Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:11][C:12](=O)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[C:20]([C:31]([F:34])([F:33])[F:32])=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]=2[C:15]1=[O:35]>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:16]3[C:15](=[O:35])[N:14]([CH2:13][C:12](=[O:11])[N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:19][CH2:18][C:17]=3[C:20]([C:31]([F:34])([F:32])[F:33])=[N:21]2)=[CH:24][CH:25]=1
Reactant: C1CCNC1
Reactant: COC(=O)CN1CCc2c(C(F)(F)F)nn(-c3ccc(OC)cc3)c2C1=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CC(=O)N2CCCC2)CC3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Part A: Pyrrolidine (0.152 mL, 1.826 mmol) was dissolved in methylene chloride (6 mL) and cooled to 0° C. 2M Trimethylaluminum (0.652 mL, 1.304 mmol) was added to the reaction and stirred for 30 min at 0° C. [1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-acetic acid methyl ester (0.100 g, 0.261 mmol) was added and the reaction was stirred overnight at rt. The reaction was quenched with water (100 mL), extracted into methylene chloride (3×50 mL), washed with brine (1×50 mL), dried over MgSO4, concentrated, and purified, by flash chromatography using 0–100% ethyl acetate/hexanes gradient and methanol flush as eluents, followed by further purification by reverse phase HPLC. Freeze-drying afforded 0.052 g (47%): 1H NMR (CDCl3) δ 7.38 (d, j=8.8 Hz, 2H), 6.87 (d, j=9.1 Hz, 2H), 4.15 (s, 2H), 3.77 (t, j=6.8 Hz, 2H), 3.76 (s, 3H), 3.40(t, j=6.8 Hz, 2H), 3.33 (t, j=6.8 Hz, 2H), 3.00(t, j=6.8 Hz, 2H), 1.92–1.85 (m, 2H), 1.82–1.73 (m, 2H) ppm; Mass Spec 423.3(M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O>CCOCC>[CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[Cl:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1ccc2nc[nH]c(=O)c2c1
Solvent: CCOCC
Product: CN(C)c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of 12.4 g. of 6-dimethylamino-quinazolin-4(3H)-one and 50 ml. of phosphorus oxychloride is refluxed under nitrogen for 10 minutes, cooled to room temperature, 150 ml. of ether added, the crystals recovered by filtering, washed with ether and dried. The solids are added to 500 ml. of ice-water, concentrated ammonia is added to neutralize the solution which is extracted with 1.0 liter of chloroform. The chloroform extract is dried and filtered through 300 ml. of silica gel using chloroform as an eluant. Evaporation of the eluant yields 6-dimethylamino-4-chloroquinazoline, m.p. 126°-127.5° C.
Reaction SMILES: [OH-].[K+].[ClH:3].C[O:5][C:6](=[O:23])[CH:7]=[C:8]1[CH2:13][CH2:12][C:11]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CCOCC.Cl>C(O)C>[ClH:3].[CH3:22][N:20]([CH3:21])[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][C:8](=[CH:7][C:6]([OH:23])=[O:5])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
1.7 M KOH (70.5 ml, 120 mmol) was added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid methyl ester hydrochloride (1.8 g, 5.8 mmol) in ethanol (200 ml) and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was taken up in water (40 ml). The aqueous phase was extracted by shaking with ether (2×40 ml), and 5.5 M hydrochloric acid (23.6 ml, 130 mmol) was added. After the aqueous phase had been concentrated, the residue was extracted with ethanol (2×40 ml), the potassium chloride which remained was separated off and the filtrate was concentrated. The hydrochloride of the acid was thereby obtained as a colourless solid in a yield of 98% (1.67 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2].CO.[CH2:31]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([O:15][CH3:31])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2]
Reactant: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-3-(5-cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoic acid (Example 148-B) (60 mg, 0.160 mmol) in DCM (639 μl) were added MeOH (16.17 μl, 0.400 mmol), DMAP (3.91 mg, 0.032 mmol) and DCC (52.8 mg, 0.256 mmol) successively. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with a saturated solution of ammonium chloride, diluted with DCM and water and passed through a phase separator. The organic layer was concentrated to give crude product that was purified via FCC with Heptane/AcOEt (100/0 to 0/100) to obtain the title compound. (ESI+) m/z 390.4 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](O)=[O:22])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH:26]([N:29](CC)C(C)C)(C)C.CN.CCO.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[CH3:26][NH:29][C:21](=[O:22])[CH2:20][O:19][CH:16]1[C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:9][CH:8]=3)[C:11]=2[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (70 mg, 0.19 mmol) in THF (0.6 mL) was added N,N-diisopropylethylamine (131 μL, 0.75 mmol), 8M methylamine in EtOH (47 μL, 0.38 mmol) and 1-propanephosphonic acid cyclic anhydride (284 μL, 0.47 mmol). The reaction was stirred at room temperature for 16 h. The mixture was evaporated and purified by flash chromatography (20 g SiO2, Telos-cartridge, 2 to 10% 2-propanol in CH2Cl2) to give the title compound (41 mg, 63%) as light yellow oil. MS: 351.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>O1CCCC1.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>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 21.0 mL of (2-methylphenyl)magnesium bromide (42.0 mmol, 2.0M in diethyl ether) was evaporated in situ at room temperature. The syrupy residue was redissolved in 50 mL of THF and cooled to -20° C. under argon. To this solution was added a solution of 6.84 g (50.0 mmol) of thrice-fused zinc chloride in 50 mL of tetrahydrofuran (THF). The resulting thick white slurry was warmed to room temperature and stirred for 1 hour. After cooling to -78° C., a solution of 11.32 g (40.0 mmol) 1-bromo-4-iodobenzene and 500 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium in 50 mL of THF was added over the course of thirty minutes. After an additional 20 minutes, the cooling bath was removed, the reaction stirred at room temperature for 2 hours and then quenched with 100 mL of 1M hydrochloric acid. The mixture was extracted twice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSo4) and evaporated. The crude product (11.3 g) was purified by distillation (bp 93°-95° C. at 0.5 Torr) to give 8.06 g (82%) of title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([CH3:32])[N:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:24][C:25]1[N:30]=[C:29]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([NH:14][C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[C:4]([CH3:23])[CH:3]=[C:2]4[NH2:1])=[O:13])=[CH:16][CH:17]=2)[CH:28]=[C:27]([CH3:32])[N:26]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(NC(=O)c3ccc4nc(C)cc(N)c4c3)cc2)nc(N)n1
Yield: 82.2 %

