Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:36](N(C(C)C)CC)(C)[CH3:37].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[C:27]1([CH2:26][C:25]([NH:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:5])[CH:36]=[CH2:37])[CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
{1-[4-(Phenylacetylamino-methyl)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.15 g, 0.31 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.25 ml, 1.54 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 100% DCM to 95% DCM, 5% Methanol) to give the title compound (0.025 g, 18% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.CC#N>O>[C:28]([C@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 17 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-tryptophan to provide the title compound in 17% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH—20, 1, 0.3).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[O:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[O:37][NH2:38]>C(Cl)CCl.CN(C=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:38][O:37][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)=[O:21])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reactant: NOC1CCCCO1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBtH2O (0.072 g), triethylamine (259 μl), DMF (10 ml), EDC?HCl (0.269 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])=[CH:15][CH:14]=2)=[N:4][N:5]([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[CH:6]=1.C1(S([N:38]2[C:42]3=[N:43][CH:44]=[CH:45][C:46](B4OC(C)(C)C(C)(C)O4)=[C:41]3[CH:40]=[CH:39]2)(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:23]1([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:3]3[C:2]([C:46]4[CH:45]=[CH:44][N:43]=[C:42]5[NH:38][CH:39]=[CH:40][C:41]=45)=[CH:6][N:5]([CH2:7][CH:8]4[CH2:12][CH2:11][CH2:10][O:9]4)[N:4]=3)=[CH:14][CH:15]=2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)OC1(C)C
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC3CCCO3)cc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC3CCCO3)cc2-c2ccnc3[nH]ccc23)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of N-{4-[4-bromo-1-(tetrahydro-2-furanylmethyl)-1H-pyrazol-3-yl]phenyl}-N′-phenylurea (0.147 mmol), 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.162 mmol), N,N-dimethylformamide (1.5 mL), saturated aqueous sodium bicarbonate (0.44 mL) and tetrakis(triphenylphosphine)palladium(0) (0.007 mmol) in a sealed tube was stirred at 100° C. for 18 hrs. The solution was cooled to room temperature, filtered though Celite and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and 6.0N aqueous sodium hydroxide (1 mL) and stirred at 70° C. for 6 h. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title compound as a white solid (11%). ESMS [M+H]+: 479.4
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[CH:16])[CH:6]=1)=[O:4].[CH:19]1[C:24]([I:25])=[CH:23][CH:22]=[C:21](I)[CH:20]=1>CN(C=O)C.[Cu]I>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[C:16][C:21]2[CH:20]=[CH:19][C:24]([I:25])=[CH:23][CH:22]=2)[CH:6]=1)=[O:4]
Reactant: C#CCn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: O=C(c1cn(CC#Cc2ccc(I)cc2)c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of product of Step B (0.25 g, 1 mmol), 1,4 di-idobenzene (0.4 g, 1.2 mmol) Cl2Pd(PPh3)2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N2. This was stirred overnight at room temperature, quenched with NaHCO3 solution and diluted to 50 ml with EtOAc. The organic layer was separated and washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.28 g, 51%), as light yellow solid. 1H-NMR (CDCl3) 8.43-8.40 (b, 1H); 8.12 (b, 1H); 7.66 (t, 2H, J=8.36 Hz); 7.55-7.51 (m, 1H); 7.44-7.38 (m, 2H); 7.14 (d, 2H, J=8.30 Hz); 5.16 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.Cl[Si:17]([CH3:28])([CH3:27])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][Si:17]([CH3:27])([CH3:28])[CH:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]2[CH3:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(Br)cc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 11.2 g (55.9 mmol) of 4-bromo-2,6-dimethylaniline in 170 ml of THF, 22.4 ml of 2.5 M (55.9 mmol) nBuLi in hexanes were added at −80° C. This mixture was warmed for ca. 1 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 12.0 g (55.9 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 80 ml of THF. