Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)=[O:2].Cl.[CH3:15][O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][O:16][C:17]([C:19]1([NH:28][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([CH:1]=[O:2])[CH:4]=2)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(C=O)c2)Cc2ccccc2C1

Procedure:
3-Formyl-4-methoxy-benzoic acid (F. D. Chattaway and F. Calvet, J. Chem. Soc. (1928), 2913-2918) (1.017 g, 5.65 mmol) was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 4 of example 3. The obtained product (1.895 g) was dissolved in acetic acid (20 ml), sodium acetate (0.57 g, 6.96 mmol) was added and the mixture was stirred under reflux for 24 h. The volatiles were evaporated in vacuo, the residue partitioned between a saturated sodium hydrogencarbonate solution and EA, and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated to dryness to yield 1.52 g of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Yield: 52.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (231 mg) was obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:18](I)[CH3:19]>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH2:18][CH3:19])[CH:16]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCI
Reactant: O=c1ccc(C2=CCC3(CC2)OCCO3)c[nH]1
Product: CCn1cc(C2CCC3(CC2)OCCO3)ccc1=O

Procedure:
The title compound was prepared as a white solid from the ethylation of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-1H-pyridin-2-one with EtI (Aldrich) using the procedure described in Step B of Example 38.
Reaction SMILES: [OH:1][C@@:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[OH:1][C@@:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[NH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccnn2COCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
(S)-6-(3-Hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinamide (Stage 13.1), ethylenediamine (57.3 μL, 0.848 mmol) and 1 M TBAF in THF (848 μL, 0.848 mmol) was added to a MW vial, which was sealed and the RM was stirred at 80° C. for 24 h. The solvent was evaporated off under reduced pressure to give a residue which was dissolved in EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to yield the title compound as a white solid. HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent: n-heptane/EtOH/MeOH (80:12:8), 1 mL/min, UV 210 nm) tR=13.92 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=448.2 [M+H]+, m/z=446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 3H) 1.65-1.81 (m, 2H) 3.01 (d, J=11.54 Hz, 1H) 3.07 (d, J=10.92 Hz, 1H) 3.24-3.33 (m, 1H) 3.43-3.53 (m, 1H) 4.64-4.75 (m, 1H) 6.34-6.41 (m, 1H) 7.34 (d, J=8.66 Hz, 2H) 7.52-7.84 (m, 1H) 7.86 (d, J=9.16 Hz, 2H) 8.00-8.07 (m, 1H) 8.69-8.78 (m, 1H) 10.19 (s, 1H) 12.89-13.13 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)=[O:4].[Li+].[OH-].O.[CH3:17]O>>[CH3:17][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=2)[NH:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Yield: 95 %

Procedure:
A solution of 1H-indazole-5-carboxylic acid methyl ester (8 g, 42.1 mmol), LiOH (5.05 g, 211 mmol), in methanol (100 mL) and water (35 mL) was stirred at room temperature for 20 hours. At the end of this time the reaction mixture was concentrated, the aqueous residue was acidified (pH˜6) using 10% aqueous citric acid (150 mL) and filtered the solid to obtain the crude product, which was washed with water (3×30 ml) and dried well to give the title compound (7 g, 95%) as a pale brown solid. 1H NMR (CDCl3): δ 8.5 (s, 1H), 8.0-8.1 (d, 1H), 7.45-7.55 (d, 1H), 2.5-2.66 (s, 3H),
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].S1C2C=CC(N)=CC=2N=C1>>[CH:1]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2cc([N+](=O)[O-])ccc2s1
Agent: Nc1ccc2scnc2c1
Product: CC(C)c1nc2cc(N)ccc2s1

Procedure:
2-Isopropylbenzo[d]thiazol-5-amine was prepared from 2-isopropyl-5-nitrobenzo[d]thiazole similar to that described in the preparation benzo[d]thiazol-5-amine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].BrC[C:12]1[CH:13]=[C:14]([B:18]([OH:20])[OH:19])[CH:15]=[CH:16][CH:17]=1.O>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C@H:3]([O:5][C:12]1[CH:13]=[C:14]([B:18]([OH:20])[OH:19])[CH:15]=[CH:16][CH:17]=1)[CH3:4]
Reactant: OB(O)c1cccc(CBr)c1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1cccc(B(O)O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 135 %

