Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[C:44]([O:46][CH3:47])=[O:45].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:47][O:46][C:44]([C:43]1[CH:42]=[CH:41][C:40]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:39][C:38]=1[Cl:37])=[O:45]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(Cl)c4)cc3Cl)C(F)(F)F)cc21
Temperature: 70 °C
Reaction time: 6.5 h
Yield: 71.2 %

Procedure:
Trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (150 mg, 0.27 mmol), 3-chloro-4-(methoxycarbonyl)phenylboronic acid (86 mg, 0.4 mmol) and 1,1,bis(diphenylphosphino)-ferrocenpalladium(II)dichloromethane (11 mg, 0.05% mol) in dioxane (0.8 ml) was treated with water (0.6 ml) and 1M-Na2CO3 (0.4 ml, 0.4 mmol) and stirred at 70° C. under argon for 6.5 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 4:1) to give the title compound (112 mg) as a white solid. MS (m/e)=582.3 [M+H+]
Reaction SMILES: [C:1]([C:3]1([O:14][Si](C)(C)C)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].CSC.B.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[NH2:2][CH2:1][C:3]1([OH:14])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(O[Si](C)(C)C)C1
Agent: B
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(CN)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of tert-butyl 3-cyano-3-(trimethylsilyloxy)azetidine-1-carboxylate (300 mg, 1.11 mmol) in THF (5 mL) was treated with borane methylsulfide complex (2M in THF, 2 mL) and the mixture was heated at 70° C. for 1 h under nitrogen. Then the mixture was cooled to room temperature and quenched with methanol (5 mL) followed by treatment with ethylenediamine (0.28 mL), this mixture was stirred at 25° C. for 1 h, and then warmed to 55° C. for 1 h. After cooling to room temperature, the reaction mixture was treated with tetrabutylammonium fluoride (1 M in THF, 2 mL, 2 mmol), then stirred at 25° C. for 1 h. The mixture was diluted with 50 mL of water, product extracted with ethyl acetate (3×25 mL), organics combined dried with sodium sulfate, filtered and concentrated to afford tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate (200 mg, crude) as white solid which was used to next step without further purification.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C1COCC1>[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:15][CH2:16][N:17]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:19]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccc(N2CCNCC2)c(C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N1CCN(c2ccc(C)cc2C(C)(C)C)CC1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
To a stirred suspension of 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (Reference Example 10, 0.300 g, 0.98 mmol) and triethylamine (548 μl, 3.93 mmol) in THF (10 mL) stirring at 0° C. was added ethyl chloro(oxo)acetate (0.175 mg, 1.28 mmol). The mixture was warmed to room temperature. After 3 days the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide ethyl [4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl](oxo)acetate (0.233 g, 71%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:53]=[CH:52][C:51]2[CH2:50][CH:49]([C:54](O)=[O:55])[CH2:48][CH2:47][C:46]=2[N:45]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:54]([CH:49]1[CH2:48][CH2:47][C:46]2[N:45]=[C:44]([C:43]([F:58])([F:42])[F:57])[CH:53]=[CH:52][C:51]=2[CH2:50]1)=[O:55])[CH3:4]
Reactant: O=C(O)C1CCc2nc(C(F)(F)F)ccc2C1
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 73.9 %

