Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C@H:11]2[C@:2]1([OH:17])[C:3]([CH3:16])([CH3:15])[O:4][C:5]1[C:10]2=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.Cl([O-])(=O)(=O)=O.[Li+].[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1.C(O)(=O)/C=C\C(O)=O>O1CCOCC1.C(OCC)(=O)C.C(O)C>[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH:31][C@H:11]2[C:10]3[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=3)[O:4][C:3]([CH3:15])([CH3:16])[C@@H:2]2[OH:17])=[CH:27][CH:26]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@H]2O[C@]21O
Agent: O=C(O)/C=C\C(=O)O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@H](NCCc2ccc(F)cc2)[C@H]1O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-2,2-dimethyl-7-nitro-3-chromanol (2.07 g, 9.37 mmol) in dioxane (4 mL), lithium perchlorate (997 mg, 9.37 mmol) and 4-fluorophenethyl amine (1.47 mL, 11.3 mmol) were added, and the resulting solution was stirred at 70° C. for 3.5 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. Then, the organic phase was dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was diluted with ethanol, and a solution of maleic acid (1.20 g, 10.3 mmol) in ethanol was added dropwise thereto. The resulting solid was filtered off, and washed with ethyl acetate. The resulting solid was suspended in ethyl acetate, the resulting suspension was neutralized with 1 mol/L sodium hydroxide aqueous solution and washed with saturated sodium chloride solution. After drying the organic phase over magnesium sulfate, it was dried under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain (3R*,4S*)-4-{[2-(4-fluorophenyl)ethyl]amino}-2,2-dimethyl-7-nitro-3-chromanol (yield: 81%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=O)[CH2:5][CH2:4]1.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].P(Cl)(Cl)(Cl)=O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1([C:6]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: NNC(N)=S
Reactant: O=C(O)C1(C(F)(F)F)CC1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1nnc(C2(C(F)(F)F)CC2)s1
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (1 g, 6.5 mmol) and thiosemicarbazide (0.6 g, 6.5 mmol) in dioxane (8 mL) was heated to 90° C. To the hot reaction mixture was added phosphorus oxychloride (0.6 mL, 6.5 mmol). The reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was then cooled, diluted with ethyl acetate (10 mL) and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (15 mL), dried (Na2SO4), filtered and concentrated. The residue was triturated in hot hexanes to afford 0.5 g (37%) of the title compound. LC/MS (ESI+) m/z 210 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:40][NH:41][O:42][CH3:43]>CN(C=O)C>[CH3:43][O:42][N:41]([CH3:40])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Commercially available 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.95 g, 8.43 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.94 g, 10.1 mmol) and 1-hydroxybenztriazole monohydrate (1.25 g, 9.28 mmol) were combined in DMF (10 mL) and stirred at rt for 15 min. before adding N,O-dimethylhydroxylamine (0.987 g, 10.1 mmol), The reaction was stirred at rt overnight. The reaction was then concentrated and partitioned between saturated NaHCO3 and 20% isopropanol in CHCl3. The organic layer was dried (MgSO4) and concentrated. The crude residue was pulled through a layer of silica using CH2Cl2 and the eluting solvent. A colorless oil was isolated (0.7 g, 30%). 1H-NMR (DMSO-d6) δ 4.31-4.18 (bs, 1 H), 3.94-3.78 (m, 2 H), 3.76-3.61 (m, 4 H), 3.48 (dt, J1=11 Hz, J2=2.7 Hz, 1 H), 3.19-2.80 (m, 5 H), 1.39 (s, 9 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCC1CCCCC1

Procedure:
In the process as described in Example 2 the product of Example 7 is treated with trifluoroacetic acid to give the titled compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[OH:13].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1>>[N:14]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=2[OH:13])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1nc[nH]n1
Reactant: OCc1cc(C(F)(F)F)ccc1O
Product: Oc1ccc(C(F)(F)F)cc1Cn1cncn1

