Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)N1CCN=C1[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(CBr)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
2-(tert-Butyl-dimethyl-silyl)-4,5-dihydro-imidazole-1-sulfonic acid dimethylamide (5.03 g) (prepared as described by Ngochindo, J. Chem. Soc. Perkin Trans. (1990) 1:1645) was dissolved in 100 ml of dry tetrahydrofuran and cooled in a dry ice-acetone bath to -78° C.; 11.9 ml of 1.6M n-butyllithium in hexane was added to this mixture. After 1 hr at -78° C., the reaction mixture was treated dropwise with 5.0 g of 4-bromomethyl-1-methyl-2-nitro-benzene dissolved in 25 ml of dry tetrahydrofuran (THF). The mixture was stirred at -78° C. for 1 hr and then allowed to come to room temperature overnight. The mixture was treated with saturated ammonium chloride, extracted with ethyl acetate washed the combined extracts with saturated sodium chloride, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel and eluted with ethyl acetate:hexane (1:4 ) to give 2.39 g of 2-(tert-butyl-dimethyl-silyl)-5-(4-methyl-3-nitro-benzyl)-imidazole-1-sulfonic acid dimethylamide as a yellow oil. ##STR126##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1>C1COCC1.CO>[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][N:8]2[C:9]3[C:5](=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=3)[C:6]([CH3:18])=[C:7]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:41][CH:40]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(Cn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 558 mg, 2.0 mmol) in THF (20 mL) is added 0.5 M KHMDS in toluene (8.8 mL, 4.4 mmol) and the mixture is stirred at room temperature for 30 min, whereupon 4-bromomethyl-benzoic acid methyl ester (916 mg, 4.0 mmol). The reaction mixture is stirred for 3 h. Methanol is added to quench the reaction and the solvents are removed in vacuo. The residue is purified by flash chromatography with 1-3% methanol in dichloromethane to give 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester. MS (ESI) m/z 391.3 and 393.3 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1([N:9]([CH3:11])[CH3:10])[CH2:8][NH:7][CH2:6]1)[CH3:4].[CH3:12]NCC>>[ClH:1].[ClH:1].[CH2:10]([N:9]([CH3:11])[C:5]1([CH2:3][CH3:4])[CH2:8][NH:7][CH2:6]1)[CH3:12]
Reactant: CCNC
Reactant: CCC1(N(C)C)CNC1
Agent: Cl
Product: CCN(C)C1(CC)CNC1

Procedure:
N,3-Diethyl-N-methyl-3-azetidinamine dihydrochloride was prepared according to procedure described for the preparation of 3-ethyl-N,N-dimethyl-3-azetidinamine dihydrochloride (Example 211), utilizing N-methylethanamine in place of dimethylamine in Part A. LCMS: (M+H)+ 144.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)COC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)OCC(C)C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), isobutyl salicylate (388 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (47 mg, yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[N:7]=1.[CH3:28][CH2:29][N:30](C(C)C)C(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>O1CCOCC1.O>[CH2:29]([NH:30][C:19](=[O:20])[CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:5][CH2:4][C:3]3[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:2]=3[F:1])[CH:11]=[CH:10][N:9]=2)[CH:14]=[N:15]1)[CH3:28]
Reactant: O=C(O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid I-2 (80 mg, 0.21 mmol, prepared by Procedure B), DIPEA (187 μL, 1.06 mmol) and TFFH (61 mg, 0.23 mmol) in dioxane (4 mL) was stirred for 10 min at room temperature. Ethylamine (2M in THF, 529 μL, 1.06 mmol) was added and the reaction was stirred for 2 h, then diluted with water and extracted with DCM. The organic layer was concentrated in vacuo and purified by prep. HPLC to afford N-ethyl-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-6 (8.8 mg, 0.02 mmol). LC-MS (Method B), RT=5.23 min. (ES+) 406.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:4]=[C:5](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>CCO.C1COCC1>[N:3]1[CH:4]=[C:5](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CCOC(=O)/C=C/c1cnc2ccccn12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1cnc2ccccn12
Temperature: 50 °C