Procedure:
A 2 mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (14 mg, 0.049 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (17 mg, 0.044 mmol). A solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (6.0 mg, 0.024 mmol) and N,N-diisopropylethylamine (21 uL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL, 4 mmol) was added, and the mixture stirred to dissolution. After 40 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (8.4 mg, 72%). 1H NMR (400 MHz, CD3OD) δ 7.73 (app t, J=8.3 Hz, 1H), 7.53 (dd, J=3.8, 8.0 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.14 (dd, J=1.4, 11.7 Hz, 1H), 5.19 (app pentet, J=7.0 Hz, 1H), 3.17-2.94 (m, 4H), 2.98 (s, 3H), 2.82-2.71 (m, 1H), 2.32 (s, 3H), 2.23-2.12 (m, 1H), 2.07-1.89 (m, 1H), 1.47 (d, J=7.0 Hz, 3H); m/z=474.4 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]3[N:46]=[C:47]([C:49](O)=[O:50])[CH:48]=[C:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].N1C=CC=CC=1CN.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[N:10]1[CH:11]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][NH:8][C:49]([C:47]1[CH:48]=[C:38]2[N:37]=[C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[N:39]2[N:46]=1)=[O:50]
Reactant: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.141 g, 0.319 mmol) was added to a suspension of 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.100 g, 0.265 mmol) and C-Pyridin-2-yl-methylamine (0.033 mL, 0.319 mmol) in tetrahydrofuran (10 mL) containing triethylamine (0.111 mL, 0.795 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (pyridin-2-ylmethyl)-amide (0.073 g, 59%)
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH2:14])=[CH:11][CH:10]=[CH:9]2)=[N+:2]=[N-:3].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CCOCC>[C:21]([NH:14][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:1]=[N+:2]=[N-:3])[CH:9]=[CH:10][CH:11]=1)(=[O:23])[CH3:22]
Reactant: [N-]=[N+]=Nc1cccc2cccc(N)c12
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2cccc(N=[N+]=[N-])c12

Procedure:
To a stirred solution of 8-azido-1-naphthylamine (1.84 g., 0.01 mole) in 70 ml. of pyridine was added a solution of acetyl chloride (0.784 g., 0.01 mole) in 10 ml. of ether. The mixture was warmed on a steam bath for 30 minutes. The solvents were removed in vacuo and the residue washed with water and dried. Recrystallization from hexane provided 1-acetamido-8-azidonaphthalene in the form of colorless, long needles having a yield of 2.1 g., 93 percent, m.p. 148°C.-149°C., Lit. m.p. 147°C.-148°C. and an analysis of: Calcd. for C12H10N4C: C, 63.70; H, 4.46; N, 24.77 Found: C, 63.90; H, 4.14; N, 24.66
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:6]=1)=[O:4].[ClH:23]>C(OCC)C>[ClH:23].[NH:13]1[CH2:14][CH2:15][CH:10]([N:7]2[CH:8]=[CH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]2)[CH2:11][CH2:12]1
Reactant: COC(=O)c1ccn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccn(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[3-(methoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate (300 mg, 0.97 mmol) (i.e. the product of Example 18, Step B) in 5 mL of diethyl ether was added a 2 M solution of hydrogen chloride in ether (4.85 mL, 9.7 mmol), and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was evaporated in vacuo, the resulting residue was dissolved in methanol and concentrated in vacuo. The residue was dried in high vacuum to give 200 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N: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.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>CN1C(=O)CCC1>[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[N: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
Reactant: CC1CCCN1
Reactant: Cc1nc(C#Cc2cnc(Cl)nc2)cs1
Solvent: CN1CCCC1=O
Product: Cc1nc(C#Cc2cnc(N3CCCC3C)nc2)cs1
Temperature: 200 °C