Procedure:
A solution of (R)-1,1,1-trifluoropropan-2-ol (212 mg) in N,N-dimethylformamide (1.5 ml) was cooled to 0° C., sodium hydride (74 mg, 60 wt. % oil dispersion) and 3-(bromomethyl)phenyl boronic acid (100 mg) were sequentially added thereto, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture were added water and an 1M aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the titled compound (147 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCc1ccccn1
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Product: CCOC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1a, using 5-bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAS Registry No. 862111-61-3) and 2-(hydroxymethyl)-pyridine as starting materials, MS (ISP) 407.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1.[Cl:24][C:25]1[C:38]([N:39]=[C:40]=S)=[C:37]([Cl:42])[CH:36]=[CH:35][C:26]=1[CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:20])[F:21])[CH2:15][CH2:14]2)=[CH:6][C:7]2[N:11]([CH3:12])[C:40]([NH:39][C:38]3[C:37]([Cl:42])=[CH:36][CH:35]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]=3[Cl:24])=[N:10][C:8]=2[CH:9]=1)=[O:23]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1

Procedure:
The sub-title compound is prepared in analogy to 6c from methyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoate (1.60 g, 4.82 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.53 g, 4.82 mmol), DIC (0.82 mL, 5.3 mmol) and DMF (20 mL). Yield: 2.54 g. HPLC Rt=1.42 min (method A). MS m/z: 614 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH3:20])[CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:51][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH3:20])[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:51])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(N)c1
Yield: 4 %

Procedure:
2-Bromo-4-[5-(4-fluoro-phenyl)-3-methyl-3H-imidazol-4-yl]-pyridine (460 mg, 1.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (254 mg, 0.28 mmol) and 2-(dicyclohexylphosphino)biphenyl (252 mg, 0.72 mmol) are mixed in dry THF (10 mL). Then Argon is bubbled through the solution for 5 min and 1.0 M LiHMDS (4.8 mL, 4.8 mmol) is added. Then the reaction mixture is heated at 65° C. for 16 hrs before the saturated NH4Cl aqueous solution (20 mL) is added along with water (25 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 15 mg of desired product.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.I[CH2:39][CH2:40][OH:41]>C(Cl)(Cl)Cl.CO>[OH:41][CH2:40][CH2:39][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1
Reactant: OCCI
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cc3)oc3ccccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](NCCO)CC1
Temperature: 25 °C

Procedure:
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(4-chlorophenyl)benzofuran-2-carboxamide hydrochloride (150 mg) obtained in Example 225 is suspended in acetonitrile/methanol (5/1, 6 ml), and thereto is added triethylamine (93 μl), and the mixture is stirred at room temperature for several minutes. The reaction solution is cooled with ice, and thereto is added 2-iodo-ethanol (29 μl), and the mixture is stirred at 50° C. for 3 hours. 2-Iodo-ethanol (58 μl) is further added thereto, and the mixture is stirred at 50° C. for 3 hours. Again, 2-iodo-ethanol (58 μl) is added thereto, and the mixture is further stirred at 50° C. for 15 hours. The reaction solution is concentrated under reduced pressure, and to the residue are poured water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate, then ethyl acetate/methanol=20/1) to give trans-3-[4-(2-hydroxyethylamino)cyclohexylcarbonylamino]-N-(4-chlorophenyl)benzofuran-2-carboxamide (104 mg). This product (104 mg) is dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure, and the resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (95 mg).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[N:11]=1)=[O:13]
Reactant: CN1CCNCC1
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(C(=O)NCc3cc(Cl)cc(Cl)c3)c(O)c3ncccc23)CC1

Procedure:
To a solution of 5-bromo-N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 50 (25 mg, 0.060 mmol), N-methyl piperazine (35.2 mg, 0.35 mmol) in DMF (0.25 ml) was heated at 135C for 48 hrs. The reaction mixture was diluted with DMF (0.25 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:4]=2[N:3]=1.[Cl:21]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]=3[N:3]=[C:2]2[Cl:21])=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)c(O)nc1c3ccccc3oc21
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: COc1ccc2c(c1)c(Cl)nc1c3ccccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 25B in stead of 19B.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(Br)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(Br)c3ccccc3)CC2)c1

Procedure:
Example 9 was prepared from bromo (phenyl)aceticacid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 500.0 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[C@@H:4]([CH3:22])[C@@H:5]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])=[O:2].N1C=CC=CC=1.FC(F)(F)C(O[C:41]1[C:46]([F:47])=[C:45]([F:48])[C:44]([F:49])=[C:43]([F:50])[C:42]=1[F:51])=O>ClCCl>[CH:1]([N:3]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[C@@H:4]([CH3:22])[C@@H:5]([CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[C:6]([O:8][C:41]1[C:42]([F:51])=[C:43]([F:50])[C:44]([F:49])=[C:45]([F:48])[C:46]=1[F:47])=[O:7])=[O:2]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O)N(C=O)OC1CCCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Reaction time: 6 h
Yield: 59.5 %

