Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Yield: 73 %

Procedure:
133.7 g (0.41 mol) of 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were heated to 100° C. with 64 g (0.5 mol) of 4-chlorophenol and 69 g (0.5 mol) of potassium carbonate in 500 ml of toluene for 5 hours. The mixture was then allowed to cool and was filtered. The filtrate was extracted by shaking with dilute sodium hydroxide solution, rinsed with water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 110.5 g (72% of theory) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a yellowish oil with a refractive index nD20 of 1.5932.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CCN(C(=O)Nc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 4-methylbenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.35-7.00 (m, 9H), 6.32 (s, 1H), 3.50-3.48 (m, 6H), 2.49-2.46 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1nn2ccnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3ccnc3s2)cc1OC
Temperature: 110 °C
Yield: 12.2 %

Procedure:
A solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (0.5 g, 2.5 mmol, 1 eq), 3,4-dimethoxyphenylboronic acid (0.683 g, 3.7 mmol, 1.5 eq), dioxane (12.5 mL) and Na2CO3 (2M aq. solution, 3.8 mL) was degassed for 20 minutes at room temperature. Pd(Ph3P)2Cl2 was added and the reaction heated at 110° C. for 2 h in an argon atmosphere. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layers were dried (Na2SO4), filtered and concentrated, and the residue was purified by column chromatography (SiO2, cyclohexane/20-100% ethylacetate). The product was further purified by triturating with Et2O, filtered off and dried affording the desired product (0.080 g). 1H NMR (300 MHz, DMSO) δ/ppm 8.18 (d, J=1.4, 1H), 7.47 (m, 2H), 7.33 (d, J=1.4, 1H), 7.15 (d, J=8.3, 1H), 3.86 (s, 3H), 3.75 (s, 3H). The filtrate was concentrated, redissolved in DCM and purified by flash-chromatography (SiO2, DCM/1% MeOH) to afford the desired product (0.65 g, containing some Ph3PO) that was used as such in the next step.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](Cl)=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24]C(=O)C)(=O)C.O.[SH2:29].[Na]>CO>[OH:24][C:6]1[CH:7]=[C:8]([C:11]2[C:12](=[S:29])[NH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: S
Reactant: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)nc2Cl)cc1OC(C)=O
Agent: [Na]
Solvent: O
Solvent: CO
Product: Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=S)cc1O
Yield: 77.4 %

Procedure:
4-(4-Chloro-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate (6.0 g) (15.7 mmol) are suspended in 200 ml of methanol. 10 g of sodium hydrogen sulphide hydrate are added at 50° C. while stirring. After a further 4 hours at 60° C. the mixture is filtered and the filtrate is concentrated. The residue is dissolved in about 150 ml of water and the solution is brought to pH 5 with 1N aqueous hydrochloric acid. The precipitated product is filtered off under suction, washed with water, dried at room temperature and crystallized from ethanol. There are obtained 3.6 g of 5-(3,4-dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinethione as yellow crystals of m.p. 220° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of 10.0 g (72.67 mmol) 3-hydroxypiperidine in 100 mL dry THF at 0° C. was added 10.1 mL (72.67 mmol) NEt3 and 15.86 g (72.67 mmol) di-t-butylcarbonate in 100 mL THF and the reaction allowed to warm to rt and stirred overnight. The solvent was removed under reduced pressure, the resulting residue dissolved in 300 mL CH2Cl2 and the solution extracted with H2O (2×200 mL), dried over MgSO4, filtered and rotary evaporated to yield 12.66 g (87%) of N-(t-butoxycarbonyl)-3-piperidinol as an oil which slowly solidified to a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=[O:25])C>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N:10][C:11]([OH:25])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(CCc2ccc(F)cc2)ccc[n+]1[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(O)ccc1CCc1ccc(F)cc1

