Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(OC(C)C)(C)C>>[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[O:26])[CH2:22][CH2:23]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CC(C)OC(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(trifluoromethyl)-aniline and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 109-111° C. (diisopropylether)
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11](S(C)(=O)=O)[S:12]([CH3:15])(=[O:14])=[O:13].[Li+].[OH-]>CCO.O>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a mixture containing N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (31 g; 75 mmol) in EtOH (230 ml), water (115 ml) and LiOH (9 g; 375 mmol) were added. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, the solvent evaporated under reduced pressure. NH4Cl (saturated solution, 250 ml) was added and the mixture was stirred until a yellow solid precipitated. The crude product was filtered and dried under vacuum to give N-(2-iodo-4-nitrophenyl)methanesulfonamide (24 g) which was used in the following reaction without any further purification.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[OH:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][O:25][CH3:26])[C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)OC)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
9 g (0.3 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 71.6 g (0.25 mol) of methyl 3-(1-adamantyl)-4-hydroxybenzoate in 500 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. 22.8 ml (0.3 mol) of methoxymethyl chloride were then added and the mixture was stirred at room temperature for one hour. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. 67.7 g (82%) of the expected compound were recovered in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)co1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1coc(CBr)c1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A solution of 2-methyl-4-trifluoromethyl-furan (J. Heterocyclic Chemistry 1970, 7, 269-272) (340 mg, 2.26 mmol), N-bromosuccinimide (423 mg, 2.38 mmol) and azobisisobutyronitrile (19 mg, 0.11 mmol) in carbon tetrachloride (10 mL) was refluxed for 1.5 h, then allowed to cool to rt and filtered through a cotton plug. The solvent was evaporated to give 2-(bromomethyl)-4-(trifluoromethyl)furan as an orange oil (508 mg, 98%). The product was pure enough by proton NMR that no further purification was necessary. 1H NMR (400 MHz, CDCl3) δ ppm 4.46 (d, J=0.44 Hz, 2H), 6.56 (d, J=0.49 Hz, 1H), 7.77 (m, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:27]6[CH2:28][CH2:29][O:30][CH2:31][CH2:32]6)=[N:34][CH:35]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, off-white solid (100 mg, 78%), MS (ISP) m/z=519.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=O)(C)(C)C.[CH3:41][C:42]1NN=[N:44][N:43]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>C1(C)C=CC=CC=1>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1[N:24]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]=[N:22][C:21]=1[C:19]([N:14]([C@H:12]1[CH2:11][C@@H:10]([C:38]2[O:40][C:42]([CH3:41])=[N:43][N:44]=2)[CH2:9][NH:8][CH2:13]1)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:20]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Reactant: Cc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nnc(C)o3)C2)nnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (200 mg) was dissolved in toluene (5 ml), 5-methyl-1H-tetrazole (36 mg) and N,N′-dicyclohexylcarbodiimide (96 mg) were added and the mixture was stirred at 80° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:3-1:1) was concentrated under reduced pressure. The residue was dissolved in toluene (1 ml), trifluoroacetic acid (1 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, basified with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (1 ml), fumaric acid (12 mg) was added and the mixture was concentrated under reduced pressure to give the object product (85 mg).
Reaction SMILES: [OH-].[NH4+:2].II.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:8][C:7]=1[CH:22]=O>O1CCCC1>[C:22]([C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])[CH:10]=[CH:11][C:6]=1[F:5])#[N:2]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C=O)c2)c1
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2ccc(F)c(C#N)c2)c1
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Add a 28% aqueous solution of ammonium hydroxide (10 mL) and iodine (279 mg, 1.10 mmol) to a solution of 5-(4-fluoro-3-formylphenylethynyl) -nicotinonitrile, (prepared as described in PREPARATION 38), (250 mg, 1.00 mmol) in tetrahydrofuran (5 mL). After 3.25 h quench with a 5% aqueous solution of sodium bisulfite (5 mL) and extract twice with ethyl acetate. Wash the organic layers with saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate. Dissolve the crude solid in dichloromethane and add PS-TsNNH2 (3g, ˜1.2 mmol, Argonaut). Stir the mixture for 20 min and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 90:10 to 80:20 (70:30 hexanes:dichloromethane):ethyl acetate, to give the title compound as a white crystalline solid (140 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>C(O)(C)C>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:23][CH:20]([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Reactant: CC(C)N
Solvent: CC(C)O
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)-styryl]-1,3,4-thiadiazole and 2.9 g (0.05 mole) of isopropylamine are brought together in 100 ml of isopropanol and the mixture is refluxed for 7 hours. After cooling, the solvent is distilled off and the residue obtained is recrystallized from toluene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:18])=[N:10][N:9]=1.[C:19]([O:23][C:24](=[O:33])[N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].O>CN1CCCC1>[Cl:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]([CH3:32])[C:24](=[O:33])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:31][CH2:30]2)=[N:9][N:10]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Cl)c3ccccc23)CC1
Yield: 36.6 %

