Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH2:23])[C:7]=2[CH:24]=1.[CH3:25][CH2:26]N=C=NCCCN(C)C.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([OH:51])=O)=[O:46])=[O:42])([CH3:39])(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:49](=[O:51])[CH2:48][NH:47][C:45](=[O:46])[CH2:44][NH:43][C:41]([O:40][CH2:36][CH2:39][CH2:25][CH3:26])=[O:42])[C:7]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc2c(c1)[C@@H](N)CCc1cc(OC)c(OC)c(OC)c1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)NCC(=O)NCC(=O)N[C@H]1CCc2cc(OC)c(OC)c(OC)c2-c2ccc(OC)cc21
Yield: 65 %

Procedure:
A solution of (5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine [Collect. Czech. Chem. Commun. 1999, 64(2), 217-228] (0.329 g; 1.36 mmol), EDCI (0.230 g; 1.2 mmol); DMAP (0.025 g, 0.2 mmol) and 2[2-(tert-butoxycarbonylamino)acetylamino]acetic acid (0.189 g; 1.2 mmol) in dichloromethane was stirred under argon atmosphere overnight. The resulting precipitate was filtered and washed with ether to give N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-(butoxycarbonylamino)acetylamino]acetamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[O:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: COc1ccc(C(=O)O)cn1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)cn1
Temperature: 20 °C
Yield: 61.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 6-methoxypyridine-3-carboxylic acid (4.7 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (9.1 g). The product produced by precipitation in water (11 g; m.p. 115° C.) is dissolved in boiling acetonitrile (50 cc). After 10 hours' cooling at 20° C., the crystallised solid is separated by filtration, washed with diisopropyl ether (3×10 cc) and dried at 30° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-6-methoxypyridine-3-carboxamide (7 g) is produced, m.p. 115°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.021 g) in methylene chloride (1 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour and 10 minutes. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 7 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.013 g of 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C>[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH:67][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH2:62][CH2:61]1
Reactant: CN1CCC(CN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC1CCN(C)CC1

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (300 mg, 0.48 mmol), DIPEA (136 mg, 2.2 eq.) and C-(1-methyl-piperidin-4-yl)-methylamine TFA salt (186 mg, 1.1 eq.) in DMF (5 mL) was stirred at rt for 72 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:27][CH:28]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[CH:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1>CN(C=O)C>[F:49][C:47]1[CH:48]=[C:43]([CH:44]=[C:45]([F:50])[CH:46]=1)[CH2:42][C@H:28]([NH:27][C:1]([C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:12])[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1
Reactant: CCc1cccc(CNCC(O)C(N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)OCO3)c1
Reaction time: 8 h

Procedure:
To a solution of piperonylic acid (0.500 g, 3.01 mmol), EDC (0.867 g, 4.52 mmol), HOBT (0.611 g, 4.52 mmol) in anhydrous DMF (10 mL) was added a solution of TEA (1.67 mL, 12.04 mmol), 3-Amino-4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzylamino)-butan-2-ol (1.693 g, 3.01 mmol), and anhydrous DMF (5 mL). Reaction mixture was stirred under nitrogen overnight. Quenched reaction mixture with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate. Washed organic layer with 1N HCl, followed by a wash with 10% sodium bicarbonate (aq.). Dried organic layer over magnesium sulfate, filtered, then concentrated in vacuo, yielding the product. (ES+: 483.2)
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][C:11]=1[C:22](=[O:24])[CH3:23].Cl.[CH3:26]COCC>>[CH:16]1([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([C:22]([CH3:26])([C:23]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[OH:24])[CH:12]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)c1cc(C2CCCCC2)ccc1O
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Agent: Cl