Procedure:
117 mg (0.50 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine, 0.50 mL (5 mmol, 10 eq) 2-methylpyrrolidine and 1 mL NMP were combined. The reaction mixture was heated at 200° C. for 15 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 40% EtOAc/Hexanes) gave 2-(2-methylpyrrolidin-1-yl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine (L-001152863). LC-MS calculated for C15H16N4S 284, observed m/e 285.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C@H:17]2[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:20])[CH2:3]1.[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O.CCCCCC>C1C=CC=CC=1.CCOC(C)=O>[CH2:22]1[O:23][C:11]2([CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@@H:17]2[C@@H:4]([CH2:3][CH:2]([OH:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)[O:20][CH2:21]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(O)CC[C@@H]43)[C@@H]1CCC21OCCO1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Compound 4(10 g, 36.2 mmol) was dissolved in dry benzene (150 ml) mixed with ethylene glycol (25 ml, 280 mmol) and pyridinium p-toluenesulfonate (1 g, 3.9 mmol) and refluxed using a Dean-stark separator overnight till no starting material was detected by TLC. The cold solution was diluted with EtOAc (100 ml), washed twice with brine, dried on Na2SO4 and the solvents removed under reduced pressure. Flash-chromatography on silica gel with EtOAc: Hexane 4:6 as eluant to give 11.0 g (94.5% yield) the title compound as a white solid.
Reaction SMILES: [C:1]1([N:7]([CH2:28][CH2:29][CH3:30])[C@H:8]([C:13]([NH:15][N:16]=[CH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#N.[Na+].C(O)(=O)C>C1COCC1>[C:1]1([N:7]([CH2:28][CH2:29][CH3:30])[C@H:8]([C:13]([NH:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(c1ccccc1)[C@@H](CC(C)C)C(=O)NN=CCCNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN(c1ccccc1)[C@@H](CC(C)C)C(=O)NNCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
This procedure is based on the method used by Gallina et al. to synthesize a series of Z-hydrazines [Calbretta et al, Eur. J. Med. Chem. 30, 931 -941 (1995); incorporated herein by reference]. PhPr-Leu-NH—N═CH(CH2)2—NH-Boc (1.928 g, 4.46 mmol) and NaBH3CN (5 eq, 1.400 g, 22.3 mmol) were dissolved in anhydrous THF (23 mL). Glacial acetic acid (104 eq, 27.85 g, 464 mmol, 26.5 mL) was added dropwise to the solution, and the reaction mixture was allowed to stir at rt overnight. The solvents were evaporated and the crude oil dissolved in ethyl acetate (20 mL). Distilled water (20 mL) was added to the solution, which was vigorously stirred while enough solid NaHCO3 was added to turn the pH of the aqueous layer basic. The organic layer was isolated and washed with a saturated NaCl solution (2×15 mL), a saturated NaHCO3 solution (10 mL), and again with a saturated NaCl solution (10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The crude solid was purified by silica gel chromatography using 1/1 ethyl acetate/hexanes as the eluent. The solvent was evaporated, leaving a white, foamy solid that was used without further purification: yield 59%; product spot on TLC, Rf=0.43 (10% CH3OH in CH2Cl2). 1H NMR (CDCl3) δ 9.80 (s, 1H), 9.54 (s, 1H), 7.30-7.13 (m, 5H), 6.94 (s, 1H), 6.60 (s, 1H), 4.60-4.47 (m, 1H), 3.25-3.06 (m, 2H), 3.04-2.93 (m, 4H), 2.60-2.51 (m, 2H), 2.87-1.72 (m, 3H), 1.70-1.60 (m, 2H), 1.42 (s, 9H), 0.98-0.82 (m, 6H). MS (ESI+) m/z 435 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[H-].[Na+]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCCCn3ccnc3)ccc2c1-c1ccc(Br)cc1
Temperature: 0 °C
Yield: 86.7 %

Procedure:
A solution of 100 mg (0.220 mmol) 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5), 0.024 g (0.35 mmol) of imidazole and 0.0144 g (0.330 mmol) sodium hydride (55% suspension in oil) in 0.5 ml of N,N-dimethylformamide was stirred for 1 hour at room temperature. The reaction mixture was then poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and methanol as the eluent yielding 84.2 mg (86.7%) 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxyl]-butyl}-1H-imidazole as colorless oil, MS: 441 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:21])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[N:24]2[CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(Cl)cc1NCc1ccncc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccncc2)c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 20.3 %