Procedure:
Heat a mixture of potassium carbonate (21.23 g, 153 6 mmol), 1,4-dichlorophthalazine (26 g, 128 mmol) and methyl-piperidin-4-yl carbamic acid tert-butyl ester (30.01 g, 134.4 mmol) in N-methylpyrrolidine (200 mL) at 80° C. overnight. Pour the reaction mixture into water, extract with dichloromethane, dry over Na2SO4, and concentrate under reduced pressure. Add diethylether and filter off the resulting solid (4-chlorophethalazin-1-ol from starting material impurity). Concentrate the filtrate. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate=2:1) to provide the title compound as a white solid (17.66 g, 37%). ES/MS m/z (37Cl) 377.0 (M+1).
Reaction SMILES: C(OC([N:11]1[C@H:33]([CH2:34][OH:35])[C@@H:24]([O:25]CC2C=CC=CC=2)[C@H:22]([OH:23])[C@@H:13]([O:14]CC2C=CC=CC=2)[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C.[Pd]>[NH:11]1[C@H:33]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:13]([OH:14])[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](OCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1CO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOCC
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Yield: 96 %

Procedure:
The diol (17) (580 mg, 1.2 mmol) was stirred in glacial acetic acid (30 ml) in the presence of palladium black (100 mg) under hydrogen for 3 days, by which time no starting material (Rf 0.2) remained by t.l.c. (diethyl ether). Filtration and removal of the solvent then gave a gum which was purified by ion exchange chromatography with Dowex 50(H+) followed by Amberlite CG-400(Cl-) resins to give 1,5-dideoxy-1,5-imino-D-glucitol (3) (188 mg, 95%), which was crystallized as its hydrochloride salt. m.p. 204°-205° C. (lit.* 203°-206° C.). All spectroscopic data were identical to that of authentic material. --C NMR (D2O) free base δ: 79.0, 72.1, 71.1 (3d, C-2, C-3, C-4), 61.9 (t, C-6), 61.0 (d, C-5), 49.2 (t, C-1). Hydrogen chloride salt δ: 77.1, 68.6, 67.8 (3d, C-2, C-3, C-4), 60.8 (d, C-5), 58.5 (t, C-6), 46.7 (t, C-1). [*Fleet et al., Tetrahedron 43, 979 (1987)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][C:37](=[O:38])[NH2:39])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)COc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 48 h

Procedure:
To a mixture of methyl 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]benzoate (510 mg) and potassium carbonate in DMF (10 ml) was added bromoacetamide (384 mg). The reaction was stirred for 48 hours, poured into ethyl acetate (50 ml), washed with 1M HCl (50 ml) and brine (50 ml), dried (magnesium sulphate) filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using ethyl acetate:hexane (75:25) as eluant. There was thus obtained methyl 4-[3-(2-benzyloxy-5-(carbamoylmethoxy)phenyl)propyl]benzoate (200 mg).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=465.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH:7]1OCC[O:8]1.Cl>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH:7]=[O:8]
Reactant: COC(=O)C(CCC1OCCO1)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C(CCC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of (±)-4-[1,3]dioxolan-2-yl-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-butyric acid methyl ester 35b (0.10 g, 0.253 mmol) in acetone (5 mL) at room temperature under Ar atmosphere was slowly added 5N HCl (1.5 mL). The reaction mixture was stirred for 2 h and then concentrated to remove acetone. NaHCO3 solution (100 mL) was added until the pH is greater than 9, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude product. 1H NMR (400 MHz, CDCl3) δ 2.24 (m, 4H), 2.34 (s, 3H), 2.39 (s, 3H), 3.70 (s, 3H), 4.38 (t, J=8.1 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 7.24 (d, J=7.3 Hz, 2H), 7.56 (m, 3H), 7.99 (s, 1H), 9.48 (s, 1H).
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:9]1[CH2:10][CH2:11][CH:12]([O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[CH2:13][CH2:14]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C1CC(=O)O1
Reactant: OC1CCN(CCc2ccccc2)CC1
Product: CC(=O)CC(=O)OC1CCN(CCc2ccccc2)CC1
Yield: 91.3 %