Procedure:
Following Example 21, the title compound was synthesized (1.55 g; 45%) from 2-hydroxymethyl-4-(trifluoromethyl)phenol (2.7 g) from Example 61 and 1H-1,2,4-triazole (1.07 g).
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]\[C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:11]([O:10][C:8]([C:7]1[C:14]([C:18]([F:19])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:6]=1/[CH:5]=[CH:4]\[C:3]([OH:22])=[O:2])=[O:9])([CH3:13])[CH3:12]
Reactant: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1c(/C=C\C(=O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (Z)-isopropyl 2-(3-methoxy-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate from Example 1, Part D (1.88 g, 5.94 mmol) in 20 mL of THF and 10 mL of water was added lithium hydroxide (157 mg, 6.53 mmol). The reaction was allowed to stir at ambient temperature for 3 h. The reaction was diluted with sat'd aq NaHCO3 and sat'd aq Na2CO3 to pH 8-9 and extracted with 1:1 hexane/ethyl acetate. The organics were discarded. The aqueous layer was acidified carefully with conc. HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated in vacuo to afford 1.65 g (92%) of the title compound as a white solid. 1H NMR (CDCl3): δ 7.65 (d, 1H, J=7.7 Hz), 7.60 (d, 1H, J=7.7 Hz), 7.48 (t, 1H, J=7.7 Hz), 7.19 (d, 1H, J=12.1 Hz), 6.09 (d, 1H, J=12.1 Hz), 5.25 (septet, 1H), 1.32 (d, 6H, J=6.1 Hz). LRMS (ESI): 325.19 (M+H+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:8].C1N=CN([C:31](N2C=NC=C2)=[S:32])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:7](=[S:8])[C:9]2[C:10](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:31]1=[S:32]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CNc1ccccc1C(=S)NCc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of ethyl 2-[2-{N-(3,4-dichlorobenzyl)thiocarbamoyl}anilino]acetate (4.0 g) and N,N'-thiocarbonyldiimidazole (8.97 g) was heated at 120° C. for 15 minutes, and the reaction mixture was chromatographed on silica gel (100 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and hexane to give ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetate (560 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CC(C)N1CCCNCC1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C(C)C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
1-isopropyl-1,4-diazepane (228 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 2 hours. The reaction was incomplete so the temperature was increased to 60° C. and the reaction mixture was stirred for a further 2 h. The reaction was still incomplete so the reaction mixture was stirred for a further 18 h at room temperature. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (167 mg, 42%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl[Sn](Cl)(Cl)Cl.[CH3:15][O:16]C(Cl)Cl.CCOC(C)=O>C(Cl)Cl.CCCCC>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:15]=[O:16])[C:2]1=2
Reactant: c1ccc2c(c1)CCO2
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCC
Product: O=Cc1cccc2c1OCC2
Temperature: 0 °C
Yield: 0.6 %

Procedure:
2,3-Dihydrobenzo[b]furan (Maybridge Chemicals) (25 g, 0.21 mole) was taken up in DCM (500 ml) and stirred under nitrogen at 0° C. SnCl4 (36.5 ml, 0.3 mole) was added in one portion to produce a pale yellow solution. Dichloromethyl methyl ether (18.8 ml, 0.21 mole) was then added and the solution stirred for 30 min, after which time the cooling bath was removed and the reaction poured onto ice-water (1000 ml). The organic layer was separated, washed with water (2×100 ml), 2N HCl (100 ml) and brine (50 ml), and then charcoal (30 g) and Na2SO4 were added to the solution. Filtration through Celite and evaporation gave a black oil, which was subjected to flash chromatography using 7-10% EtOAc in pentane to give the title product (190 mg, 0.01%); 1HNMR (400 MHz, CDCl3) δ: 3.24 (t, 2H), 4.75 (t, 2H), 6.93 (t, 1H), 7.40 (d, 1H), 7.59 (d, 1H), 10.2 (s, 1H); LRMS: (M+H) 149, TS+. Anal. Found: C, 72.98; H, 5.46%. C9H8O2 requires C, 72.96; H, 5.44%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C>[C:19]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: COc1ccc(CNc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (4-bromophenyl)(4-methoxyphenyl)methylamine, 1-1-c, (2 g, 6.8 mmol) in acetonitrile (25 ml) was added BOC2O (1.5 equivalents) and stirred at room temperature for 24 h. The reaction mixture was evaporated to dryness and purified over silica gel (5% MeOH/DCM) to give N-Boc-(4-bromophenyl)(4-methoxyphenyl)methylamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: OB(O)c1cccnc1
Product: COc1cccc2c(-c3cccnc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-5-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].CCCCCC.C([Li])CCC.[F:24][C:25]1[C:26]([CH:31]=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>C(OCC)C.C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][O:11][CH3:12])=[C:2]([CH:7]=1)[CH:31]([C:26]1[C:25]([F:24])=[CH:30][CH:29]=[CH:28][N:27]=1)[OH:32]
Reactant: COCOc1ccc(Br)cc1Br
Reactant: O=Cc1ncccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOc1ccc(Br)cc1C(O)c1ncccc1F
Reaction time: 0.33 h
Yield: 40.5 %

