Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.CN(C)[CH:19]=[O:20]>O1CCCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:19]=[O:20])=[CH:8][N:9]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cncc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 32.5 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 11.0 ml, 17.6 mmol) is added dropwise to a stirred solution of 4-bromoisoquinoline (3.02 g, 14.5 mmol) and anhydrous tetrahydrofuran (100 ml) at −78° C. under nitrogen. The reaction is stirred for 45 min at −78° C. and then dimethylformamide (6.0 ml, 77.5 mmol) is added. The reaction is then stirred for 3 h at −78° C. before it is quenched with water. The reaction is then poured into saturated sodium bicarbonate solution (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is washed with brine and dried over sodium sulfate. The sodium sulfate is filtered and the crude product is concentrated on a rotary evaporator. The crude product is purified by flash chromatography on silica gel eluting with 50% ethyl acetate/hexanes to yield (0.74 g, 33%) of isoquinoline-4-carboxaldehyde: mass spectrum (ion spray): m/z=158.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.C1C(=O)N([Br:33])C(=O)C1.OS([O-])=O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:33][C:10]1[C:2]([Cl:1])=[N:3][C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)c1cc(Br)c(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A suspension of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (500 mg, 1.385 mmol) and NBS (250 mg, 1.4 mmol) in acetonitrile (10 mL) was stirred at overnight. The reaction mixture was treated with 1M NaHSO3 and stirred at rt for 2 h. Next, the reaction mixture was diluted with ethyl acetate and the precipitate filtered to give a solid. The organic layer of the filtrate was separated and concentrated to an additional amount of solid. The above solids were combined and triturated with 250 mL of MeOH/CH2Cl2 (˜1:1 ratio) to give 235 mg of 5-bromo-6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a grey solid. LCMS: (M+H)+=338.80, 440.83, 442.87 (Br, Cl pattern). 1H NMR (400 MHz, methanol-d3-MIX) δ ppm 8.38 (1H, s), 7.77 (2H, d, J=8.35 Hz), 7.42 (2H, d, J=8.79 Hz), 3.69 (8H, br. s.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)n1
Reactant: CNC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc2nccc(Nc3ccnc(-c4nc(C)ccc4F)c3)c2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (50 mg, 0.156 mmol) and NaH (3.75 mg, 60% in oil, 0.15 mmol) were combined in DMF (2 mL). 2-Bromo-N-methylacetamide (23.72 mg, 0.15 mmol) was added and the mixture heated in a microwave at 80° C. for 15 minutes and then at 100° C. for 30 minutes and finally at 110° C. for a further 45 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-25% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.60 (s, 3H) 2.81 (s, 3H) 5.11 (s, 2H) 7.08 (br. s., 1H) 7.41 (d, J=8 Hz, 1H) 7.50 (br. s., 1H) 7.65 (t, J=12 Hz, 1H) 7.92 (br. s., 1H) 8.08 (d, J=8 Hz, 1H) 8.28 (br. s., 1H) 8.68 (br. s., 1H) MS [M+H] found 392.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH2:9](OB(C=C)OCCCC)[CH2:10]CC.C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CN(C)C=O>[CH:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH2:10]
Reactant: O=Cc1cc(Br)co1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CN(C)C=O
Product: C=Cc1coc(C=O)c1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (1.1 g, 6.29 mmol) and vinylboronic acid dibutyl ester (1.67 mL, 7.54 mmol) using the same conditions used to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that the reaction was run in N,N-dimethylformamide (DMF) (20 mL). Purification by flash chromatography (0-30% EtOAc in heptane) provided 4-vinylfuran-2-carbaldehyde as an orange oil; Yield 282 mg (37%). 1H NMR (400 MHz, CDCl3) δ ppm 5.31 (dd, J=10.88, 0.93 Hz, 1 H), 5.61 (dd, J=17.57, 0.54 Hz, 1 H), 6.56 (dd, J=17.55, 10.91 Hz, 1 H), 7.37 (s, 1 H), 7.67 (s, 1 H), 9.66 (d, J=0.59 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C1COCC1>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:15]