Procedure:
655 mg (3.01 mmol) of 4-chlorobenzenesulfonylisocyanate and 620 mg (2.35 mmol) of 4-chloro-2-(4-pyridylmethyl)aminobenzoic acid were treated in the same way as in Example 1 to obtain 220 mg of the above-identified compound (yield 16.6%). Properties: colorless crystal, Melting point: >240° C. (decomposition), PMR (δppm, DMSO-d6):5.35 (2H,s), 7.2-7.4 (5H,m), 7.4-7.8 (4H,m), 8.01 (1H,d), 8.50 (2H,d), 11.85 (1H,s)
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]=[C:15](OC)[C:14]2=[O:21])=[CH:9][CH:8]=1>CN(C=O)C>[Cl:3][C:15]1[C:14](=[O:21])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nccn(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Product: O=c1c(Cl)nccn1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
POCl3 (5.6 mL, 61.3 mmol) was added dropwise to a solution of 1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one in DMF (30 mL) with stirring at 0° C. followed by heating at 90° C. for 1.5 hours. The residue was cooled to 0° C., quenched by adding saturated sodium acetate solution, extracted with CH2Cl2, washed with water, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (0.7% MeOH in CH2Cl2) to afford 3.52 g (64%) of the desired product. LRMS (ESI pos) m/e 224.9, 227.0 (M+1, Cl pattern). 1H-NMR (400 MHz, CDCl3) δ 7.41 (m, 2H), 7.21 (m, 4H); 19F-NMR (376 MHz, CDCl3) δ −110.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21](C#N)[CH:22]=1)[O:6][C:7]1[C:8]([F:19])=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:2].C(C1C=C(C=C(C(F)F)C=1)OC1C(F)=C(CC(O)=O)C=CC=1OC)#N.CN1C2C(C(OC)=O)C(OC(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)CC1CC2.[Cl:79]C1C=C(C=C(O)C=1)C#N>>[Cl:79][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH:22]=1)[O:6][C:7]1[C:8]([F:19])=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: N#Cc1cc(O)cc(Cl)c1
Reactant: COc1ccc(CC(=O)O)c(F)c1Oc1cc(C#N)cc(C#N)c1
Agent: COC(=O)C1C(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC2CCC1N2C
Agent: COc1ccc(CC(=O)O)c(F)c1Oc1cc(C#N)cc(C(F)F)c1
Product: COc1ccc(CC(=O)O)c(F)c1Oc1cc(Cl)cc(C#N)c1

Procedure:
[3-(3,5-Dicyano-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-45) and [3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-46) can be prepared similarly except R-10 and R-26 respectively are used in place of 3-chloro-5-hydroxy-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:27]([C:31]1[N:32]=[N:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=NN=1)([O:29][CH3:30])=[O:28].N1C=NN=CN=1.CCOC(C)=O.C(Cl)Cl>C1(C)C=C(C)C=C(C)C=1>[CH3:22][O:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:13]([C:12]2[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:31]([C:27]([O:29][CH3:30])=[O:28])[N:32]=[N:33][C:34]=2[C:37]([O:39][CH3:40])=[O:38])=[C:14]([O:23][CH2:24][O:25][CH3:26])[CH:15]=1
Reactant: COCOc1cc(OC)c(OC)cc1C#Cc1ccc(OC)c(OC)c1
Reactant: COC(=O)c1nnc(C(=O)OC)nn1
Agent: c1nncnn1
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)nnc(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Temperature: 140 °C
Yield: 91.8 %

Procedure:
A solution of 6 (1.10 g, 3.07 mmol, 1.0 equiv) and 3,6-dicarbomethoxy-1,2,4,5-tetrazine (2,13 0.91 g, 4.60 mmol, 1.5 equiv) in mesitylene (15.4 mL) was warmed at 140° C. under Ar for 24 h. Additional 2 (0.91 g, 4.60 mmol, 1.5 equiv) was added, and the mixture was maintained at 140° C. for an additional 24 h before the reaction mixture was cooled to 25° C. and the solvent was evaporated. Chromatography (SiO2, 4.5 (20 cm, 30% EtOAc/CH2Cl2) provided 7 (1.49 g, 92% yield) as an orange oil. An analytically pure sample was prepared by recrystallization from EtOAc-hexanes: mp 131-133° C.; FABHRMS (NBA/NaI) m/z 551.1663 (M+Na+, C26H28N2O10 requires 551.1642).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:7](=[O:9])[C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Yield: 50.5 %

Procedure:
Reaction of 1.24 g of (R)-methoxycarbonylamino-cyclohexyl-acetic acid and 1.40 g of (L)-proline benzyl ester hydrochloride using the procedure described for example 91b gave 1.17 g (50%) of the title compound as a colorless oil. (+)-APCI-MS: 403 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)(=[O:10])[CH3:9]>ClCCl>[NH:15]1[CH2:16][CH2:17][O:18][C@H:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[CH2:14]1
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@@H]1CNCCO1

Procedure:
To a 4:1 solution of dichloromethane and TFA (0.1 M) was added (R)-tert-butyl 2-(acetamidomethyl)morpholine-4-carboxylate. After 1 h the solution was then concentrated in vacuo to give crude (S)—N-(morpholin-2-ylmethyl)acetamide which was used in the next step without further purification. LCMS (m/z) (M+H)=159.0, Rt=0.11 min.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.29 min.; [M+H]+: 423.10 g/mol.