Procedure:
The solution of 27 mg (0.05 mmol) 4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzylamine, 15 mg (0.1 mmol) 2-amino-4-chloro-6-methylpyrimidine, and 0.05 ml (0.3 mmol) diisopropyl ethylamine in 1 ml DMF was stirred at 120° C. for 5 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (51%) of the title compound. MS 414.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.19 (s, 3H), 2.60 (s, 3H), 4.56 (d, 2H), 5.94 (s, 1H), 6.65 (s, 1H), 7.33 (d, 2H), 7.75 (d, 2H), 7.88 (d, 1H), 8.35 (d, 1H), 8.97 (s, 1H), 8.96-9.01 (m, 2H), 10.51 (s, 1H), 12.30 (br. 1H), 13.60 (br. 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:16]([CH2:27][CH2:28][CH:29]=O)[C:15]=2[CH:31]=1)=[O:4].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:16]([CH2:27][CH2:28][CH2:29][N:41]3[CH2:42][CH2:43][N:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)[C:15]=2[CH:31]=1)=[O:4]
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccc(OC)cc3)n(CCC=O)c2c1
Reactant: c1ccc(N2CCNCC2)cc1
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccc(OC)cc3)n(CCCN3CCN(c4ccccc4)CC3)c2c1

Procedure:
6-[(5-(Methoxycarbonyl)pentyl)oxy]-2-(4-methoxy-phenyl)-1-(3-oxo-propyl)-benzimidazole is reacted with N-phenyl-piperazine according to general operating instructions 8. 6-[(5-(Methoxycarbonyl)pentyl)oxy]-2-(4-methoxy-phenyl)-1-[3-(4-phenyl-piperazin-1-yl)-propyl]-benzimidazole is obtained as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:26])[N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: COc1cccc(CNC2CC2)c1
Product: COc1cccc(CN(C(=O)CN(c2ccccc2C(N)=O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1.C(OC(=O)C)(=O)C>>[CH3:5][C:6]1([C:10]2[CH:11]=[CH:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CC1(c2ccccc2)CCC1
Solvent: CC(=O)OC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
70% Nitric acid (7:3, Nitric acid:Water, 0.375 ml, 5.92 mmol) was added dropwise over 60 minutes to a solution of (1-methylcyclobutyl)benzene (346 mg. 2.37 mmol) in Acetic anhydride (1.4 mL, 15 mmol) cooled at 0° C. The temperature of the solution was maintained below 5° C. during the addition. Upon completion of the addition, the reaction was stirred for 60 minutes with cooling. The reaction mixture was poured into 40 ml ice water and the ice was allowed to melt. The aqueous phase was extracted with three×20 ml portions of Et2O and the combined organic phase was washed with 25 ml H2O followed by two 20 ml portions of sat NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a light the product as an oil (418 mg) which was used as is in the next step. 1H NMR (400 MHz, CDCl3) d ppm 8.16 (d. J=8.71 Hz, 2H), 7.29 (d, J=8.71 Hz, 2H), 2.41 {m, 2H), 2.15 (m, 3H), 1.88 (m, 1H). 1.48 (s, 3H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[C:4]([CH2:13][CH2:14][CH3:15])=[N:3]1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[C:4]([CH2:13][CH2:14][CH3:15])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CCCc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1nn(C)c(C(N)=O)c1N