Procedure:
Similarly as in Reference Example 1, 5.40 g of 1-phenethyl-4-hydroxypiperidine and 2.65 g of diketene were reacted. The reaction mixture was concentrated, and then purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 6.95 g of acetoacetic acid-N-phenethyl-4-piperidinyl ester (yield: 91.3%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.CS(O)(=O)=O.FC1C=CC=CC=1C1OC(C([NH:36][C:37]([NH2:39])=[NH:38])=O)=CC=1>CO.[Cl-].[Na+].O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:6][C:5]([C:3]([NH:38][C:37]([NH2:39])=[NH:36])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)o1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(N)NC(=O)c1ccc(-c2ccc(F)cc2)o1
Yield: 51.4 %

Procedure:
5-(4-fluorophenyl)furan-2-carboxylic acid methyl ester (220 mg, 1.0 mmol) was dissolved in methanol (4 ml), to which 2 M guanidine solution (3.0 ml, 6.0 mmol) prepared in Example 1 was added, and the mixture was heated at reflux for 12 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane), to give 127 mg of a title compound (yield: 51%).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: [Li]CCCC
Reactant: O=Cc1ccncc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol) in THF (27 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.8 mL, 4.5 mmol). The resulting yellow reaction mixture was stirred for 30 min at −78° C. In a separate flask THF (6 ml) was added to 3-bromoisonicotinaldehyde (CAS#113118-81-3, 558 mg, 3.00 mmol). The resulting 3-bromoisonicotinaldehyde solution was the transferred, via cannula, to the phosphonium ylide mixture followed by a 2 mL THF wash. The reaction was allowed to warm to room temperature over 60 minutes and then permitted to stir for an additional 30 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated to near dryness. The resulting residue was then diluted with ethyl acetate and 1M sodium bisulfate and the layers were separated. The organic layer was extracted two additional times with 1M sodium bisulfate. The aqueous layers were combined, diluted with dichloromethane, and neutralized via the careful addition of saturated aqueous sodium bicarbonate and solid sodium carbonate. The layers were separated and the now basic aqueous layer was extracted three additional times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine; MS: (ES+) m/z 183.9 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:21]Br>ClCCl>[Br:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:8]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:9]=1
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C)cnc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(C)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.9 g, 6.62 mmol) in dichloromethane (40 mL) was treated dropwise with a solution of bromine (0.678 mL, 13.24 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was partitioned between dichloromethane (150 mL) and a 1:1 mixture of a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of Na2S2O3 (250 mL). The organic phase was separated and the aqueous phase was re-extracted twice with DCM (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as an off-white solid (2.381 g, 99% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:40])([C:36]([F:39])([F:38])[F:37])[C:10]([NH:12][NH:13][C:14]([C:16]1[C:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][C:19]([C:30]([F:33])([F:32])[F:31])=[C:18]([O:34][CH3:35])[N:17]=1)=[O:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([C:10]1[O:15][C:14]([C:16]2[C:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:20][C:19]([C:30]([F:33])([F:31])[F:32])=[C:18]([O:34][CH3:35])[N:17]=2)=[N:13][N:12]=1)([CH3:40])[C:36]([F:37])([F:38])[F:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)NNC(=O)C(C)(OCc2ccccc2)C(F)(F)F)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
A stirring suspension of tert-butyl 2-(2-(2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoyl)hydrazine carbonyl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (step 1) (1 g, 1.723 mmol) in dry THF (20 ml) was treated with Burgess reagent (3 equiv.) and heated at reflux under N2 for 1 h 45 min. The RM was reduced in vacuo to approximate volume of 5 ml and diluted with EtOAc (150 ml). The mixture was washed with 2M NaOH, 0.5M HCl, water, brine and dried (MgSO4) and concentrated in vacuo. The crude product was triturated with MeOH to afford the title compound. LC-MS Rt=1.59 min [M+H]+ 563.5 Method High pH_v003.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[C:27]([O:31][C:32](=[O:40])[N:33]([CH:35]([CH3:39])[CH2:36][CH2:37]Br)[CH3:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:40])[N:33]([CH3:34])[CH:35]([CH3:39])[CH2:36][CH2:37][CH:4]([N+:1]([O-:3])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(CCBr)N(C)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(CCC(c1ccccc1)[N+](=O)[O-])N(C)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 28.1 %

Procedure:
To a −78° C. solution of 304 mg (2.219 mmol) nitromethyl-benzene (CAS: 622-42-4) in 5 ml tetrahydrofuran over mol-sieve and 1.29 ml HMPA, was added dropwise 2.91 ml (4.654 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 590.7 mg (2.219 mmol) (3-bromo-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester in 1.5 ml tetrahydrofuran over mol-sieve was added dropwise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly, during 2 hours, to −15° C. The mixture was then cooled again to −78° C. and quenched with 0.75 ml of acetic acid, then with 13 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted two times with ethylacetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 10%) to provide 201 mg (28%) of the title compound as a colorless oil. MS (m/e): 323.3 (M+H).