Procedure:
A solution of 3-(4-fluorophenethyl)-2-(methoxycarbonyl)pyridine-1-oxide (7.96 g) in DMF (100 ml) and trifluoroacetic anhydride (40.9 ml) was stirred under an inert atmosphere at ambient temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (150 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were dried and concentrated under reduced pressure and the residue purified on a silica flash column eluting with methanol/dichloromethane (1:9) to give methyl 3-(4-fluorophenethyl)-6-hydroxypyridin-2-carboxylate as a cream solid (7.7 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([B:28]([OH:33])[OH:29])[C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(OCc2ccccc2)cnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of diisopropylamine (Aldrich) (0.33 mL, 2.16 mmol) in THF (5 mL) was cooled to 0° C. and treated with n-butyllithium (Aldrich) (0.94 mL, 2.36 mmol). The resulting mixture was stirred at 0° C. for 30 min and then cooled to −78° C. 5-(Benzyloxy)-2-fluoropyridine (Aldrich) (0.200 g, 0.982 mmol) in THF (3 mL) was added dropwise and the solution was stirred at −78° C. for 40 min before being treated with triisopropyl borate (Aldrich) (0.50 mL, 2.16 mmol) in THF (2 mL). After the addition, the cooling bath was removed and the reaction mixture slowly warmed up to rt and was stirred for 1 h. The reaction mixture was quenched with 5% NaOH (10 mL). The aqueous layer was separated and acidified to pH 5 using 5N HCl. The resulting mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the crude product as yellow solid (0.210 g). m/z (ESI, +ve ion) 248.0 (M+H)+. 1H NMR (300 MHz, d4-MeOH) δ 6.60 (br s., 1H); 6.36 (br. s., 1H); 6.00-6.24 (m, 5H); 3.87 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]2[C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]2[C:18]([CH2:19][NH:20][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ncccc2CN)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OC)c(-c2ncccc2CNC(=O)OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
[3-(3-Aminomethyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid methyl ester (0.140 g, 0.49 mmol) and triethylamine (0.17 mL, 1.23 mmol) was dissolved in CH2Cl2 (5 mL). Benzyl chloroformate (0.08 mL, 0.54 mmol) was added, and the reaction was stirred for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[O:37])=[CH:34][N:33]=[CH:32]1.[Li]CCCC>>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][C:11]3[C:12]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:39]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=3)[OH:37])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Product: CCN(CC)c1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-N,N-diethylquinolin-2-amine (380 mg, 0.809 mmol, Intermediate 46) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (206 mg, 0.809 mmol, Intermediate 36, step c) and was evacuated and re-filled with argon. THF (13.5 mL) was added, and the solution was cooled in a dry ice acetone bath for 10 minutes. n-BuLi (1.6 M in hexane, 0.506 mL, 0.809 mmol), was added dropwise by syringe. The mixture was stirred at −78° C. for 30 minutes, then in an ice water bath for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 50-100% EtOAc-heptanes) to provide the title compound as a white foam.
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH2:16][CH2:17][CH3:18])[CH:9]=2)[O:4]C1.C1(C)C=CC=CC=1>C(O)=O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]=[O:4])=[CH:9][C:10]=1[O:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCOc1cc(C2OCC(C)(C)CO2)ccc1O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 1.26 g (4.74 mmol) of 4-(5,5-dimethyl-1,3-dioxan-2-yl)-2-propoxyphenol, 20 ml of toluene and 20 ml of formic acid was vigorously stirred for 2 hours at room temperature. Thereafter, the reaction mixture was partitioned between toluene and water and the organic phase was washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Crystallization of the residue from a mixture of 10 ml of diethyl ether and 20 ml of hexane gave 0.78 mg of 4-hydroxy-3-propoxybenzaldehyde.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH2:13]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1)[CH2:14][CH3:15]>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH2:13][CH2:14][CH3:15])[CH:17]=1)=[O:26]
Reactant: OCC1CCN2CCCCC2C1
Reactant: CCCn1cc(C(=O)O)c2ccccc21
Product: CCCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem,1957, 22, 1445) was reacted with the acid chloride of 1-n-propylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting yellow oil was crystallised from n-pentane to afford the title compound (E17) as a white solid mp 75°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35].Cl.COC(=O)[C@H](CCSC)N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[CH:17]=[C:16]([NH:15][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH:24]=[CH:23][C:19]=2[C:20]([NH:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35])=[O:22])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of 4-{1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoic acid (1.67 g; 4 mmol), methyl (2S)-2-amino-4-(methylsulfanyl)butanoate, (L-methionine methyl ester hydrochloride) (0.96 g; 4.8 mmol), HOBT (0.65 g; 4.8 mmol), EDC (0.925 g; 4.8 mmol) and DMAP (0.54 g; 4.4 mmol) in dichloromethane (100 ml) was stirred at ambient temperature for 5 hours. The solution was diluted with dichloromethane (200 ml), washed with 5% aqueous sodium hydrogen carbonate solution and evaporated to dryness. The residue was purified by flash chromatography eluting with dichloromethane/ethanol 95/5 to give the title compound as a solid (1.8 g; 80%).
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH3:30])[N:8]=1)([OH:3])=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:11][CH:10]=[C:9]([CH3:30])[N+:8]=1[O-:39])([OH:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CCCCCCCCOc2ccc(C)nc2/C=C/CC(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCOc2ccc(C)[n+]([O-])c2/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine (17.1 g, 41.5 mmol) was dissolved in dry CH2Cl2 (105 mL) and cooled to 0° C.; 50% m-chlorperbenzoic acid (15.8 g, 45.8 mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2Cl2. The organic extract was washed with H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:9][O:8]1)([CH3:4])([CH3:3])[CH3:2].[F:10]CC1COC(=O)C=1.F.[F-].[K+]>>[C:1]([O:5][CH2:6][CH:7]([OH:8])[CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCC1CO1
Reactant: O=C1C=C(CF)CO1
Agent: F
Agent: [F-]
Agent: [K+]
Product: CC(C)(C)OCC(O)CF