Procedure:
A stirred suspenson of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 mol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50° C. for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EP-A-0463756) which was of sufficient purity to use directly in the next stage of the reaction sequence.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[N+:20]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N+:20]([C:23]1[CH:24]=[N:25][N:26]([CH2:6][C@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:27]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc([N+](=O)[O-])cn2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
To a solution of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (2.8 g, 9.5 mmol) and 4-nitro-1H-pyrazole (715 mg, 6.3 mmol) in acetonitrile (100 mL) was added cesium carbonate (6.2 g, 19.0 mmol). The reaction mixture was stirred at 55° C. overnight and then concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL), dried over sodium sulfate, filtered and concentrated. The crude sample was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=8:1, to afford (S)-tert-butyl 2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellow oil (2.12 g, 71%). MS (ES+) C13H20N4O5 requires: 312, found: 257 [M+H-56]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].Cl>COCCOC>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[C:9](=[O:21])[NH:10][C:11]4([CH2:14][CH2:15][C:16]([F:20])([F:19])[CH2:17][CH2:18]4)[C:12]=3[OH:13])[CH:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1ccc(Br)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(F)c(F)c2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O

Procedure:
0.74 g (2.0 mmol) of the compound from Example 11A was initially charged in 5 ml of ethylene glycol dimethyl ether, 14.5 ml of 2M aqueous sodium carbonate solution were added dropwise and 10 mg of bis(trisphenylphosphine)palladium(II) chloride were added. 0.35 g (2.2 mmol) of 3,4-difluorophenylboronic acid was then added, and the mixture was stirred under reflux overnight. After cooling, the mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate, and the extract was dried and concentrated. Purification was carried out by MPLC separation on silica gel using the mobile phase hexane/ethyl acetate 1/1. This gave 0.7 g (70% of theory) of the title compound. 395 mg were then purified again by HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm; mobile phase: water/acetonitrile gradient with addition of 0.1% formic acid]. This gave 121 mg of the title compound.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:21]=[C:22]=[S:23].[K+]>ClCCCl>[CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([N:21]=[C:22]=[S:23])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: [N-]=C=S
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: C=CCNS(=O)(=O)c1cccc(C(=O)N=C=S)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a suspension of 3-(N-allylsulfamoyl)benzoic acid (2 g, 8.29 mmol) in 1,2-dichloroethane (25 mL) was added thionyl chloride (1.271 mL, 17.41 mmol) dropwise. The suspension was stirred for 2 hours at 80° C. After 2 hours, the reaction mixture was concentrated to an off-white solid. The solid was redissolved in 25 mL acetone, and potassium isothiocyanate (0.967 g, 9.95 mmol) was added. A precipitate formed immediately upon addition. The reaction was stirred at 50° C. After 2 hours, the reaction was filtered, concentrated, and adsorbed onto a silca-gel pre column. The residue was purified by column chromatography, eluting with 20-100% EtOAc in hexanes, to provide 3-(N-allylsulfamoyl)benzoyl isothiocyanate as an off-white solid (0.71 g, 30.3% yield). MS, m/z (C11H10N2O3S2): calcd, 282.0. found, 282.9 [M+H].
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:33])([F:35])[F:34])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 9.7 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.52 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as a light yellow solid (0.045 g, 6%). MS (ISN) 484.2 [(M−H)−]; mp 284° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]([CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:6][C:7]([O:9]C)=[O:8])[CH3:4].Cl>C(O)C>[CH2:3]([C:5]([CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:6][C:7]([OH:9])=[O:8])[CH3:4]
Reactant: C=CCCC(=CC(=O)OC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCC(=CC(=O)O)CC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 5 N aqueous sodium hydroxide solution (14.5 mL) was added to an ethyl alcohol (40 mL) solution of methyl 3-ethylhepta-2,6-dienoate (3.04 g, 18.1 mmol), and the mixture was stirred at room temperature for 17 hours. The mixture was neutralized with a 5 N aqueous hydrochloric acid solution (15 mL), followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (2.01 g, 71%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][S:5][C:6](=N)N.[OH-].[Na+].COS(OC)(=O)=O>O>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][S:5][CH3:6]
Reactant: N=C(N)SCc1ccccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSCc1ccccc1I
Temperature: 105 °C
Yield: 89 %

Procedure:
To a mixture of 2-(2-iodo-benzyl)-isothiourea (13.53 g, 36.2 mmol) from previous step and a solution of NaOH (22 mL) in water (15 mL) was added dropwise dimethylsulfate (4.1 mL, 43.4 mmol). The reaction mixture was heated to reflux (105° C.) for 2 h, cooled. The resulting oil was then extracted into diethyl oxyde, the organic layer was washed with water, dried over Na2SO4. On concentration the solution generated a yellow oil that was directly used in the next step without any further purification (8.5 g, yield=89%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(F)(F)F)ccnc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF (dry) (10 mL) was added MeI (0.317 mL). The mixture was stirred at room temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[NH2:28][OH:29]>C(O)C>[F:1][CH:2]([F:27])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=[N:28][OH:29])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: NO
Reactant: O=Cc1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Solvent: CCO
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (2.00 g) in ethanol (33 ml) was added dropwise hydroxylamine (50% in water, 0.36 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then the solvent was removed under reduced pressure. This gave 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde oxime (2.00 g).