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 170-175° C./0.6 mm Hg. The product crystallizes slowly at ambient temperature. Yield 8.45 g (40%).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[C:20]([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH3:20][O:18][C:17](=[O:19])[C@H:6]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Thionyl chloride (4.25 mL, 58.10 mmol, 2.4 eq) was added dropwise to a suspension of L-tryptophan (5.0 g, 24.48 mmol, 1.0 eq) in dry MeOH (50 mL) at −15° C. The cold bath was removed and the solution was stirred at room temperature for 24 h, then concentrated under vacuum at 40° C. gave a residue which was dissolved in H2O (75 mL) and then neutralized with Na2CO3 to a pH 8. Extraction with CHCl3 (3×50 mL) and dried over anhydrous MgSO4. Evaporation of the solvent gave the L-tryptophan methyl ester as a brick-red viscous oil (5.37 g, 98%); IR (liquid film) ν 1755 (CO), 3290 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.78 (2H, s, —NH2), 3.10 (1H, dd, J=6.8 and 14.8 Hz, —CHαTrp), 3.32 (1H, dd, J=6.0 and 14.8 Hz, —CHβTrp), 3.80 (3H, s, OMe), 4.50 (1H, t, J=6.8 Hz, —CH—), 7.06 (1H, t, J=7.4 Hz, H-5′), 7.13 (1H, t, J=7.4 Hz, H-6′), 7.23 (1H, s, H-2′), 7.39 (1H, d, J=7.8 Hz, H-7′), 7.55 (1H, d, J=7.8 Hz, H-4′) and 8.47 (1H, s, pyrrol NH), which was sufficiently pure and used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]3[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=3[C:3]=12.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[N:32]1>>[C:8]([C:7]1[C:2]([NH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:32]=[CH:33]3)=[C:3]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=3[S:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc5c(cnn5Cc5ccccn5)c4)c23)C1

Procedure:
In analogy to Example 54A, the compound was synthesized from tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 53A (220 mg, 0.63 mmol) and 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine from Example 61A (141 mg, 0.63 mmol) to yield 177 mg (52%).
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)([Cl:23])=O.[CH:25]([Cl:28])([Cl:27])[Cl:26]>>[Cl-:23].[Cl-:26].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH:25]([Cl:28])([Cl:27])[Cl:26]
Reactant: O=C(Cl)Cl
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: [Cl-]
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
reacting triphenylphosphine oxide with phosgene in chloroform to produce a triphenylphosphine dichloride-chloroform adduct; and
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:30][C:14]1[CH:13]=[C:12]([C:8]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:11][NH:10][N:9]=2)[CH:29]=[CH:28][C:15]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Fc1cc(-c2n[nH]cc2-c2ccncc2)ccc1OCc1ccc2ccccc2n1

Procedure:
Following the procedure for the preparation of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (bs, 2H), 8.19 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.71 (m, 4H), 7.54 (t, J=7.1 Hz, 1H), 7.18 (m, 3H), 7.07 (m, 2H), 5.42 (s, 2H); MS: (M+H m/z=397.0).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1Cl.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C(Cl)Cl>[C:4]1([CH2:9][C:10]([NH2:15])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
A solution of 4.23 g of 3,4-dichlorophenylacetic acid in 200 ml of methylene chloride is treated at 0° C. with 3.35 g of carbonyldiimidazole. The mixture is stirred for 40 minutes. Then 2.86 g (0.0159 mole) of the (±)-amine from Example 1, Part C, above, is added. The mixture is stirred for 24 hr and partitioned with saturated aqueous sodium bicarbonate. The organic phase is dried and concentrated to yield the titled (±)-benzeneacetamide product free base which is dissolved in a minimum volume of methanol and treated with one equivalent of maleic acid which has been dissolved in a minimum volume of methanol and the mixture is diluted with diethyl ether to give the titled maleate salt, mp 152°-155° C.
