7.58 (10H, m).
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:19]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[N:24]=[C:23]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH:22]=[CH:21]2)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:19]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[N:24]=[C:23]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH:22]=[CH:21]2)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 139.7 %

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.40 mL) was added to a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol (10 mg) in wet acetonitrile (1.5 mL, 0.75% H2O) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. Filtration and purification by reverse phase HPLC (0.1% TFA/CH3CN-0.1% TFA/H2O) gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid (7.2 mg). 1H-NMR 400 MHz, (CD3OD) δ 7.76 (m, 2 H), 7.62 (m, 3 H), 7.30 (m, 2 H), 5.14 (s, 1H), 3.89 (m, 8H), 2.66 (s, 3H), 0.97 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30ClN2O4: 469.2. Found: 469.3; LCMS-ESI− (m/z): [M−H]− calcd for C26H28ClN2O4: 467.2 Found: 467.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:27][C:26](=[CH:28][C:29]#[N:30])[CH2:25]2)[CH2:23][O:22]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:26]4([CH2:28][C:29]#[N:30])[CH2:27][C:24]5([CH2:23][O:22][CH2:21]5)[CH2:25]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=C1CC2(COC2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(COC5)C4)c3)n2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
A mixture of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (25 mg; 0.094 mmol), 2-(2-oxaspiro[3.3]heptan-6-ylidene)acetonitrile (19 mg; 0.14 mmol) and DBU (7.2 mg; 0.047 mmol) in acetonitrile (1 mL) was stirred in a sealed vial at 50° C. for 24 hours. The solvent was removed under reduced pressure and the material was purified by silica gel chromatography, eluting with (6% ammonium hydroxide in methanol)/methylene chloride (1:25 to 1:15 gradient) to provide pure desired product as a white solid (27.5 mg). MS (apci) m/z=401.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:4](=[O:6])[CH2:3][N:2]([CH3:7])[CH3:1])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN(C)CC(=O)O
Product: C[C@@H](CN(C)C(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 27 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 27% yield; NMR spectrum (DMSO-d6) 1.37 (d, 3H), 2.06 (s, 6H), 3.08 (s, 3H), 3.23 (dd, 1H), 3.25 (s, 2H), 4.26 (dd, 1H), 5.10 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.56 (s, 1H), 7.68 (m, 2H), 7.87 (dt, 1H), 8.13 (d, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H); Mass Spectrum MH+ 535.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[NH2:10][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C)cc1N

Procedure:
A solution of 4-methyl-2-nitroanisole (Aldrich) (10 g, 0.06 mol) in 100 ml of absolute ethanol was hydrogenated in the presence of 0.25 g of Pd/C (10%) at room temperature. The catalyst was removed by filtration and the clear solution was concentrated to give 2-amino -4-methylanisole as a white solid. To this solid was added 70 ml of acetic anhydride and a few drops of concentrated sulfuric acid. After stirring for 1 h, the mixture was poured into ice/water and the precipitated product was filtered and dried to give 9.48 g (88%) of S1 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:38])=[N:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:38])=[N:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(OC2CCOCC2)ccc1Br
Product: Cc1nc(OC2CCOCC2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-bromo-2-methyl-6-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 15) in analogy to Example 1a): MS (ISN): 493.1 and 495.3 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccccc2)nc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc(-c2ccccc2)nc2ccccc12
Yield: 54 %

Procedure:
A mixture of 4-methyl-2-phenylquinazoline (15 g), N-bromosuccinimide (13.3 g) and benzoyl peroxide (1.65 g) in carbon tetrachloride (150 cc) is brought for 3 hours to 90° C. The mixture is filtered, the filtrate evaporated and the residue chromatographed on silica gel with a cyclohexane/ethyl acetate (9:1 by volume) mixture as eluant. 4-Bromomethyl-2-phenylquinazoline (11 g), m.p. 110° C., is obtained.