Procedure:
To a solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid (3.65 g, 0.009 mol) in dichloromethane (20 mL) at 25° C. is added via syringe pyridine (0.87 g, 0.011 mol) followed by pentafluorophenyl trifluoroacetate (3.1 g, 0.011 mol). The mixture is stirred for 6 h, diluted with dichloromethane and washed with 0.1 M aqueous HCl, 1 M aqueous sodium carbonate, saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo followed by chromatography on silica gel with hexanes-EtOAc (2:1) as eluent gives 3.05 g (60%) of pentafluorophenyl (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoate as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:36]>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:36][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCN3CCOCC3)cc12
Product: O=c1[nH]c2nccc(Nc3c(Cl)ccc4c3OCO4)c2c2ccc(OCCN3CCOCC3)cc12
Yield: 6.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using 222 (90 mg, 0.25 mmol) and 5-chloro-benzo[1,3]dioxol-4-ylamine (56 mg, 0.33 mmol) to provide 225 (8 mg, 6% yield) as a white solid. LC-MS (M+H=568, obsd.=568).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:18]#[N:19].[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH:31]1[CH2:33][O:32]1>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([CH2:33][CH:31]([OH:32])[C:22]4[CH:23]=[CH:24][C:25]5[C:26](=[O:30])[O:27][CH2:28][C:29]=5[C:21]=4[CH3:20])[CH2:16][CH2:17]3)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:18]#[N:19]
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC3CCc4c3ccc(F)c4C#N)CC2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
5-Fluoro-1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-indene-4-carbonitrile (60 mg, 0.23 mmol), 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (88 mg, 0.46 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2.5 mL). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 120° C. for 1 hour; LC indicated formation of some desired product. The tube was again placed in a microwave reactor and heated again at 150° C. for 30 min; LC indicated formation of more product. The solution was concentrated to dryness, re-dissolved in DCM (20 mL) and was then absorbed into silica gel. It was then loaded onto a silica column for separation with the solvent system of (10% MeOH in DCM), to give 5-fluoro-1-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-2,3-dihydro-1H-indene-4-carbonitrile. LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([C:33](OCC)=[O:34])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12.[Cl-].[NH4+]>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([CH:33]([OH:34])[CH2:1][CH3:2])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12
Reactant: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21

Procedure:
Under an argon atmosphere, ethylmagnesium bromide (1 M THF solution, 11.8 mL) was added to a suspension of ethyl 8-(3,4-difluorophenoxy)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1200 mg) in THF (12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (400 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[CH:11](N)=[O:12]>>[OH:10][C:3]1([CH2:2][NH:1][CH:11]=[O:12])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1
Reactant: CN1CCC(O)(CN)CC1
Reactant: NC=O
Product: CN1CCC(O)(CNC=O)CC1
Temperature: 145 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
A mixture of 50 g (0.35 mole) of 4(aminomethyl)-1-methyl-4-piperidinol and 15.8 g (0.35 mole) of formamide was stirred at 145° C. for 6 hr and allowed to stand overnight. The mass spectra indicated the starting amine was still present. The reaction mixture was reheated to 160° C. and stirred for 1 hr. The heat was removed and 150 ml of toluene was added. On cooling 61 g of crystals were formed, m.p. 116°-122° C. A 5 g sample was recrystallized from toluene to give 4.2 g of the title compound, m.p. 122°-124° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)=[O:2].[N+:27]([CH:29](S(C1C=CC(C)=CC=1)(=O)=O)[CH:30]([CH3:32])[CH3:31])#[C-:28].C[O-].[Na+]>CO>[CH:30]([C:29]1[N:27]=[CH:28][O:2][C:1]=1[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)([CH3:32])[CH3:31]
Reactant: COC(=O)/C=C/c1ccc(Oc2c(C=O)sc3cc(OC)ccc23)cc1
Reactant: [C-]#[N+]C(C(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ocnc3C(C)C)sc3cc(OC)ccc23)cc1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.081 mmol) and 1-((l-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (38.7 mg, 0.163 mmol) in MeOH (1.5 mL) at room temperature was added NaOMe (13.20 mg, 0.244 mmol) as a solid. The resulting mixture was warmed to 80° C. for 3 h after which time the reaction was quenched by addition of brine and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-(4-isopropyloxazol-5-yl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (10 mg, 0.022 mmol, 27% yield) as a yellow oil. LC/MS (m/z, MH+): 450.0.