Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]([CH3:52])[CH2:31][CH2:32][N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH2:32][CH2:31][N:30]([CH3:52])[CH3:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CN(C)CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CCN(C)C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=494.3.
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.C(O)(=O)C>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([CH:39]([CH3:40])[CH3:41])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC=C(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(N)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)CC1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.1 g, 0.178 mmol) in ethanol (5 mL), 1,4-dioxane (2 mL) and acetic acid (0.051 mL, 0.890 mmol) was added 10% palladium on carbon (0.095 g, 0.089 mmol). The mixture was evacuated and refilled with nitrogen three times then was stirred under 1 atmosphere of hydrogen gas for 16 h. The mixture was evacuated and flushed with nitrogen, then was filtered through celite and was concentrated under reduced pressure to give the expected product (0.100 g, 0.178 mmol, 100% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ=5.36 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.19-4.11 (m, 2H), 2.57-2.47 (m, 1H), 2.31 (dd, J=2.9, 2.1 Hz, 2H), 2.17 (dd, J=4.6, 2.6 Hz, 2H), 2.12-0.70 (m, 52H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][NH2:14]>C(O)(C)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[NH:14][N:13]=1
Reactant: NN
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Solvent: CC(C)O
Product: Nc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-4-nitrobenzonitrile (10 mmol) in isopropanol (30 mL) was added aqueous hydrazine (4 mL). The resulting solution was heated at 80° C. for 12 h. The reaction mixture was then concentrated, water (30 mL) was added, and the solution was extracted with ethyl acetate (2×25 mL). The combined organics were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The volatiles were removed in vacuo yielding 3-amino-6-nitroindazole as an orange solid, which was utilized for further transformation without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21][CH2:20]1>>[CH2:26]([CH:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:20][CH2:21]1)[CH2:28][CH3:29])[CH3:27]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCC(CC)N1CCC(N)CC1
Product: CCC(CC)N1CCC(Nc2ccc(-c3ccc(S(C)(=O)=O)cc3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-amino-1-(1-ethylpropyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].P(Cl)(Cl)([Cl:18])=O.CN(C=O)C>S(Cl)(Cl)=O>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Yield: 81 %

Procedure:
A mixture of 7-chloro-6-nitro-3,4-dihydroquinazolin-4-one (40 g, 0.18 mol), (J. Org. Chem. 1975, 40, 356), phosphorus oxychloride (50 ml) and DMF (1 ml) in thionyl chloride (300 ml) was heated at reflux for 4 hours. The reaction mixture was allowed to cool and the volatiles removed by evaporation and by azeotroping with toluene. The residue was basified with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride (4×100 ml). The extracts were combined, washed with brine and filtered through phase separating paper. The solvent was removed by evaporation and the residue triturated with ether/isohexane to give 4,7-dichloro-6-nitroquinazoline (35.2 g, 81%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH:25][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)C(N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and Example 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 23, which can be purified in appropriate solvent.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.[C:21]([OH:26])(=[O:25])[CH:22]([CH3:24])[CH3:23].CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:39][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>C1COCC1>[CH2:43]([O:42][C:40]([CH:39]([CH3:1])[C:22]([CH3:24])([CH3:23])[C:21]([OH:26])=[O:25])=[O:41])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCOC(=O)CBr
Reactant: CC(C)C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)C(C)C(C)(C)C(=O)O
Temperature: 45 °C
Yield: 12.3 %

