Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][NH:31][C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([N:31]([C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1)[CH3:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C(C)(C)C)nc2c1C#N
Yield: 92.9 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.15 ml, 0.88 mmol) and N-methyl-tert-butylamine (0.10 ml, 0.84 mmol) were added. After heating under reflux for 3 hours, N-methyl-tert-butylamine (50.0 μl, 0.42 mmol) was added, followed by heating under reflux for 2 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a pale yellow solid (0.22 g, 0.65 mmol, 93%).
Reaction SMILES: C1C=CC=CC=1.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([SH:27])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([OH:32])=[O:31]>C(N(CC)CC)C>[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([S:27][CH2:29][C:30]([OH:32])=[O:31])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:16]=1[OH:17])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Reactant: O=C(O)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2csc(SCC(=O)O)n2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To 20 ml of benzene were added 0.64 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoacetic acid and then 0.5 g of triethylamine was added dropwise to the mixture with stirring. After one hour, triethylamine hydrobromide thus precipitated was filtered off and the benzene solution was extracted with 10 ml of a 2% sodium hydroxide solution. The aqueous extract was acidified by the addition of hydrochloric acid and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The crystals thus obtained were recrystallized from benzene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:26][N:27](C)C)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:37]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:37][NH:27][CH:26]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)c(F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccc(F)c(F)c2)ccn1
Yield: 87 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 9.28 g (23.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(3,4-difluorophenyl)-3-dimethylamino-2-propen-1-one obtained in Example 24-2) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 7.41 g of the title compound as a white powder. (Yield: 87%)
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:31][CH2:30][O:29][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Reactant: COCCBr
Product: COCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 20 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and 2-bromoethyl methyl ether. Yield: 20%. MS M+H calculated 425.19. Found 425.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[O:19])[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][C:11]([CH2:10][C:9]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:21][CH:20]=1)=[O:19])([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
0.65 g (2.1 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in Example 43(ii)] was dissolved in 20 ml of anhydrous tetrahydrofuran, and 92 mg (2.3 mmol) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting solution, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 10 minutes, after which 1.1 ml (2.5 mmol) of methyl iodide were added, whilst ice-cooling, and the mixture was stirred for 2 hours. At the end of this time, water was added to the mixture, which was then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 0.54 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:22]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:32]([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(N(C)C)=O>[CH2:22]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:32]([CH2:42][O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:31]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccccc1CCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC1COc1ccccc1CCc1ccccc1
Yield: 81.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 200 mg of 2-(2-phenylethyl)phenol (prepared as described in Preparation 19), 124 mg of potassium t-butoxide and 500 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 400 mg (yield 81%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[Cl:17][C:18]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])=[CH:26][C:18]=1[Cl:17]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: [C-]#N
Reactant: ClCCCCCCc1ccncc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCc1ccncc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
NaCN (509 mg) in DMSO (4.25 ml) is added to 4-(6-chlorohexyl)pyridine (1.71 g) dissolved in DMSO (4.25 ml). The mixture is stirred at 60° C. for 3 hours, poured into water (100 ml) and extracted with chloroform (3×15 ml). The combined extracts are washed with water (2×20 ml), dried (Na2SO4) and the solvent evaporated to give 4-(6-cyanohexyl)-pyridine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: c1ccc(-c2cc(N3CCCC3)cc(-c3ccccn3)n2)nc1

Procedure:
28 mg (<5 mol %) of zinc(II) chloride and 4.4 g (61.5 mmol) of pyrrolidine are added in succession to a mixture of 1.1 g (4.1 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine in 15 ml of 2-methyl-2-butanol. The mixture is heated at reflux for 20 hours, cooled and filtered. After recrystallisation from toluene, pure 4′-pyrrolidin-1-yl-[2,2′;6′,2″]terpyridine is obtained in the form of a white solid. MS (EI, 70 eV): m/z=303 (15); 302 (90, [M+]); 273 (100); 233 (25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[Mn]([O-])(=O)(=O)=[O:33].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:33])=[O:16])=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)c1c(S(=O)N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a suspension of ethyl N-(3,4-dichlorobenzyl)-3-morpholinosulphinylindole-2-carboxylate (803 mg) in acetone (40 ml) was added a solution of potassium permanganate (528 mg) in water (15 ml). The resulting mixture was stirred for 18 hours. The mixture was poured into water (20 ml) and extracted with diethyl ether, dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane:ethyl acetate (3:1) as eluent to give the desired product (681 mg, 82%); NMR d (CDCl3) 1.3 (t, 3H), 3.2-3.2 (m, 4H), 3.7-3.8 (m, 4H), 5.4 (s, 2H), 6.95 (d, 1H), 7.3-7.4 (m, 5H), 8.05 (d, 1H); M/z (+) 499.2 (MH+), 497.3.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.3 mL, 18.4 mmol) was added dropwise to a solution of methyl 4-(hydroxymethyl)benzoate (2.0 g, 12.0 mmol) and triethylamine (3.3 mL, 23.7 mmol) in anhydrous THF (80 ml) cooled to 0° C. A precipitate formed and the stirring was continued at 0° C. for 1 h. The mixture was diluted with hexanes (50 mL) and precipitates eliminated by vacuum filtration through a sintered funnel. Volatiles were removed by rotary evaporation. The residue was purified by flash chromatography (DCM:Hex 1:1+1% TEA) through a short silica column providing methyl 4-[(trimethylsiloxy)methyl]benzoate as a clear liquid in a yield of 2.5 g (87%). 1H-NMR (500 MHz, CDCl3): δ=0.16 ppm (s, 9H), 3.90 ppm (s, 3H), 4.74 ppm (s, 2H), 7.38 ppm (d, J=8.0 Hz, 2H), 8.00 ppm (d, J=8.0 Hz, 2H); 13C-NMR (500 MHz, CDCl3): δ=−0.41, 52.09, 64.12, 126.08, 128.90, 129.68, 146.39, 167.10 ppm. HRMS [+Scan]; calculated m/z for C12H19O3Si 239.1098; observed mass: 239.1095.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:41][OH:42]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:41][OH:42])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Intermediate (16b) (7.7 g, 17.2 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (3.6 g, 51.5 mmol) was added, followed by the addition of water (20 mL, 1 mol). The mixture was stirred at room temperature overnight. Water (50 ml) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (16c) (7.8 g). MS m/z: [M+H+] calcd for C26H28FN3O4, 466.2. found 466.4. 1H-NMR (CDCl3): 9.78 (1H, s), 7.81 (1H, d), 7.48 (2H, m), 7.26 (1H, s), 7.0 (4H, m), 6.20 (1H, d), 5.53 (1H, d), 5.50 (2H, s), 4.55 (2H, q), 1.43 (3H, t), 1.25 (9H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[H][H].[ClH:12]>O.[Pt]=O>[ClH:12].[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: OCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: OCCC1CCNCC1