Product: CC(O)(c1ccccc1)c1cc(C2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 ml of an ether solution titrating 0.76 M/liter of phenyl magnesium bromide were added over 1 hour to a mixture of 23.4 g of the product of Step A and 230 ml of anhydrous ether and the mixture was stirred for 16 hours at room temperature and was poured over ice. The mixture was acidified with 200 ml of 2 N hydrochloric acid and was extracted 3 times with 250 ml of ether. The organic phase was washed 3 times with 100 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was taken up in 120 ml of petroleum ether (b.p.=60° to 80° C.) and the mixture was vacuum filtered. The product was dried to obtain 22.55 g of 5-cyclohexyl-2-hydroxy-α-methyl-α-phenyl-benzene-methanol melting at 119° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[CH:16][C:15]=3[F:30])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:31][N:32]([CH3:52])[CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[C:25]([O:24][CH2:23][CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:30])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:39]=[N:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:52])=[CH:42][CH:41]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCOC(C)(C)C)ccc4F)cnc3c2)cn1

Procedure:
7-Bromo-N-(5-(2-tert-butoxyethylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 2A) (300 mg, 0.629 mmol), N,N-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)propan-1-amine (202 mg, 0.660 mmol) and cesium carbonate (819 mg, 2.51 mmol) were combined in 1,2-dimethoxyethane (7 ml) and water (3 ml). The mixture was degassed thoroughly refilling with nitrogen and treated with PdCl2(dppf).CH2Cl2 adduct (25.7 mg, 0.031 mmol). The mixture was once again degassed thoroughly refilling with nitrogen and heated using microwave radiation at 100° C. for 1 hr. The aqueous was removed by pipette and the organic portion was absorbed onto silica and purified by chromatography eluting with 0-20% MeOH in DCM. The resulting solid was recrystallised from EtOAc to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 1.19 (s, 3H), 1.20 (s, 3H), 4.354.38 (m, 1H), 6.63 (d, J=9.2 Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.70-7.73 (m, 1H), 8.51 (bs, 1H), 8.68 (bs, 1H), MS: M/z=431.0 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 53.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and 4-fluorobenzoyl chloride (0.19 mL, 1.60 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.45 mL, 3.20 mmol) at room temperature under nitrogen. After 18 h, water (200 mL) was added and the solids were isolated by filtration. The crude product was triturated in 1 N aq. HCl (50 mL) for 2 h then in EtOAc (50 mL) for 18 h. The product was isolated by filtration, washed with EtOAc (25 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-fluoro-benzamide as a white solid (0.34 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.06 min (94.63%); mp: 295-297° C.; 1H NMR (DMSO-d6) δ 1.85-2.12 (m, 1H, CHH), 2.22-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.79-3.03 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.45 (d, J=17.4 Hz, 1H, CHH), 4.59 (d, J=5.7 Hz, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.32 (t, J=8.9 Hz, 2H, Ar), 7.47 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 7.99 (dd, J=5.6, 8.8 Hz, 2H, Ar), 9.18 (t, J=5.9 Hz, 1H, NH), 10.98 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.78, 47.13, 51.59, 115.26 (d, J=22.0 Hz), 122.08, 122.94, 127.08, 129.93 (d, J=8.8 Hz), 130.39, 130.64 (d, J=2.2 Hz), 142.39, 143.85, 163.93 (d, J=248.7 Hz), 165.22, 167.92, 170.98, 172.85; LCMS: MH=396; Anal Calcd for C21H18N3O4+0.1H2O: C, 63.50; H, 4.62; N, 10.58. Found: C, 63.19; H, 4.54; N, 10.55.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.O>CO>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)=[CH:16][CH:15]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)c(OC)c1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 4,6-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, water 400 ml was added, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.95 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([N:29]=[C:30]=[O:31])=O)=[C:25]([F:32])[C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([F:32])[C:26]=1[C:27]1[NH:29][C:30](=[O:31])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.19 (s, 9H), 4.40 (m, 2H), 6.22 (m, 1H), 7.26 (m, 1H), 7.35 (m, 1H), 7.62 (d, J=8.1 Hz, 2H), 8.12 (d, J=7.8 Hz, 2H); MS (m/z): 471.18 