Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[CH2:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:33]=1.Cl.[CH3:41][NH:42][CH3:43]>C(O)(C)(C)C>[CH3:41][N:42]([CH3:43])[C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:28][C:29]2[CH:30]=[N:31][N:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:33]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:20][CH:21]=1
Reactant: ClCc1cnn(-c2ccccc2)c1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Agent: Cl
Solvent: CC(C)(C)O
Product: CN(C)c1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cnn(-c3ccccc3)c2)nc1

Procedure:
An operation similar to that of Example 442-1 was performed using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and 4-(chloromethyl)-1-phenyl-1H-pyrazole synthesized in Reference Example 18 as starting materials. An operation similar to that of Example 442-2 was performed (solvent was changed to tert-butanol) using the obtained compound and dimethylamine hydrochloride as starting materials. The obtained compound was subjected to an operation similar to that of Example 442-3 to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:8][CH2:7]1)C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:37])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of ethyl{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.04 g), 1M aqueous sodium hydroxide solution (6 mL), tetrahydrofuran (10 mL), and ethanol (10 mL) was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (700 mg, yield 71%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH:13]([C:18]([OH:20])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:24][C:18]([CH:13]1[CH:14]([CH3:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:20]
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 4.62 mmol) in DCM (40 mL) was added oxalyl chloride (0.930 mL, 10.6 mmol) followed by the drop-wise addition of DMF (0.072 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield crude benzyl 3-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate (1.4 g, 4.7 mmol) which was dissolved in a mixture of Et2O and MeCN (1:1, 16 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 9.47 mL, 18.5 mmol) in Et2O and MeCN (1:1, 16 mL) that was cooled to about 0° C. The resulting mixture was stirred at about 0° C. for about 4 h and quenched by a drop-wise addition of 48% aqueous HBr. The organic solvents were removed and the residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in heptane. The product-containing fractions were concentrated under reduced pressure to give benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 47%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 356 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(Cl)cccc1N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-(morpholin-4-yl)benzaldehyde (1.34 g, 5.92 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol, 0.910 equiv), 1,2-dichloroethane (30 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (3.42 g, 16.1 mmol, 2.72 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with 1,2-dichloroethane (20 mL). The resulting mixture was washed with H2O (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/2) to yield 1.80 g (77% yield) of tert-butyl 4-[[2-chloro-6-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:32][O:33][C:34]1[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)=[CH:41][C:35]=1[O:36][CH2:37][C:38](O)=[O:39]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)[CH:43]=[CH:44][C:34]=1[O:33][CH3:32]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 78 %

Procedure:
To a solution of 2-aminobenzothiazole (150 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 1.0 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8a) (395 mg, 80% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:10]=1)=O)C.[NH3:20]>CO>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([NH2:20])=[O:3])[N:7]=[CH:8]1
Reactant: N
Reactant: CCOC(=O)c1cn(Cc2cccc(F)c2F)cn1
Solvent: CO
Product: NC(=O)c1cn(Cc2cccc(F)c2F)cn1

Procedure:
5.34 g of 1-(2,3-difluorobenzyl)-imidazole-4-carboxylic acid ethyl ester are dissolved in 80 ml of methanol and transferred to an autoclave. 20.0 g of ammonia are introduced under pressure and the whole is heated at 100° for 19 hours. When the excess ammonia has been blown off, the resulting product is filtered off and recrystallised from ethanol. 1-(2,3-difluorobenzyl)-imidazole-4-carboxamide having a melting point of 221°-222° is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C>C1(C)C=CC=CC=1.C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Agent: C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(-n2cccc2)cc1

Procedure:
A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methane. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluting with n-hexane-ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>O.C(O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([O:8][C:27]2[CH2:26][CH2:9][O:12][N:23]=2)[CH:6]=1.[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:25]=[N:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc(O)cn2)cn1
Product: c1cncc(OC2=NOCC2)c1
Temperature: 80 °C

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-70a and III-70b were prepared in 2 steps according to the following procedures: 6-bromopyridin-3-ol (1.0 equiv) and sodium carbonate (10.0 equiv) are added to a microwave vial. Toluene, ethanol, and water (0.16 M, 2:2:1 v/v) are added followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed by the addition of palladium tetrakis (4 mol %). The reaction tube is then covered with aluminum foil and heated to 80° C. in an oil bath for 17 h. After cooling the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1×), saturated ammonium chloride (1×) and brine (1×). The aqueous layers were combined and washed with ethyl acetate (1×). The organic layers were then combined, dried over sodium sulfate, concentrated and purified using flash silica gel chromatography (gradient methanol/methylene chloride) to provide 6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol III-69 as a white solid. This compound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole III-66 using Method 5 to provide the desired racemic compound III-70. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=430.0 m/z. Activity: A
Reaction SMILES: OCCC[N:5]1[C:9]2[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:8]=2[N:7]=[CH:6]1.[NH+]1C=CC=CC=1.[C:22]([CH2:24][CH2:25][O:26][P:27](=[O:30])([O-:29])[O-:28])#N.[NH+]1C=CC=CC=1>>[CH3:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:6]([CH2:22][CH2:24][CH2:25][O:26][P:27](=[O:28])([OH:30])[OH:29])[NH:5][C:9]=2[CH:10]=1
Reactant: Cc1cc2ncn(CCCO)c2cc1C
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Product: Cc1cc2nc(CCCOP(=O)(O)O)[nH]c2cc1C

