Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[N:13]([CH3:23])[C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[N:13]([CH3:23])[C:14]4[C:19]([C:20]=3[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=4)(=[O:11])=[O:10])=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Yield: 58.2 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.100 g), 4-pyridineboronic acid (0.040 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (1.0 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.025 g) to obtain the title compound (0.058 g) as a brownish foam. MS (ISN): 462.4 (M−H)−
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1ccc(N2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8](I)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[N:13][C:14]=3[NH2:15])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)[CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)nn2C1CCCC1
Temperature: 85 °C
Yield: 12.3 %

Procedure:
To a mixture of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.631 mmol, 1 equiv) and 3-(benzyloxy)phenylboronic acid (0.110 g, 0.487 mmol, 1.0 equiv) in DME (6 mL) was added tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol, 0.07 equiv) and a solution of sodium carbonate monohydrate (0.187 g, 1.51 mmol, 2.4 equiv) in water (2 mL). The mixture was heated at 85° C. for 16 h, then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to afford an oily red-orange solid. Recrystallization from hot EtOAc afforded a red-orange solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford 3-[3-(benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.023 g, 0.060 mmol): 1H NMR (d6 CDCl3, 400 MHz): δH 8.34 (1H, s), 7.27-7.46 (8H, m), 7.07-7.10 (1H, m), 5.63 (2H, bs), 5.31 (1H, quint, J=7.6 Hz), 5.16 (2H, s), 2.15-2.20 (4H, m), 1.96-2.01 (2H, m), 1.72-1.75 (2H, m); RP-HPLC (Hypercil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 15 min, 1 mL/min) Rt 14.00 min. MS: MH+ 386.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(O)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:24][CH:20]([CH2:22][CH3:23])[CH3:21])[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([CH3:19])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CCC(C)N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Yield: 57.2 %

Procedure:
15 ml of triethylamine are added to a solution of 15.6 g of 2,4-dichloro-5-nitro-6-methylpyrimidine (0.075 mole) in 300 ml of absolute ethanol. With ice cooling, 6.6 g of sec. butylamine (0.09 mole) are added dropwise at 0°-5° C over the course of c. 40 minutes to the dark red solution. After the mixture has been stirred for c. 3/4 hour at this temperature, it is poured into c. 700 ml of ice water and the water is extracted 3 times with ether. The ethereal extracts are dried over magnesium sulphate and evaporated. The resultant red oily substance is crystallised from petroleum ether to yield 10.5 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine of m.p. 40°-43° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:28](=[CH2:33])[C:29]([F:32])([F:31])[F:30])O1.O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:28](=[CH2:33])[C:29]([F:32])([F:31])[F:30])=[N:3][N:4]=[CH:5]3)=[CH:14][CH:15]=1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 1-chloro-N-(4-fluorophenyl)phthalazin-6-amine (0.300 g, 1.1 mmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.28 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium (0.063 g, 0.055 mmol) and sodium carbonate monohydrate (0.41 g, 3.3 mmol) in 6 mL of dioxane/water (3/1) was heated in a microwave at 100° C. for 40 min. Additional 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.100 mL) and tetrakis(triphenylphosphine)palladium (0.063 g, 0.055 mmol) was added and the mixture was heated at 100° C. for an additional 30 min. After cooling to RT, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified on an ISCO column (12 g, 50-80% EtOAc in hexanes) to afford N-(4-fluorophenyl)-1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-amine as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([B:16]([OH:21])[OH:17])[CH:3]=[N:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1cncc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
1.91 g of 3-bromo-5-benzyloxypyridine, under argon, are added to a solution of 2 ml of triisopropyl borate in a mixture of 12 ml of toluene and 3 ml of tetrahydrofuran. The solution is cooled to −70° C. and then 5.42 ml of n-butyllithium (1.6N in hexane) are added dropwise. The reaction medium is stirred for 3 hours, and brought back to −20° C., and 7.23 ml of 2N hydrochloric acid are added dropwise. The reaction mixture is left to return to ambient temperature and poured into distilled water. The aqueous phase is extracted with ethyl acetate, and then the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure, so as to give 0.21 g of [5-(benzyloxy)pyridin-3-yl]boronic acid in the form of a white powder (adapted from Wenjie Li et al. An Improved Protocol for the Preparation of 3-Pyridyl- and Some Arylboronic Acids J. Org. Chem., (2002), 67(15), 5394-5397), the characteristics of which are the following:
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[S:24]([CH3:27])(=[O:26])=[O:25])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: c1ccncc1
Product: CS(=O)(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reaction time: 1 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in pyridine (1.19 ml) containing mesyl chloride (12 μl). The solution was stirred for 1 hour in a dry ice-carbon tetrachloride bath under nitrogen atmosphere. The solution was evaporated in vacuo and the residue was subject to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 4-formyl-6,9-dihydroxy-11-mesyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (47 mg).
Reaction SMILES: [N:1]([CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17].C(Cl)Cl>C(O)(=O)C>[CH3:15][N:16]([CH3:18])[NH:17][C:2]([NH:1][CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])=[O:3]
Reactant: CN(C)N
Reactant: CCOC(=O)C(N=C=O)c1cccs1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)NC(=O)NC(C(=O)O)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.02 mole) of DL-α-isocyanato-2-thiopheneacetic acid, ethyl ester and 1.2 g. (0.02 mole) of N,N-dimethylhydrazine in 80 ml. of methylene chloride is stirred overnight. The solution is concentrated and to the syrupy residue are added 10 ml. of 2N sodium hydroxide solution. After stirring for 30 minutes, a clear yellow solution results. By the addition of acetic acid, 3.9 g. of α-dimethylhydrazinocarbonylamino-2-thiopheneacetic acid are obtained, m.p. 208°-210°.
Reaction SMILES: [NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OC2CCCCO2)CC1