Reaction SMILES: N[C@H](C=O)CCSC.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.Cl>C(O)C>[O:24]=[C:19]1[CH:20]([C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH2:21][CH2:22][O:23]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCO1
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCOC1=O
Temperature: -12.5 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
Metal sodium in an amount of 25.80 g was added to 500 ml of dried ethanol and dissolved therein. Then, 148.21 g of diethyl oxalate were added, and the reaction system was chilled to −15 to −10° C. A solution of 88.79 g of γ-butyrolactone in 60 ml of ethanol was added dropwise to the mixture while maintaining this temperature, and after the resultant mixture was stirred for 2 hours, it was stirred at room temperature for 16 hours. The reaction mixture was poured into 1 liter of ice water, and the pH of the mixture was then adjusted to 4 to 5 with concentrated hydrochloric acid, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product thus obtained was distilled under reduced pressure to give a fraction of 150 to 160° C. (5-6 mmHg) as the intended product. Pale yellow liquid, 156.21 g (yield: 83.1%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>ClCCl>[Cl:11][C:4]1[N:3]=[C:2]([NH:22][CH2:19][CH:20]=[CH2:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This was prepared by a modification of the method of Schmid, S., et al, Synthesis (2005), (18), 3107-3118. A solution of 2,6-dichloro-3-nitropyridine (8.0 g, 41.45 mmol) in anhydrous dichloromethane (180 ml) was cooled to −15° C., under argon. Triethylamine (6.0 ml, 43 mmol) was added and then allylamine (3.23 ml, 43 mmol) was added in small portions over 3 hours, keeping the temperature at −15° C. The reaction mixture was stirred overnight during which time it warmed to room temperature. The reaction mixture was washed with 0.2M aqueous citric acid (100 ml), saturated aqueous NaHCO3 solution (100 ml), passed through a hydrophobic frit and evaporated to a yellow oil which was purified by chromatography on silica eluting with a 0 to 50% ethyl acetate in hexane giving a yellow solid (7.49 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C(O)(=O)C.[Na]>O1CCCC1.C(OCC)(=O)C>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccnc(NCc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
A solution of methyl 2-aminoisonicotinate (1.52 g, 10.00 mmol), 3-(trifluoromethyl)benzaldehyde (2.09 g, 12.00 mmol) and acetic acid (0.572 mL, 10.00 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. To this reaction mixture was added sodium triacetoxyhydroborate (4.46 g, 20.00 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the title compound (1.06 g, yield 34%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1.CO>O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:22]1([CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH2:21]1)[CH2:1][C:2]2=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104 g, 485 mmol), N-Boc-piperidin-4-one (98.6 g, 494 mmol), 20 mL of pyrrolidine (17.3 g, 243 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give intended compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase:petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid was taken up in ethyl acetate and washed with 10% strength aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30]([N:7]2[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:31])=[CH:22][CH:23]=1
Reactant: CC1CCCC(CNC(=O)OC(C)(C)C)N1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2C(C)CCCC2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1

Procedure:
rac-tert-Butyl (1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6-methylpiperidin-2-yl)methylcarbamate was prepared according to general procedure A using rac-tert-butyl (6-methylpiperidin-2-yl)methylcarbamate and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][C@H:9]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])=[O:30])[C@H:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>CO>[CH3:39][C:38]([NH:42][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][C@H:9]([O:27][CH2:28][C:29]([N:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])=[O:30])[C@H:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2)([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: CCCN(CCC)C(=O)CO[C@H]1Cc2c(cccc2OCC2CO2)C[C@H]1OCC(=O)N(CCC)CCC
Solvent: CO
Product: CCCN(CCC)C(=O)CO[C@H]1Cc2c(cccc2OCC(O)CNC(C)(C)C)C[C@H]1OCC(=O)N(CCC)CCC

Procedure:
A solution of 1.5 g (0.0029 M) of cis-2,2'-[[1,2,3,4-tetrahydro-5-(oxiranyl-methoxy)-2,3-naphthalenediyl]bis(oxy)]bis-[N,N-dipropylacetamide] in 5 ml of methanol and 20 ml of t-butylamine is stirred at room temperature overnight. The solution is evaporated in vacuo to give 1.7 g of oil. This material is dissolved in ether and extracted with 5% aqueous HCl. The aqueous layer is basified with aqueous NaOH and extracted with ether. The ether is washed (saturated NaCl solution), dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a dense oil, 1.52 g.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1C=CC(C)=CC=1)[CH2:7][OH:8].BrCCCCC(C)(C)C(OCC)=O.[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:9])[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCBr
Yield: 99 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2 H, J=7.4), 3.50-3.40 (br. s, 1 H, OH), 3.22 (d, 2 H, J=5.6), 1.85 (qv, 2 H, J=7.4), 1.50-1.35 (m, 2 H), 1.30-1.20 (m, 2 H), 0.85 (s, 6 H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.