Procedure:
Using 0.2 g of the crude 1-(3-hydroxypropyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) as the starting substances, according to the same processes as in Example 1, 0.3 g of crude 3-(5,6-dimethylbenzimidazolyl)propylphosphoric acid was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.[N:12]([O-])=O.[Na+]>C(OCC)C.O>[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Cl:2])=[N+:10]=[N-:12]
Reactant: O=N[O-]
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-Chlorophenylhydrazine hydrochloride (1.0 g) suspended in 6.0 ml of diethyl ether was dropped into 5 ml of concentrated hydrochloric acid cooled at 0° C. After the reaction solution was stirred for 10 minutes, 462 mg of sodium nitrite dissolved in 2.0 ml of water was dropped into the reaction solution and the mixture was stirred for 2 hours together with raising the temperature up to room temperature. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated aqueous saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 506 mg of the title compound as a red oily crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:30])/[CH:21]=[CH:22]/[CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.BrC[C:33]1[N:34]([CH3:41])[CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[N:37]=1.[CH3:42]N1C(=O)CCC1>>[Br-:1].[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:30])/[CH:21]=[CH:22]/[CH2:23][N+:24]3([CH2:42][C:35]4[N:34]([CH3:41])[CH:33]=[N:37][C:36]=4[N+:38]([O-:40])=[O:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc([N+](=O)[O-])nc1CBr
Reactant: O=C(/C=C/CN1CCCCC1)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CN1CCCC1=O
Product: Cn1cnc([N+](=O)[O-])c1C[N+]1(C/C=C/C(=O)Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)CCCCC1
Product: [Br-]
Yield: 61 %

Procedure:
Reaction of (E)-N-(4-(3-bromophenylamino)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide (12) (1.0 g, 2.14 mmol) in NMP (4 mL) with 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (315 mg, 1.43 mmol) for 3.5 days, according to general procedure D gave 1-((2E)-4-{[4-(3-bromoanilino)-6-quinazolinyl]amino}-4-oxo-2-butenyl)-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium bromide (23) (600 mg, 61%), m.p. 188° C. (dec.). 1H NMR [(CD3)2SO] δ 10.73 (s, 1H), 9.94 (s, 1H), 8.82 (s, 1H), 8.61 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.88-7.83 (m, 2H), 7.37-7.29 (m, 2H), 7.08 (td, J=7.3, 15.1 Hz, 1H), 6.80 (d, J=15.1 Hz, 1H), 5.02 (br s, 2H), 4.62 (br s, 2H), 3.87 (s, 3H), 3.58-3.55 (m, 2H), 2.04-1.99 (m, 2H), 1.78-1.75 (m, 2H), 1.64-1.61 (m, 1H), 1.46-1.36 (m, 1H). Analysis found: C, 48.24; H, 4.58; N, 15.89. C28H30Br2N8O3.½H2O requires: C, 48.36; H, 4.49; N, 16.11. HRMS (FAB+) found: 605.16226, 607.15997 (M-Br), calcd. for C28H3079/81BrN8O3+: 605.16242, 607.16038.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:5][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][S:9][N:10]=1)[CH3:4]>CC(C)=O>[I-:2].[CH2:3]([O:5][C:6]1[C:7]([C:11]2[CH:12]=[N+:13]([CH3:1])[CH:14]=[CH:15][CH:16]=2)=[N:8][S:9][N:10]=1)[CH3:4]
Reactant: CI
Reactant: CCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.3 ml, 5 mmol) and 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)pyridine (520 mg, 2.5 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.72 g (83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:17][N:26]3[CH2:27][CH2:28][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:25]3)=[CH:3][CH:4]=2)[O:9]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.114 g, 0.4 mmol) and potassium carbonate (0.060 g, 0.43 mmol) in DMF (3 mL) was added tert-Butyl 1-piperazinecarboxylate (0.071 g, 0.4 mmol) and the resulting reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate obtained was used without further purification. LCMS (1) Rt: 2.56 min; m/z (ES+) 403.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:49])[NH:18][C:19]3[S:20][C:21]4[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=4[C:23]=3[C:24](=[O:44])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)=[CH:28][CH:27]=3)[CH:12]=2)[CH2:6][C:7](O)=[O:8])[CH2:4][CH2:3]1.Cl.[CH3:51][NH:52][CH2:53][C:54]([O:56][CH3:57])=[O:55].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C(N(CC)CC)C.ClCCl>[CH:2]1([N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:49])[NH:18][C:19]3[S:20][C:21]4[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=4[C:23]=3[C:24](=[O:44])[NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)=[CH:30][CH:31]=3)[CH:12]=2)[CH2:6][C:7]([N:52]([CH3:51])[CH2:53][C:54]([O:56][CH3:57])=[O:55])=[O:8])[CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CC(=O)O)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN(C)C(=O)CN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.5 %