Procedure:
To a mixture of lithium diisopropylamide (prepared from 4.8 g, (47.8 mmol) of diisopropylamine and 19.1 ml, (2.5M, 47.8 mmol) of n-BuLi) in 50 ml of THF was added isobutyric acid (2.2 ml, 23.9 mmol) at 0° C. and the mixture was allowed to warm to 45° C. with stirring. To the mixture cooled to -78° C., was added 4.3 g (23.9 mmol) of HMPA followed by a solution of 1-octyl bromoacetate (6 g, 23.9 mmol) in 50 ml of THF under argon at -78° C. The mixture was quenched with 1N HCl, warmed to room temperature, and extracted with ether (3×50ml). The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (10% methanol/ethyl acetate) to afford 0.8 g of 3-(1-octyloxycarbonyl)-2,2-dimethylbutyric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:41](=[N:42][CH:43]=2)[N:40]([C:44]([NH2:46])=[O:45])[CH2:39][CH2:38][CH2:37]3)O1.CCOC(C)=O>O>[CH3:12][N:11]([CH3:13])[C:9]([CH2:8][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[C:36]3[C:41](=[N:42][CH:43]=2)[N:40]([C:44]([NH2:46])=[O:45])[CH2:39][CH2:38][CH2:37]3)[CH:7]=[N:6][CH:5]=1)=[O:10]
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: CN(C)C(=O)Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Yield: 7.9 %

Procedure:
2-(5-Bromo-pyridin-3-yl)-N,N-dimethyl-acetamide (73 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.30 mL, 0.60 mmol) are added into the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide 1,4-dioxane solution (3.0 mL, 0.36 mmol) which is synthesized according to the procedure for Step 3 of Example 16. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (11 mg, 0.015 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs before EtOAc (15 mL) and water (15 mL) are added. The aqueous layer is separated and extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 8.0 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A round-bottom flask was charged with 2-amino-3-nitrophenol (10.64 g, 60 mmol, commercially available from Aldrich), tert-butyl 4-(methylsulfonyloxy)-piperidine-1-carboxylate (18.05 g, 66 mmol, commercially available from AnandChem Ltd.,), DMA (100 mL) and cesium carbonate (21.6 g). The mixture was stirred at room temperature overnight. The mixture was filtered, and the recovered solid was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and combined organic solvent was washed with saturated brine, dried and concentrated under reduced pressure. The residue was triturated with ether to give tert-butyl 4-(2-amino-3-nitrophenoxy)piperidine-1-carboxylate (8.0 g, 56% yield). MS (EI): 338 (MH+).
Reaction SMILES: C1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.[C:24](=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C@H:4]1[CH2:8][C@@H:7]([CH3:24])[N:6]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=2)[C@H:5]1[CH3:9]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(F)ccc1C#N
Agent: [Li+]
Product: COc1cc(N2[C@H](C)C[C@H](O)[C@@H]2C)ccc1C#N

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,5-dimethylpyrrolidin-3-ol 0.5 oxalate (62 mg), 4-fluoro-2-methoxybenzonitrile (70 mg) and lithium carbonate (63 mg), the title compound was obtained as a colorless solid (yield: 7 mg, yield: 7.3%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:13]([O-:15])=[O:14])[C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=O.[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[OH:12][C:6]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]([CH:1]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[O:33])[NH:31]2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=Cc1cc(C(=O)O)c(O)c([N+](=O)[O-])c1
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(C(=O)O)c(O)c([N+](=O)[O-])c2)N1
Temperature: 78 °C
Yield: 18.5 %

Procedure:
A mixture of 5-formyl-2-hydroxy-3-nitrobenzoic acid (Intermediate 55) (200 mg, 0.95 mmol), 1,2-diphenylethanone (185.8 mg, 0.95 mmol), urea (170.5 mg, 2.84 mmol), concentrated hydrochloric acid solution (0.3 mL) in ethanol (2 mL) was refluxed at 78° C. for 33 h. The reaction mixture was evaporated in vacuo, and purified by preparative HPLC to give Compound 110 (75.7 mg, yield 18.5%). 1H NMR (DMSO-D6, 400 MHZ): δ 8.78 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.26-7.19 (m, 5H), 7.04-6.99 (m, 3H), 6.81 (d, J=6.4 Hz, 2H), 5.27 (d, J=2.8 Hz, 1H); MS (ESI): m/z 432.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[C:26]3[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH:23]=2)=[CH:16][CH:15]=1)=[N:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:32]([O:35][C@@H:36]1[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[O:45][C@@H:37]1OC(=N)C(Cl)(Cl)Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>ClCCl>[C:32]([O:35][C@@H:36]1[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[O:45][C@H:37]1[O:31][C:27]1[C:26]2[C:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:2]([NH2:1])=[N:3][C:4]([O:6][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:5])=[CH:15][CH:16]=3)=[CH:23][O:24][C:25]=2[CH:30]=[CH:29][CH:28]=1)(=[O:34])[CH3:33]
Reactant: NC(=NC(=O)OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(N)=NC(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.9 %