Procedure:
2-(4-pyridyl)ethanol (70. g, 0.57M) and platinum oxide (2 g) in water (600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at the pressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidine hydrochloride in quantitative yield. Treatment of 4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12M) with phosphorus tribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration with diethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidine hydrogen bromide (20.76 g, 77% yield). The solution of the 4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085M) in tetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. To this solution was added formic acetic anhydride (12.7 ml) at 0° C., followed by the addition of triethylamine (25 ml) with vigorously stirring. The reaction mixture was stirred overnight. After the reaction, it was filtered and the filtrate was stripped in vacuo to dryness and water (100 ml) was then added to the residue and the mixture was extracted with diethyl ether (3×100 ml). Removal of the solvent and purification on silica gel columns, eluted with ethyl acetate-hexane (9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde (12.06 g, 66% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([S:26][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(SCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
12.8 g of 2-chloro-6-methylpyridine, 18 g of anhydrous potassium carbonate and 100 ml of dimethylsulfoxide were mixed to obtain a suspension. This suspension was preliminarily heated to a temperature of from 120° to 130° C., and 10 ml of a dimethylsulfoxide solution of 18.6 g of benzyl mercaptan was dropwise added thereto over a period of about 30 minutes. Then, the mixture was reacted at 150° C. for about one hour. Thereafter, the reaction solution was cooled, then put into water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7.53 g of oily 2-benzylthio-6-methylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH2:17][Br:35])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(C)cc2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(CBr)cc2c1=O

Procedure:
A mixture of 7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-6-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (3.5 g, 8 mmol), prepared according to the procedure outlined in PCT application WO97/14682, Reference Example 3, NBS (1.5 g, 8.4 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 100 mg) in DCM (200 mL) was stirred at reflux for 4 h. Additional NBS (750 mg) was added and the mixture was refluxed for 4 h. Column chromatography (hexanes:ethyl acetate=3:7) yielded the product as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1csc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise fuming nitric acid(90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39g, 183 mmol) in TFA(100 mL) and dichloromethane (400mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2 L). Extract with dichloromethane (3×500mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259 (M+1); 1HNMR(300 MHz, DMSO-d6) δ ppm: 7.70 (tt, 2H), 8.04 (d, 1H), 8.17 (d, 1H). 3CNMR(75 MHz, DMSO-d6) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:20])[C:12]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C:12]2([N:11]([CH3:20])[CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)C1(C(=O)O)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 200 mg, 1.57 mmol) in DMF (10 mL) were added Intermediate 99a (247 mg, 1.57 mmol), EDC (333 mg, 1.73 mmol) and HOBt (21 mg, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% (2M NH3 in MeOH) in DCM, to give the title compound (282 mg, 67%). 1H NMR (400 MHz, CDCl3): 1.54-1.73 (4H, m), 1.76-2.04 (4H, m), 2.25 (6H, s), 6.46 (1H, s), 6.64 (1H, dd, J=9.0, 3.5 Hz), 7.23-7.33 (1H, m), 8.04 (1H, d, J=3.0 Hz), 8.94 (1H, s).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([Cl:21])=[O:17])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(CC(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (3-acetoxy-4-nitro-phenyl)acetic acid (2.0 g, Reference Example 18) in dichloromethane (20 mL) was treated with a solution of oxalyl chloride in dichloromethane (4.4 mL, 2M) and then with dry dimethylformamide (1 drop). After a vigorous effervescence the mixture was stirred at room temperature for 4 hours, then evaporated to give the title compound as a viscous oil which was used immediately without further purification.