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([OH:39])=[O:38]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:36][CH2:35][CH2:34][C@H:33]4[C:37]([OH:39])=[O:38])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)[C@@H]1CCCN1Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (S)-pyrrolidine-2-carboxylic acid (111 mg; 0.97 mmol) to give Example 159 as an off-white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.77-8.74 (2H, m), 7.98-7.87 (3H, m), 7.76-7.69 (1H, m), 7.64-7.57 (4H, m), 7.52 (2H, t, J=8.5 Hz), 4.11 (1H, d, J=13.5 Hz), 3.72 (1H, d, J=13.5 Hz), 3.31 (1H, dd, J=8.9, 5.9 Hz), 3.04-2.96 (1H, m), 2.50 (1H, d, J=8.5 Hz), 2.16-2.07 (1H, m), 1.94-1.84 (1H, m), 1.84-1.73 (2H, m). LC/MS (Method C): 412 (M+H)+. HPLC (Method I) Rt 15.21 min (Purity: 95.3%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1.B(F)(F)F.CCOCC>CCS>[CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1ncc(C)s1
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: COC(=O)CC(Cc1ccc(O)cc1)c1ncc(C)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of methyl (±)-3-(5-methylthiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate (0.99 mmole, crude) in EtSH (5 mL) at RT was added BF3 OEt2 (0.6 mL). After 18 hr. additional BF3.OEt2 (0.6 mL) was added. After another 18 hr, the mixture was cooled to 0° C. and carefully quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (50% EtOAc/hexanes) to give the title compound (249 mg, 86% over 3 steps) as a yellow solid: MS (ES) m/e 292 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[N+:20]([O-])=O)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[N:9]([CH3:25])[C:10]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)=[C:13]([NH2:20])[CH:14]=1
Reactant: CI
Reactant: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1H-indole (1.0 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (160 mg) on an ice bath. The solution was stirred for 20 minutes at room temperature, then methyl iodide (570 mg) was added dropwise thereto on an ice bath, and the solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), the total amount of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1-methyl-1H-indole was used according to an analogous synthetic method to Example 22 to provide the title compound (720 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH2:27][C:26]2=[O:42])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH:40]=[O:41])=[CH:38][CH:39]=3)(=[O:32])=[O:33])[CH2:27][C:26]2=[O:42])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CO)cc3)CC2=O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C=O)cc3)CC2=O)CC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
To a solution of oxalyl chloride (0.70 ml) in dichloromethane (60 ml) was added dropwise at −70° C. a solution of dimethylsulfoxide (0.85 ml) in dichloromethane (10 ml). Ten minutes later, to the mixture was added dropwise a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-(hydroxymethyl)benzenesulfonyl]-2-piperazinone (1.87 g) in dichloromethane (20 ml), and the mixture was stirred at about −65° C. for 1 hour. To the mixture was added triethylamine (2.79 ml), and the mixture was stirred at −60° C. to −30° C. for 2 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, dried and concentrated, and the the residue was purified with silica gel column chromatography (ethyl acetate). Precipitated crystals were washed with ether to give colorless crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-formylbenzenesulfonyl]-2-piperazinone (2.02 g).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][S:24]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:4]2([CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:10]=1)(=[O:26])=[O:25]
Reactant: CC1(c2cccc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-methanol (1.68 g, 8.65 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (1.60 mL, 11.38 mmol) followed by DMAP (109 mg, 0.88 mmol) and Ms-Cl (0.80 mL, 10.13 mmol). After stirring at 0° C. for 0.5 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 0:1) to give pure (3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl)methyl methanesulfonate as a white solid. Part of this material (300 mg, 1.10 mmol) was dissolved in dry DMF (5 mL) and treated with NaN3 (220 mg, 3.35 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 3-(azidomethyl)-(2-methyl-[1,3]dioxolan-2-yl)benzene as a yellow oil. LC-MS-conditions 02: tR=0.99 min.