Procedure:
To a mixture of 3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)-4-hydroxybenzofuran (30 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (43 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.009 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-2/3) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)benzofuran (42 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)-4-(β-D-glucopyranosyloxy)benzofuran (20 mg). This material was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: C[Mg]I
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3R)-3-(trityl-amino)-pentan-2-one (0.87 g, 1 eq, 2.54 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in ether, 2.54 mL, 3 eq, 7.62 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.21 g (23%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.26 (t, J=7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.00 & 1.25 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 0.72-1.43 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.84 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 2.90 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH (CH2CH3)C(CH3)2OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.NC1C=C(Cl)C=CC=1CO.C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CN(C=O)C>[NH2:1][C:2]1[C:3](/[CH:29]=[CH:28]/[C:27]([O:31][CH3:32])=[O:30])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: C=CC(=O)OC
Agent: Nc1cc(Cl)ccc1CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncc(Cl)cc1N
Yield: 63.6 %

Procedure:
A solution of 3-amino-2-bromo-5-chloropyridine (2.257 ml, 19.96 mmol), Reactant 2 (0.283 g, 0.399 mmol), triethylamine (3.03 g, 29.9 mmol) and methyl acrylate (3.44 g, 39.9 mmol) in 5 mL of DMF was heated at 145° C. under microwave irradiation for 35 min. The reaction mixture was evaporated to dryness and was loaded to flash column (DCM to DCM/EA=10:1) to give 1.98 g of pure (E)-methyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (2.7 g, 12.70 mmol, 63.6% yield) as a light yellow solid and 820 mg of less pure product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.01 (d, J=1.8 Hz, 1H), 7.72 (d, J=15.1 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.92 (d, J=15.3 Hz, 1H), 4.02 (br. s., 2H), 3.81 (s, 3H).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:40][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:31][CH2:32]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Formaldehyde (37 wt % in H2O; 8.8 μL, 0.12 mmol) was added to a solution of 1-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (2) (20 mg, 39 μmol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added in one portion and stirring continued for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and the volatiles were removed under reduced pressure. The residue was dissolved in DCM (1 mL) to which cyclohexane (5 mL) was added to form a cloudy suspension. The solvent was removed in vacuo and the resulting solid was dried under high vacuum to give the title compound 3 as a white powder (18 mg, 88%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.40-7.27 (m, 3H), 7.22 (dd, J=14.4, 8.0 Hz, 3H), 6.99 (s, 1H), 6.01 (s, 1H), 3.21-3.05 (m, 4H), 2.88 (d, J=10.9 Hz, 2H), 2.50-2.30 (m, 1H), 2.21 (s, 3H), 1.99 (s, 2H), 1.79-1.58 (m, 4H), 1.44 (s, 2H), 0.97 (s, 2H). LCMS-A: 5.028 min; m/z 524 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([F:24])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:25]([CH:27]1[CH2:30][CH:29]([C:31](Cl)=[O:32])[CH2:28]1)[CH3:26].C(C1CC(C(Cl)=O)C1)CCCCCCC>>[CH2:25]([CH:27]1[CH2:30][CH:29]([C:31]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([F:24])[CH:10]=3)=[CH:3][C:2]=2[F:1])=[O:32])[CH2:28]1)[CH3:26]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Reactant: CCC1CC(C(=O)Cl)C1
Agent: CCCCCCCCC1CC(C(=O)Cl)C1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)C3CC(CC)C3)c(F)c2)cc1F
Yield: 70.2 %

Procedure:
Except that 0.60 g of 3,3'-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.3 g of 3-ethylcyclobutanecarboxylic acid chloride obtained in Example 13-(d) in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=4/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.56 g (yield 30.9%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl 3-ethylcyclobutanecarboxylate.