Procedure:
Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL). After 16 hours the reaction was quenched with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an Analogix SF65-200 g column (hexanes/ethyl acetate 95:05-9:1) afforded the title compound (clear oil) as a mixture of isomers (11.1 g, 85%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ncccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccnc1OC)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a 100-mL round-bottomed flask were added 3-(bromomethyl)-2-methoxypyridine (1.10 g, 5.44 mmol), ethyl N-(diphenylmethylene)glycinate (1.46 g, 5.44 mmol, Acros, N.J.) and 5N sodium hydroxide (5.44 mL, 27.2 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(2-methoxy-3-pyridinyl)alaninate (1.52 g) as viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:42][CH2:43][CH3:44])[C:23]([Cl:45])=[CH:22][N:21]=1>C(OC(O)C)C.Cl>[C:39]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:24]3[C:23]([Cl:45])=[CH:22][N:21]=[C:20]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]5)=[CH:4][C:3]=4[O:17][CH3:18])[N:25]=3)=[C:28]([O:42][CH2:43][CH3:44])[CH:29]=2)[CH2:38][CH2:37]1)(=[O:41])[CH3:40]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Reactant: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CCOC(C)O
Agent: Cl
Product: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2OC)ncc1Cl

Procedure:
1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (40 mg) prepared in Preparation Example 1 and 1-(4-(4-(2,5-dichloropyrimidine-4-ylamino)-3-ethoxyphenyl)piperazin-1-yl)ethanone (50 mg) prepared in Preparation Example 15 were dissolved in 0.08M HCl ethoxyethanol solution (1.2 mL), and allowed to react at 115° C. overnight. Upon completion of the reaction, the solvent of the mixture was removed under reduced pressure, diluted with ethyl acetate, neutralized with an aqueous saturated sodium carbonate solution, water was removed from the organic layer with sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain a target compound.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenol (0.410 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.644 g, 2.72 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.571 g (85%) of the tide compound as a light brown solid, mp 93-95° C. 1H NMR consistent. mass spectrum (−ESI) m/z 493 (M−H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([NH2:14])[CH:3]=1.[C:15](=S)=[S:16].[OH-].[K+].C>C(O)C.O>[F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]2[N:13]=[C:15]([SH:16])[NH:14][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(-n2ccnc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc2[nH]c(S)nc2cc1-n1ccnc1