Reactant: CC(C)=CC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice bath cooled solution of 1.66 g (69.2 mmol) of NaH (60% suspension in mineral oil) in 25 ml of dry THF was added slowly under argon a solution of 10.0 g (57.8 mmol) of 4-bromophenol in 50 ml of dry THF. The mixture was stirred at 0 degrees C. for 30 minutes and then treated with a solution of 6.85 g (6.44 ml, 57.8 mmol) of dimethylacryloyl chloride in 25 ml of dry THF. The cooling bath was then removed and the mixture allowed to warm to room temperature. The organic layer was separated and the aqueous layer was washed with 2×25 ml of ether. The combined organic layers were washed with 2×50 ml of water, brine and dried (MgSO4). The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2 ; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:24][C:25]1[CH:30]=[CH:29][C:28](C2C=CC(F)=CC=2F)=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([O:24][C:25]1[CH:30]=[C:29]([C:54]([F:57])([F:56])[F:55])[CH:28]=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate was prepared in a similar fashion as ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C32H39F3O4=544.64; found: [M+Na]+=567.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[OH:32][NH2:33].Cl.N1C=CC=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:33][OH:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 70 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
3-Phenyl-6-(3-phenylpropyloxy)-1-oxo-1H-indene-2-carboxylate ethyl ester (2 g, 4.85 mmol) and hydroxyamine.hydrochloric acid (1.01 g, 14.6 mmol) were dissolved in pyridine (1.57 ml, 19.4 mmol). The reaction mixture was stirred for 1 hour at 70° C., and washed with saturated ammonium chloride. The organic layer obtained by extracting the reaction mixture with ethyl acetate was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1-hydroxyimino-3-phenyl-6-(3-phenylpropyloxy)-1H-indene-2-carboxylate ethyl ester (yield 9.5%) as a yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (2.00 g, 7.29 mmol) and triethylamine (4.07 mL, 29.2 mmol) in tetrahydrofuran (70 mL) was added acetic anhydride (828 μL, 8.75 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (1.65 g, yield 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=O)[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([Cl:20])=[O:17])[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C2(C(=O)O)CC2(Cl)Cl)cc1
Reactant: O=S(Cl)Cl
Product: CCOc1ccc(C2(C(=O)Cl)CC2(Cl)Cl)cc1

Procedure:
The 1-p-ethoxyphenyl-2,2-dichlorocyclopropane-1-carboxylic acid (1.38 g) was refluxed on a water bath with thionyl chloride (1.19 g) for 15 minutes. The excess thionyl chloride was then evaporated under vacuum (1 Torr.) and the residue of carbonyl chloride reacted without further purification with one of the alcohols (a), (b), (c) or (d). ##STR11##
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:32][CH3:33])[CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:33])[C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNc1cc(C)cc(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N(C)C(=O)CCN(C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (550 mg, 4.04 mmol) in dichloromethane (5 mL) was cooled to 0° C., triethylamine (1.12 mL, 8.08 mmol) was added followed, after 5 min, by (4,6-dimethyl-pyridin-2-yl)-methyl-amine (1.14 g, 4.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min then partitioned between water and dichloromethane. The organic phase was separated, washed with saturated bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate in hexane as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide (600 mg, 43%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: OCCc1ccco1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccco2)cc1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To a stirred solution of 2-furan-2-yl-ethanol (1.6 g, 14.0 mmol) in a mixture of pyridine (5 mL) and chloroform (15 mL) was added para-toluenesulfonyl chloride (5.5 g, 28.0 mmol) and heated at 60° C. for 3 hrs. The reaction was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, sat. sodium bicarbonate solution and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the crude compound purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate/petroleum ether as eluent to afford toluene-4-sulfonic acid 2-furan-2-yl-ethyl ester (2.0 g, 32%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[N:21]=[CH:20][C:19]([I:22])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(I)cnc1Cl
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, methyl 2-chloro-5-iodonicotinate (J. Org. Chem. 1989, 54, 3618, 594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by flash column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (2/1) to afford 644 mg (86%) of the title compound: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.3 Hz), 8.41 (1H, s), 7.09 (4H, d, J=6.2 Hz), 3.95 (3H, s); MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ncccn2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-pyrimidinyl)tin 54 were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 429 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:17])=[C:11]([N+:1]([O-:4])=[O:2])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccc(Br)cc2o1
Solvent: ClC(Cl)Cl
