Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][CH2:11][CH2:12][C:13]3[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=3[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCOCC1.[Cl:40]N1C(=O)CCC1=O>O>[Cl:40][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][CH2:11][CH2:12][C:13]2[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=2[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]([CH2:26][CH2:27][CH3:28])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCN(CC(O)COc1ccccc1CCCc1cccc2[nH]ccc12)C(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CCCN(CC(O)COc1ccccc1CCCc1cccc2[nH]cc(Cl)c12)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.9 %

Procedure:
A mixture of 6.3 g of the product of Step A, 100 ml of dioxane and 2 g of N-chlorosuccinimide was stirred under an inert atmosphere for 19 hours at room temperature and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-cyclohexane-triethylamine mixture to obtain 4.73 g of N-[3-[2-[3-(3-chloro-1H-indol-4-yl)-propyl]-phenoxy]-2-hydroxypropyl]-N-propyl-trifluoroacetamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CN(C(=O)CCC(C)C)CCN1C(=O)OC(C)(C)C
Yield: 48.6 %

Procedure:
Dissolve 2-(R)-(2-(R)-Acetylamino-1-(S)-hydroxy-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (122 mg, 0.32 mmol) in 3 ml of dry CH2Cl2. Add 4-methylpentanoic acid (0.04 ml, 0.32 mmol), EDCI (73.6 mg, 0.38 mmol), HOBT (51.8 mg, 0.38 mmol), triethylamine (0.13 ml, 0.96 mmol) and dimethylaminopyridine (3.9 mg, 0.032 mmol), and stir at room temperature overnight. Dilute with CH2Cl2, and wash with 5% NaHCO3 followed by saturated aqueous sodium chloride. Dry organic layer with MgSO4 and remove the solvent under reduced pressure. Subject residue to silica gel chromatography, eluting with ethyl acetate/methanol 9:1 to obtain 74 mg (48% yield) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
A suspension of 100 g of p-(2-chlorophenyl)cinnamic acid in 1 l. of 95% ethanol is hydrogenated at atmospheric pressure using platinum oxide catalyst (1 g). The uptake of hydrogen ceases when approximately 9-10 l. of hydrogen is consumed. The catalyst is then filtered off and the reaction evaporated to dryness to give β-(2'-chloro-4-biphenylyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.[Cu][C:15]#[N:16].[Cu](C#N)C#N>CC(N(C)C)=O>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[CH:3][C:4]=1[F:13]
Reactant: N#C[Cu]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(OC(F)(F)F)c(F)c1
Reaction time: 4 h

Procedure:
49 g 1-Bromo-3-fluoro-4-trifluoromethoxybenzene was stirred into 100 mL dimethylacetamide together with 20 g copper(I)cyanide at 140° C. overnight. Additional 10 g copper cyanide was added and heating was continued at 150° C. for 4 h. Further 12 g copper cyanide was added and stirring continued at 150° C. overnight. After cooling, the mixture was filtered through Celite/Cellulose and washed with ethyl acetate. The filtrate was added to ice water and filtered again through Celite/Cellulose. The filtrate was extracted with ethyl acetate (×3), dried over magnesium sulfate and concentrated to provide a brown oil which was distilled at 7 mbar and 60° C. to yield two product fractions with 23.5 g and 12 g (content 80%) yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:42]=[CH:41][C:25]([C:26]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:30]([O:32]C(C)(C)C)=[O:31])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1>FC(F)(F)C(O)=O.C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:42]=[CH:41][C:25]([C:26]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:30]([OH:32])=[O:31])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoate (33.0 mg, 0.056 mmol) in trifluoroacetic acid (1.0 mL) and methylene chloride (1.0 mL) was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure to afford the desired product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=528.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:23])[C:15]=2[N+:14]=1[O-])#[N:2].P(Cl)(Cl)Cl>C(OCC)(=O)C.C(#N)C>[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:13]1[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:23])[C:15]=3[N:14]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2c(c1)C(c1ccc3c([n+]1[O-])C(O)CCC3)C(=O)N2
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc4c(n3)C(O)CCC4)c2c1
Temperature: 25 °C
Yield: 18 %