Procedure:
A 1M aqueous solution of KOH (2.2 mL) was added to a solution of (E)-ethyl 3-(imidazo[1,2-a]pyridin-3-yl)acrylate (0.19 g, 0.88 mmol) in EtOH:THF (1:1 v/v) (10 mL). The resulting solution was heated at 50° C. for 3 h. After completion of the reaction the reaction mixture was evaporated and water (10 mL) was added to the residue. This solution was carefully acidified to pH 4 with a 3 M HCl aqueous solution. Since the product, (E)-3-(imidazo[1,2-a]pyridin-3-yl)acrylic acid, was soluble in water, the solution was concentrated under reduced pressure and the solid residue was used directly for the next step. ES+(M+H)+189.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[OH:11].Cl[CH2:13][C:14](Cl)=[O:15].C([O-])([O-])=O.[K+].[K+]>>[CH:8]([C:4]1[C:3]2[O:11][CH2:13][C:14](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([CH3:9])[CH3:10]
Reactant: CC(C)c1cccc(N)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1cccc2c1OCC(=O)N2

Procedure:
Crude 2-Amino-6-isopropylphenol (95MF80(2240) (0.16 g, 1.1 mmol), 2-chloroacetyl chloride (0.14 g, 1.2 mmol) and K2CO3 (0.32 g, 2.3 mmol) were mixed according to GP1 to give the title compound as a crude (95MF83) (0.115 g).
Reaction SMILES: [OH:1][C@:2]1([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:7][C@@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3]1.O[C@:33]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3][C@:2]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:1][CH3:33])[CH2:7]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(O)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH2:17][OH:18])[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:26])([CH3:25])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[C:14]2[CH:13]=[C:12](/[C:15](/[CH2:20][CH3:21])=[C:16](/[F:19])\[CH:17]=[O:18])[C:11]([O:22][CH2:23][CH3:24])=[CH:10][C:9]=2[C:8]([CH3:25])([CH3:26])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-56, 487 mg, 1.61 mmol), tetrapropylammonium peruthenate (316 mg, 2.7 mmol) and 4-methylmorpholine N-oxide (3.5 mg) were reacted in acetonitrile (4 mL) and dichloromethane (8 mL) to produce the title compound as an oil after flash chromatography (silica gel, 10% ethyl acetate in hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:20]([F:22])([F:21])[F:23])[CH:18]=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc(C(F)(F)F)cc2N1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc1

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.2) (200 mg, 0.50 mmol) and commercially available 4-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 208516-15-8] (161 mg, 0.60 mmol) according to the general procedure II. Obtained as a white solid (125 mg, 46%). MS (ISP) 515.9 [(M+H)+]; mp 229-233° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:3][CH:4]=2)[N:11]=1
Reactant: C1CCNCC1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(N3CCCCC3)nc2)cs1
Temperature: 90 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.25 mL (2.5 mmol, 3 eq) piperidine and 2 mL DMF were combined. The reaction mixture was heated at 90° C. for 16 h, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2-piperidin-1-ylpyridine (L-001106455). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.3 (M+H)+. 1H-NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.92-7.93 (m, 2H), 7.30 (d, 1H), 3.73 (m, 4H), 2.68 (s, 3H), 1.61-1.66 (m, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CSc1nc(-c2ccc(-c3ccccc3)cc2)cc2ccnn12
Yield: 77.1 %