Procedure:
Starting from 2-tert-butoxymethyl-oxirane (5), 4-fluoromethyl-5H-furan-2-one can be prepared according to the method described in scheme 2. In the first step, the oxirane ring is opened with potassium hydrogendifluoride to form 1-tert-butoxy-3-fluoro-propan-2-ol (6) which is then oxidized to the corresponding ketone (7). The oxidation can be carried out according to known methods such as e.g. with sodium hypochlorite in the presence of a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). In a next step 1-tert-butoxy-3-fluoro-propan-2-one (7) is reacted with tert-butyl acetate in the presence of a strong base such as lithium diisopropylamine (LDA) to form 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8) which can be cyclizised to 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) under strong acidic conditions (e.g. by employing trifluoroacetic acid or sulfuric acid 95%). Preferably, the cyclization is carried out with only a small amount of sulfuric acid 95% (e.g. 0.025 mol equivalent in relation to the educt) in a solvent such as 1,2-dimethoxyethane or dioxane. These two last steps can alternatively be carried out in a one-pot procedure, e.g. without isolating 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8). In a final step 4-fluoromethyl-5H-furan-2-one (III) is obtained by dehydration of 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9). The dehydration can be performed according to known methods, e.g with acetic anhydride in the presence of an amine base such as triethylamine. Alternative dehydration methods include the use of thionyl chloride in the presence of pyridine or mesyl chloride in the presence of triethylamine. In a further alternative dehydration method, 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) is reacted with acetic anhydride to form the intermediate 4-acetoxy-fluoromethyl-dihydro-furan-2-one which is then reacted with sodium acetate in de-ionized water to obtain the compound of formula III.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)(O)[NH:7][C:6]=2[C:5]([N+:19]([O-])=O)=[C:4]([F:22])[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([NH2:19])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[N:7]2
Reactant: O=[N+]([O-])c1c(F)cc(Br)c2c1NC(O)(c1cccnc1)CO2
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)c2c1N=C(c1cccnc1)CO2
Temperature: 60 °C

Procedure:
Iron (91 mg, 1.6 mmol) was added to a mixture of 8-bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol (121.0 mg, 0.3269 mmol) in acetic acid (3 mL), and heated overnight at 60° C. The mixture was extracted with ethyl acetate and the organic layer concentrated. Purification on silica gel eluting ethyl acetate in hexanes afforded product. LCMS calc. for C13H10BrFN3O (M+H)+: m/z=322.0. found: 322.0.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH3:21].[C:22]12(O)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.B(F)(F)F.CCOCC>CCCCC>[C:22]12([C:19]3[C:2]([OH:1])=[C:3]([CH3:21])[C:4]4[CH2:5][CH2:6][C@@H:7]5[C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]5[CH2:9][CH2:10][C:11]3=[O:20])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(O)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1c(O)c(C23CC4CC(CC(C4)C2)C3)cc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.2 %

Procedure:
To a suspension of the known 3-hydroxy-4-methylestra-1,3,5(10)-trien-17-one (ref. Kaneko et al., 1964; Chemical Abstracts Registry Number [68969-90-4], 30 mg, 0.11 mmol) and 30 mg (0.197 mmol) of 1-adamantanol in 1 mL of anhydrous pentane was added 0.02 mL of boron trifluoride diethyl etherate while cooling with an ice bath and stirring. After stirring at 0° C. for 15 min. the reaction was stirred at room temperature for 45 min. Ice was added and the white solid that formed was filtered, washed with water and dried over P2O5. The crude product was purified by chromatography (silica gel eluted with 7% ethyl acetate in hexanes) to give 30 mg of pure product (68% yield). After recrystallization from methylene chloride-hexanes the product had: m.p. 262-263° C.; 1H NMR(CDCl3) δ 0.90 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.7 (m, 2H, CH2), 7.11 (s, 1H, Ar—H); 13C NMR (CDCl3) δ 11.02, 13.70, 21.44, 26.22, 26.67, 27.54, 28.95 (3×C), 31.56, 35.84, 36.60, 36.98 (3×C), 37.63, 40.82 (3×C), 44.60, 47.91, 50.34, 121.41, 121.51, 131.45, 133.32, 150.79, 221.49. (Anal. calc'd. for C29H39O2: C, 83.21; H, 9.15. Found: C, 83.45; H, 8.94.)
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([F:13])[CH:7]=1>CS(C)=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=1[F:13]
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 61 %

Procedure:
KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: CCN1CCN(c2ccc(N)cc2)CC1

Procedure:
4-(4-Ethyl-piperazin-1-yl)-phenylamine is prepared in 2 steps from 1-bromo-4-nitro-benzene and 1-ethyl-piperazine as described in Example 1, Step A and B.
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH:14]([CH3:18])[CH2:15][O:16][CH3:17])[N:6]=2.[CH3:25][OH:26]>>[CH3:18][CH:14]([O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:26][CH3:25])[N:4]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:9]([NH2:12])[N:8]=1)[CH2:15][O:16][CH3:17]
Reactant: COCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: CO
Agent: [Na]
Product: COCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
Sodium (1.16 g, 50.5 mmol) was dissolved in methanol (40 ml) and 8-bromo-2-{[1-methyl-2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6.5 g, 16.8 mmol) added with stirring. The mixture was heated to reflux for 2 h. The solvent was removed by evaporation. The residue was purified on a silica column using DCM: MeOH 150:1 as eluent. This gave product (4.7 g, 82.9%).