Procedure:
To a suspension of crude 2-(5-cyano-2-oxoindolin-3-yl)-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (263 mg, 0.819 mmol) in ethyl acetate (12 mL) and acetonitrile (12 mL) was added dropwise a solution of phosphorous trichloride (0.644 mL, 7.37 mmol) in ethyl acetate (4 mL). The resulting suspension was stirred at RT. After 24 h the mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution (2×). The aqueous phase was re-extracted with ethyl acetate (1×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness (52 mg). The crude was dissolved in a mixture of water (2 mL) and dimethylformamide (3 mL) and the solution was heated in a microwave oven at 120° C. for 5 min. After cooling to RT the reaction mixture was diluted with ethyl acetate was washed with brine (5×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol) yielding yellow solid. Amount 8.6 mg. Yield 18%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][O:17][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26]1)=[O:31])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Yield: 80.2 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.23 g, 30.1 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and cooled to 0° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.23 g, 10.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.03 g, 12.3 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. A sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give 3-(4-phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.35 g, 80%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccc(OC)cc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)ncc23)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.12 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.574 g, 7.64 mmol) and sodium ethoxide (0.391 g, 5.73 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 94 mg of the title compound. MS: (+) m/z 344.37 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[C:7]([NH:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])=[N:6]1)CC=C.[NH+]1([O-])CC[O:33]CC1.[CH3:37][C:38]([CH3:40])=[O:39]>O.O=[Os](=O)(=O)=O>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[NH:21][C:7]1[C:8]2[C:9](=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][CH:13]=2)[N:5]([CH2:1][CH2:37][CH:38]([OH:39])[CH2:40][OH:33])[N:6]=1
Reactant: CC(C)=O
Reactant: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Nc3ccccc3)nc21
Reactant: [O-][NH+]1CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1cccc(C)c1Nc1nn(CCC(O)CO)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 363 mg (0.9 mmol) of 1-(but-3-enyl)-N3-(2,6-dimethylphenyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 33 (Example 1, Step D) and a catalytic amount of OsO4 in 28.5 mL acetone and 10 mL water was treated with 400 mg (97%, 3.3 mmol) of morpholine-N-oxide. The resulting yellow solution was stirred at room temperature for 18 h. The reaction mixture was diluted with water (95 mL) and extracted with CH2Cl2 (3×240 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 96:4) to give the title compound. 1H-NMR (DMSO-d6) δ 1.58-1.69 (m, 1H), 1.91-2.01 (m, 1H), 2.20 (s, 6H), 3.19-3.27 (m, 1H), 3.28-3.36 (m, 1H), 3.88-3.97 (m, 1H), 4.05-4.19 (m, 2H), 4.48 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.0 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 7.05-7.14 (m, 3H), 7.27 (t, J=7.9 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 8.08 (s, 1H), 8.36 (s, 1H), 9.65 (s, 1H). Mass Spectrum (ESI) m/e=419.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1.CCOC(C)=O.O>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
2-Amino-5-chlorobenzophenone (5.33 g, 23 mmol) was dissolved in 100 mL pyridine and stirred at room temperature. 4-Bromobenzenesulfonyl chloride (6.17 g, 24.1 mmol) was added and the mixture was stirred overnight. The mixture was poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a reddish oil. The solution was diluted with 100 mL EtOAc and 200 mL H2O, shaken in a separating funnel and the aqueous layer discarded. The organics were dried and reduced in vacuo to yield title compound (10.2 g, 98%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 7.43–7.48 (m, 5H), 7.62 (t, 1H), 7.74 (d, 1H), 9.62 (s, 1H). MS: m/z=449.9 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[CH:15][CH:16]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 16, 55 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (41 mg) as white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20]1[C:33]2[C:32]3([CH2:35][N:36]4[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]4)[CH2:34][CH:25]([C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[Br-].[Li+]>C1COCC1.CCCCCC.C1COCC1>[CH:30]1[C:31]2[C:32]3([CH2:35][N:36]4[CH2:41][CH2:40][C:39]([C:19]5[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=5)([OH:42])[CH2:38][CH2:37]4)[CH2:34][CH:25]([C:24]4[C:33]3=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Fc1ccccn1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -20 °C
Yield: 77.4 %

Procedure:
To a cooled solution (-72° C.) of distilled diisopropylamine (7.86 mL, 56.1 mmol, 1.3 eq) in THF/hexane (57 mL/37 mL) under nitrogen was added n-butyllithium (2.5M in hexane, 23.8 mL, 59.4 mmol, 1.4 eq). The resulting solution was warmed to -20° C. to assure deprotonation and then recooled to -72° C. A THF solution (13 mL) of 2-fluoropyridine (4.50 mL, 53.5 mmol, 1.25 eq) was then added dropwise resulting in a yellow precipitate. The deprotonation reaction was warmed to -50° C. for 45 min and briefly allowed to reach -30° C. before being recooled to -72° C. To this solution was added a mixture of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidone (described in 1d above) (13.0 g, 42.9 mmol) and lithium bromide (7.45 g, 85.8 mmol, 2 eq) in THF (48 mL) in a dropwise fashion. In the course of the addition, the yellow precipitate dissolved. The reaction was warmed to -20° C. over 1.5 h and quenched with acetic acid (10 mL). The solution was diluted with water (400 mL), basified with 2.5N NaOH and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and reduced to a solid. The product was purified by recrystallization from ethyl acetate (3 crops) to yield 13.3 g (77%) of the title compound as a white solid. TLC analysis (Rf 0.22, 30% ethyl acetate in hexane). 1H NMR (CDCl3, 300 mHz) 8.09 (d, J=8.2 Hz, 1H), 7.91 (dd, J=8.2, 9.4 Hz, 1H), 7.21 (m, 5H), 6.94 (m, 4H), 4.27 (s, 1H), 3.48 (s, 2H), 2.91 (m, 2H), 2.74 (m, 2H), 2.62 (s, 2H), 2.26 (m, 2H), 1.78 (m, 2H) MS (Cl, CH4) m/z 401 (M+1, 100), 429 (M+29,15), 383 (21) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, washed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 188°-191° C. (dec).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].C(OCC)(=O)C(C)=C.[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:17](C)=[CH2:18].[CH2:26]=[CH:27][C:28]1C=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCCO)(=O)C(C)=C>C(O)(C)C>[CH3:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:7][O:6][C:1]([CH:2]=[CH2:3])=[O:5])[CH2:31][CH3:32].[CH3:25][CH2:24][CH2:23][CH2:22][O:21][C:16]([CH:17]=[CH2:18])=[O:20]
Reactant: C=C(C)C(=O)OCCCC
Reactant: C=C(C)C(=O)OC
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)OCC
Agent: C=C(C)C(=O)OCCO
Solvent: CC(C)O
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC
Reaction time: 5 h