Procedure:
To a solution of 2,4-dibromo-1-methoxymethoxybenzene (3.50 g) in diethyl ether (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (8.1 ml). The mixture was stirred for 20 minutes at the same temperature, to which was added a solution of 3-fluoro-2-formyl-pyridine (1.48 g) in THF (10 ml), followed by stirring for one hour at temperatures ranging from -78° to 60° C. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-fluoropyridine (1.64 g) (Compound D-6). The physical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:21])([CH3:20])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1.N1C=CC=CC=1>CCOCC>[C:1]([NH:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:20])([CH3:21])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC(C)C(C)c1cc(NC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (0.39 g., 5 mmole) was added to a stirred solution of 0.78 g. (2.2 mmole) of 10-amino-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine in 10 ml. of dry pyridine, cooled in an ice bath. After stirring at room temperature for 18 hours, the mixture was poured into 100 ml. of ice water and exracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florisil column (60-100 mesh) and eluted with chloroform and then graded chloroform-methanol mixtures to give the pure product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[OH:12][C@@H:13]1[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[OH:12][C@@H:13]1[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N+:23]([O-:9])=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
mCPBA (0.420 g, 1.87 mmol) was slowly added to a solution of tert-butyl [(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (0.200 g, 0.510 mmol) in DCM (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was then washed with aq. Na2S2O3, followed by 1 M NaOH. The organic layer was separated, dried and concentrated under reduced pressure. The resulting residue was further purified by silica gel column chromatography (eluting with 0-30% MeOH in EtOAc) to give the sub-title compound (90 mg, 43%) as a light orange powder. LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. Found: 409.2.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].BrN1C(=O)CCC1=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCc2ccccc2)c1
Yield: 60.9 %

Procedure:
According to the procedure of Preparation 4 (b), except using tert-butyl 4-fluoro-3-methylbenzoate (6.25 g, 29.7 mmole), N-bromosuccinimide (5.75 g, 32.3 mmole), benzoyl peroxide (375 mg, 1.6 mmole), CCl4 (50 mL), and benzylamine (17 mL, 156 mmole), the title compound (5.70 g, 60%) was prepared as a yellow oil following flash chromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 316.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[CH2:33][C:34](O)=[O:35]>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[CH2:33][C:34]([NH:20][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:35])[C:29]([O:31][CH3:32])=[O:30]
Reactant: NC(c1ccccc1)c1ccccc1N1CCCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)c(OC)c1
Product: COC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)c(OC)c1

Procedure:
Prepared from α-phenyl-2-piperidino-benzylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[CH2:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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>[O:20]1[C:16]2[CH:15]=[C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)[CH:22]=[CH:21][C:17]=2[CH2:18][CH2:19]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)c1
Reactant: COc1ccc(B(O)O)cn1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide (50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.0 mg, 0.15 mmol), and tetrakis(triphenylphosphine)palladium (0) (8.8 mg, 0.0076 mmol) in 1,2-dimethoxyethane (1.0 mL) and 2 M Na2CO3 (0.2 mL) was stirred at 80° C. for 16 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 20 mg (32%) of 1-(2,3-dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.2. found 402.0 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:45]=[CH:46][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1

Procedure:
0.31 g of compound 59 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.11 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2O[C:25]([CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:26][N:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35].CC(O)=O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:35]([CH3:34])[C:25]([CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:26][N:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2-c2nnc(CCS(C)(=O)=O)o2)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1c(CCS(C)(=O)=O)nnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-{4-chloro-5-fluoro-2-[5-(2-methanesulfonyl-ethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-benzenesulfonamide (48 mg, 0.093 mmol), methylamine (13 μL, 0.372 mmol), AcOH (21 μL, 0.372 mmol), and dioxane (1.0 mL). The vial was sealed, heated to 120° C., and stirred overnight. The following day, the volatiles were evacuated in vacuo and the residue was purified via automated silica gel chromatography to afford 4-tert-butyl-N-{4-chloro-5-fluoro-2-[5-(2-methanesulfonyl-ethyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenyl}-benzenesulfonamide as a white powder: MS (ES) M+H expected 529.1, found 529.0.