Procedure:
The diamine (6.7 g, 0.035 mol) (obtained in step 4 above) was dissolved in ethanol (20 mL) and added to a stirred mixture of carbon disulfide (3.0 g, 0.04 mol), potassium hydroxide (2.3 g, 0.04 mol), water (5 mL) and ethanol (15 mL). The resultant solution was refluxed for 6 h. Animal charcoal (2.0 g) was added and further refluxed for 1 h. The mixture was filtered and washed with hot water. A mixture of acetic acid and water (1:2, 15 mL) was added to the filtrate slowly with vigorous stirring to separate 6-fluoro-5-(imidazol-1-yl)-2-mercapto-1H-benzimidazole (5.0 g, 60%) as a brown solid. mp 280° C. (decomp.); IR (KBr) 3078, 1481 cm-1 ; 1H NMR (DMSO-d6) δ 2.20 (s, 1H, SH), 7.10 (s, 1H), 7.24 (d, J=6.0 Hz, 1H), 7.26 (d, J=4.1 Hz, 1H), 7.56 (s, 1H), 8.00 (s, 1H), 12.90 (brs, 1H, NH); Mass (m/z) 234 (M+.).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][NH:7][C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>CC(O)C>[CH3:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl) piperazine-1-carboxylate. To a solution of (2S,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate hydrochloride (1.17 g, 4.67 mmol, Acesys Pharmatech, A1653, Sample ID 119-99-18) in 2-Propanol (20 mL) was added 4-chloro-3-nitropyridine (1.11 g, 7.00 mmol, Alfa Aesar, Ward Hill, Mass.) and DIPEA (4.06 mL, 23.33 mmol). The mixture was heated and stirred at 85° C. for 2 h. Additional DIPEA (0.81 mL, 4.67 mmol) was added and the heat was raised to 90° C. The mixture was stirred at this temperature for 18 h. The mixture was then cooled to RT and concentrated. The residue was diluted with EtOAc (150 mL) and washed with water (15 mL) followed by brine (15 mL) and then dried over MgSO4. The crude material was purified by silica gel chromatography (30-70% EtOAc in hexanes) to afford (2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (918 mg, 2.73 mmol, 59% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 337.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1 H), 8.38 (d, J=5.9 Hz, 1 H), 6.99 (d, J=6.1 Hz, 1 H), 4.12 (dd, J=14.0, 4.4 Hz, 1 H), 3.99-4.07 (m, 1 H), 3.94 (dt, J=10.8, 5.5 Hz, 1 H), 3.23 (dd, J=13.5, 9.4 Hz, 1 H), 2.98 (dd, J=14.1, 10.8 Hz, 1 H), 2.77 (dd, J=13.5, 5.7 Hz, 1 H), 1.46 (s, 9 H), 1.16 (d, J=6.3 Hz, 3 H), 1.13 (d, J=6.1 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C([O:22][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=O)C.O>O1CCOCC1>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=[O:22]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (259 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (4 ml) under an argon atmosphere was added trimethylaluminium (0.63 ml; 2 M solution in heptane)-->foaming. The mixture was stirred at r.t. for 2 h. A solution of 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (100 mg) in dioxane (4 ml) was then added. The mixture was heated to 100° C. over night. The mixture was cooled to r.t. and H2O (0.8 ml) was added (-->bubbling). After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The mixture was then filtered and the cake was washed with dichloromethane. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide as light yellow solid. 474.1 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH3:18].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH2:16][CH2:17][CH3:18])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.78 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (300 mg, 0.78 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.