Procedure:
180 parts of isopropyl alcohol were put in an one-liter four-necked flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel. After nitrogen replacement, the interior temperature of the flask was regulated to about 85° C. Afterwards, a monomer mixture consisting of 180 parts of methyl methacrylate, 15 parts of ethyl methacrylate, 30 parts of n-butyl methacrylate, 30 parts of styrene, 30 parts of N-n-butoxyethyl methacrylate and 15 parts of hydroxyethyl methacrylate were added dropwise into the flask with a catalyst comprising 6 parts of 2,2-azobis(2,4-dimethylvaleronitrile) over about 2 hours. After the completion of the dropwise addition, the reaction was continued at that temperature for further five hours to obtain a colorless, transparent resin solution having a solid content of about 63%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:16])=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1c(Br)cccc1SCc1ccccc1
Reactant: O=C1COCCN1
Product: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 9 (10 g, 31.38 mmol) was treated with morpholin-3-one (389 mg, 3.85 mmol) according to the procedure described in example 1; 1.5).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(I)ccc1N
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
(DPPF)PdCl2—CH2Cl2 (82 mg, 0.1 mmol) was added to 0.5 M benzylzinc bromide in dry THF (10 mL, calculated to contain 5 mmol), and the mixture was stirred at room temperature for 5 min under N2. A solution of 9 (488 mg, 2 mmol) in dry THF (2 mL) was then added, and the reaction was heated under reflux and monitored by TLC (silica gel, 2:1 CH2Cl2-hexanes). After 30 min the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) followed by saturated aqueous Na2EDTA (10 mL), and stirring was continued for another 30 min. The brown mixture was extracted several times with CH2Cl2, and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (2:1 CH2Cl2-hexanes) to obtain 2-amino-5-benzylbenzonitrile (10a) as a white powder (210 mg, 51%): mp 68-69° C.; 1H NMR (DMSO-d6) δ 3.75 (s, 2H, CH2), 5.85 (br s, 2H, NH2), 6.70 (d, J=8 Hz, 1H, H-3), 7.13-7.26 (m, 7H, aromatic protons). The product was used directly in the next reaction (Step 3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O1CCOCC1.[S:15](=[O:19])(=[O:18])([OH:17])O>ClC(Cl)=C(Cl)Cl>[OH:1][C:2]1([S:15]([OH:19])(=[O:18])=[O:17])[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]1[S:15]([OH:17])(=[O:19])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=S(=O)(O)C1C=C(O)C=CC1(O)S(=O)(=O)O
Temperature: 140 °C
Reaction time: 4 h
Yield: 139 %

Procedure:
190 g of p-dihydroxy benzene monosulfonic acid, 100 ml of dioxane, and 100 ml of perchloroethylene are mixed in a flask provided with a reflux condenser. The flask is heated in an oil bath to the reflux temperature (in the oil bath at 140° C.). It is refluxed for half an hour, and then is left to cool a little to set the coolant for distillation. In the flask, two layers are formed: a colourless lower layer, and a coloured upper layer in which the acid is dissolved. The flask is heated again and 100 ml of the solvent mixture are distilled. In the mixture collected, two layers form, the upper, moderate, is aqueous. To the flask provided with a reflux condenser, 98 g of sulfuric acid containing 20 % of SO3 are added, and it is heated again, to a lower temperature, so that the reflux is barely noticeable (bath temperature: 130° C.), for 4 hours. The liquids accompanying the acid are removed by distilling at reduced pressure, the residue is dissolved in a little water, 2 g of active charcoal are added, and it is filtered. The solution is concentrated, cooled, and is precipitated by adding five volumes of acetone. The precipitate is filtered, and 189 g of p-dihydroxy benzene disulfonic acid, with a melting point of 166°-169° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of benzyl ester (1) (25.7 mg, 0.0664 mmol) in 1:1 THF/H2O (3 mL) at 0° C. was added LiOH (9 mg, 0.348 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h at room temperature. The desired product 3 was obtained in 99% yield after purification by column chromatography (CH2Cl2/MeOH=85:15). FABMS: 298 (M+1); HREIMS calcd. for C17H15NO4 298.1079, found 298.1078.