Procedure:
Under an inert gas atmosphere is dissolved 5-(4-iodo-phenyl)-7-methylsulfanyl-pyrazolo[1,5-c]pyrimidine (compound D1)(0.45 g) and phenylboronic acid (0.35 g) in dimethoxyethane. To this solution are added bis-(triphenylphosphine)-palladium(II) chloride (0.19 mmol) and an aqueous sodium carbonate solution (2M, 6 ml). The reaction mixture is heated to reflux for 4.5 h. After 1 h further phenylboronic acid (0.2 g) is added in order to complete the reaction. The mixture is diluted with ethyl acetate and filtered over silica gel. The product is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (0.3 g) in 50% yield is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]=23)=[CH:13][CH:14]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc3c2CCC3)cc1
Yield: 21.4 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.110 g, 0.33 mmol) was reacted with tert-butyl piperazine-1-carboxylate (0.073 g, 0.40 mmol) to afford the title compound (0.034 g, 21%) as an orange foam. MW=480.59. 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.17 (s, 1H), 5.59 (s, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.60 (s, 2H), 3.54-3.48 (m, 4H), 3.40-3.34 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.12 (quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); APCI MS m/z 481 [M+H]+.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[NH2:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.C1N=CN(C(N2C=NC=C2)=O)C=1>O>[Cl:29][C:27]1[CH:28]=[C:20]2[C:21]([C:22](=[O:24])[N:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)(=[O:14])=[O:15])[C:17](=[O:18])[NH:19]2)=[CH:25][CH:26]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Following Synthesis Method (A), into 200 ml of anhydrous tetrahydrofuran (hereinafter referred to as THF) was dissolved 4.90 g (22.5 mmol) of 4-chlorobenzenesulfonylisocyanate, then 3.51 g (20.5 mmol) of 2-amino-4-chlorobenzoic acid was added and the mixture was stirred at room temperature for two hours. The reaction solution was cooled by ice water, then 3.98 g (24.55 mmol) of CDI was added and the mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the precipitated crystal was obtained by filtration and the obtained crystal was washed by water, then was washed by ethyl acetate to obtain 5.03 g of the above-identified compound (yield 66.5%). Properties: colorless crystal, Melting point: 286°-287° C., PMR (δppm, DMSO-d6): 7.12 (1H,s), 7.23 (1H,d), 7.26 (2H,d), 7.86 (1H,d), 8.17 (2H,d), 11.71 (1H,br).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH3:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)N1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-methyl-benzoic acid (29 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered then purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 23 mg (25%) of N-Biphenyl-4-yl-3-[4-(2-methyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 442.21 (M+1)+, 95.7%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.32 (t, 2H), 7.22 (m, 1H), 7.16 (d, 1H), 3.8 (m, 4H), 3.5 (m, 4H), 3.3 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[O:35]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:36])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCOc2ccccc2)cc1
Yield: 92.7 %

Procedure:
A mixture of alpha-oxo-4-[[2-[3-(2-phenoxyethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester (0.50 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (2 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.45 g of alpha-oxo-4-[[2-[3-(2-phenoxyethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid as a colorless solid, mp 176°-177° C.
Reaction SMILES: CN1CCC([NH:8][C:9]2C=[C:11]([NH:19][C:20](=[O:28])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])F)[CH:14]=2)CC1.N1C=CC=C[CH:30]=1.ClC(OC1C=CC=CC=1)=O>C(Cl)Cl>[F:18][C:15]([C:13]1[CH:14]=[CH:9][N:8]=[C:11]([NH:19][C:20](=[O:28])[O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1)([F:17])[CH3:30]
Reactant: c1ccncc1
Reactant: CN1CCC(Nc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)CC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CC(F)(F)c1ccnc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Add the amine obtained in Step 3 (624 mg, 3.95 mmol), pyridine (780 mg, 9.85 mmol) in DCM (15 mL), cool to 0° C. on ice bath. Add slowly a solution of phenyl chloroformate (678 mg, 4.34 mmol) in DCM. After addition, stir on ice bath for 1 hr. Concentrate the mixture to get a crude residue. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the target compound (780 mg, 71%). MS: (M+1): 279.1.
Reaction SMILES: COCCOC[O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[OH:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH:27][S:41]([CH3:40])(=[O:43])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2
Reactant: CCOC(=O)C(N)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-amino-4-methyl-4-hexenoate (373 mg) was dissolved in CH2Cl2 (10 ml), cooled to 0° C., and triethylamine (0.17 ml) and methylsulfonyl chloride (0.09 ml) were added. The mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 (10 ml), washed with water (10 ml), dried over Na2SO4, and evaporated to dryness to give a residue which was passed through a column (silica gel, hexanes-EtOAc 1:1) giving 368 mg (82%) of ethyl (E)-6-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5yl) -2-methylsulfonylamino-4-methyl-4-hexenoate as a colorless oil.