Procedure:
To a mixture of 306 mg of N-cyclopropyl-N-[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]glycine hydrochloride and 5.0 mL of dichloromethane were added 0.182 mL of triethylamine, 91 mg of methyl N-methylglycinate hydrochloride, 125 mg of WSC.hydrochloride and 88 mg of HOBt, followed by stirring for 15 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 152 mg of methyl N-cyclopropyl-N-[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]glycyl-N-methylglycinate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.C([Sn](CCCC)(CCCC)[C:20]([F:22])=[CH2:21])CCC>ClC(Cl)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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:20]([F:22])=[CH2:21]
Reactant: C=C(F)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=C(F)c1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.4 g, 1.210 mmol), tributyl(1-fluorovinyl)stannane (0.608 g, 1.816 mmol), and bis(triphenyl-phosphine)palladium(II) chloride (0.127 g, 0.182 mmol) were combined in dichloroethane (2.4 mL) and stirred at 70° C. overnight. The reaction mixture was concentrated onto celite and purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (211 mg, 0.849 mmol, 70.1% yield) as a yellow solid: mp 98-100° C.; 1H NMR (400 MHz, CDCl3) δ 5.28 (dd, J=15.0, 3.6 Hz, 1H), 4.94 (s, 2H), 4.81 (dd, J=47.3, 3.6 Hz, 1H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −89.04, −138.74; ESIMS m/z 249 [(M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to piperidine (3.53 g) in triethylamine (40 ml) at 0° and the suspension was stirred at room temperature under nitrogen for 1 h. The reaction mixture was poured into 2N aqueous hydrochloric acid (200 ml) and extracted with EA (3×100 ml). The combined extracts were washed with water (100 ml), 8% aqueous sodium bicarbonate (100 ml) and water (10 ml), dried and concentrated. The resultant solid (10.25 g) was purified by FCC eluting with ER-H (1:2→1:1) to give the title compound as a white solid (9.33 g) m.p. 126°-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)C(C)C)(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:32][C:33]1([CH2:42][OH:43])[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:32][C:33]1([CH2:42][OH:43])[CH2:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:41]1)=[O:23]
Reactant: NC1(CO)Cc2ccccc2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC(=O)NC2(CO)Cc3ccccc3C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 244.2 %

Procedure:
To a mixture of 2-chloro-4-cyano-aniline (150 mg) and N,N-diisopropylethylamine (0.34 ml) in THF (15 ml), a solution of triphosgene (96 mg) in THF (5 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 min. To the mixture, a solution of 2-amino-2,3-dihydro-1H-indene-2-methanol (160 mg, WO 9110644) in THF (2 ml) was added at room temperature. The mixture was stirred for 1 hr at room temperature. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and evaporated. The residue was triturated with CH2Cl2 to obtain the title compound (270 mg, 80%) as a white solid.
Reaction SMILES: N#N.[F:3][C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1F.C([Mg][Br:18])C.BrBr.Cl>C(Cl)Cl.C1COCC1>[C:5]1([Br:18])[C:6]([F:13])=[C:7]([F:12])[C:8]([F:11])=[C:9]([F:10])[C:4]=1[F:3]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: BrBr
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1c(F)c(F)c(Br)c(F)c1F
Yield: 83 %

Procedure:
In a 2 l, N2 purged flask were combined hexafluorobenzene (145 g), FeCl2 (0.8 g) and THF (600 ml). The solution was cooled to 0°-5° C., and ethyl magnesium bromide (3.12M in Et2O, 500 ml) was then added dropwise. After the addition was complete, the reaction mixture was stirred for one-half hour. A solution of bromine (125g) n methylene chloride (250 ml) was then added dropwise to the cold (0°-5° C.) reaction mixture. After stirring 15 minutes, 4N HCl was added until all solids were dissolved. The two phases were separated and the organics were washed sequentially with water, aqueous sodium bicarbonate and brine. After drying over sodium sulfate, the mixture was distilled providing 160 g of C6F5Br (83% yield).