Product: O=c1oc2cc(Br)ccc2c(O)c1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (27 ml) was added to a stirred suspension of 7-bromo-4-hydroxycoumarin (m.p. 247.5°-248.5°; 4.18g) in chloroform (400 ml) at room temperature over 1.5 hours. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (100 ml) added to the residue. Filtration gave the product, m.p. 155°-7°, (C9H4NO5Br requires C, 37.79; H, 1.41; N. 4.90; Br, 27.94. Found: C, 37.46; H, 1.45; N, 4.78; Br, 27.93).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[N:25]1([C:29]([O-:31])=[O:30])[CH2:28][CH2:27][CH2:26]1>>[C:7]([O:30][C:29]([N:25]1[CH2:28][CH:27]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:26]1)=[O:31])([CH3:8])([CH3:2])[CH3:6]
Reactant: O=C([O-])N1CCC1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 9.170 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidinecarboxylate and 11.00 g of tertbutyl 3-toluenesulphonyloxy)azetidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=023 (3:1 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:22][C:2]([F:21])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:32]([O:33][CH3:34])=[O:35])=[CH:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of methyl 2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylate (8.19 g, 25.81 mmol) in DCM (100 mL) was added DIPEA (5.40 mL, 30.97 mmol) followed by methyl carbonochloridate (2.236 mL, 28.39 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to give a yellow oil. Dimethyl 2-(4-(trifluoromethoxy)benzyl)piperidine-1,4-dicarboxylate (9.72 g, 100%) was isolated. MS m/z 376 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:44]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[CH2:45][CH2:46][CH3:47])[CH2:42][CH3:43]>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:44]([CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42][CH3:43])=[CH:50][CH:51]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
In chloroform (20 ml) and DMF (8.0 ml), 4-(t-butoxycarbonylaminomethyl)benzoic acid (1.95 g) was dissolved. Then, the solution was added with WSCI hydrochloride (1.50 g) and HOBt (1.08 g), followed by stirring at room temperature at 1 hour. The reaction solution was added with the compound (1.23 g) obtained in Example 19-2 and chloroform (10 ml), followed by stirring at room temperature for 15 hours. The solvent was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (2.86 g) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Zn]>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Na+]
Agent: [Zn]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A three-necked 250-mL round bottom flask equipped with a magnetic stirrer, thermocouple and condenser was charged with of 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (10.0 g, 41.1 mmol), sodium cyanide (2.26 g, 44.6 mmol, ground prior to use), zinc (0.815 g, 12.3 mmol, 23.6 meq, particle size −200 mesh (−74 μm)) and [1,1′-bis(diphenylphosphino)ferrocene][(1,2,5,6)-1,5-cyclooctadiene]nickel (prepared by the method of Reference Example 2) (0.297 g, 0.41 mmol) under a nitrogen atmosphere in a glovebox. The flask was removed from the glovebox and swept with nitrogen for 1 h, after which time oxygen-free acetonitrile (48 mL) was added by syringe. The reaction mixture was heated at 80° C. for about 3 h. After 3 h, HPLC analysis of the reaction mixture indicated complete conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product and 2-amino-N,3-dimethylbenzamide a minor product (molar ratio 98.5 to 1.5). Toluene (55 mL) was added to the reaction mixture, and most of the acetonitrile solvent was removed by distillation at atmospheric pressure (67 mL of distillate boiling at 80-82° C. was collected). Toluene (20 mL) and water (20 mL) were added to the concentrated reaction mixture, and the mixture was heated at reflux for 1.5 h, and then cooled to room temperature and filtered. The solid collected was washed with water (90 mL) and dried under vacuum at 45° C. to give the title compound as an off-white powder (7.96 g, 91.4% purity by HPLC, 93.4% yield).
Reaction SMILES: C(OC([N:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[NH:12]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>C(O)C>[NH:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[NH2:12]
Reactant: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)C1(NN)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
To a solution of the compound of Example 1 (1.00 g) in ethanol (30 ml) was added 5% palladium-carbon ethylenediamine complex (100 mg). The mixture was stirred vigorously at room temperature under hydrogen (atmospheric pressure) for 2.5 hours. During this reaction, to remove carbon dioxide generated with the progress of the reaction, the gas in the reactor was replaced with hydrogen gas several times. The reaction mixture was filtered through a Celite pad and then the Celite was washed with ethanol. The filtrate combined with the washers was concentrated to give the desired product (432 mg, quantitative) as oil