Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].[CH:21]1[C:26]([CH:27]=O)=[CH:25][C:24]2[O:29][CH2:30][O:31][C:23]=2[CH:22]=1.N>>[O:31]1[C:23]2[CH:22]=[CH:21][C:26]([CH2:27][N:18]3[CH2:19][CH2:20][CH:15]([NH:14][C:6]4[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=5)[O:9][C:8](=[O:13])[CH:7]=4)[CH2:16][CH2:17]3)=[CH:25][C:24]=2[O:29][CH2:30]1
Reactant: CCc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: N
Product: CCc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1

Procedure:
Prepared from 6-Ethyl-4-(piperidin-4-ylamino)-chromen-2-one and piperonal in a manner analogous to that described above. 1H NMR (300 MHz, MeOD-d4) δ ppm 1.28 (t, J=7.63 Hz, 3H) 1.92 (m, 2H) 2.34 (m, 2H) 2.74 (q, J=7.46 Hz, 2H) 3.22 (m, 2H) 3.60 (m, 2H) 3.86 (m, 1H) 4.26 (s, 2H) 5.40 (s, 1H) 6.04 (s, 2H) 6.94 (m, 2H) 7.01 (m, 2H) 7.25 (m, 1H) 7.48 (m, 1H) 7.86 (s, 1H); MS (DCI/NH3) m/z 407 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:17][CH2:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OCCc1cccnc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OCCc2cccnc2)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 2-(3-pyridyl)ethanol (405 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The crude product, obtained as an oil (0.62 g, 88% yield), was used directly in the next step. MS m/z 235 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([O:1][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ncccc1[N+](=O)[O-])c1ccccc1
Yield: 50 %

Procedure:
A solution of 2-hydroxy-3-nitropyridine (0.42 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.41 g, 50% yield) as a yellow solid.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][C:31]6[S:32][CH:33]=[CH:34][N:35]=6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: Brc1nccs1
Product: O=c1c2ccc(Oc3nccs3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
According to Method AB, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-bromothiazole. In this way the product was obtained with molecular weight 476.58 (C26H25FN4O2S); MS (ESI): 477 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]([CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=O.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([CH:18]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]4)[N:13]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)CBr)C1
Reactant: Nc1nccnc1N1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cn3ccnc(N4CCOCC4)c3n2)C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of compound 1b (2.4 g, 13 mmol) in DMF (20 mL), Na2HPO4 (4.7 g, 33 mmol) was added followed by tert-butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (6.0, 21 mmol). The resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was allowed to cool to rt and water (50 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOAc/hexanes) to obtain compound 29a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H25N5O3: 360.2 (M+H). found: 360.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:38]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:23][N:38]=[C:24]3[S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.83 h
Yield: 70.1 %

Procedure:
A suspension of 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (2.36 g, 4.57 mmol) in ethanol and 1.0 N hydrochloric acid (85 mL) was heated to aid dissolution. The reaction mixture was treated slowly with sodium nitrite (0.549 g, 7.96 mmol) in water, stirred at ambient temperatures for 50 minutes, basified with solid sodium carbonate, stirred at ambient temperatures for 30 minutes and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified twice by flash chromatography with 2% methanol in chloroform and with 1.5-10% methanol in chloroform to afford 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff-colored foam, 1.69 g (70.1% yield), Mass spectrum (+EI, [M+H]+) m/z 528. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.72-8.75 (m, 1H), 8.55 (d, 1H, J=7.44 Hz), 8.17-8.27 (m, 1H), 7.98-8.03 (m, 1H), 7.52-7.74 (m, 4H), 7.19-7.34 (m, 6H), 7.06 (d, 1H, J=8.78 Hz), 4.99-5.09 (m, 3H), 3.61-3.70 (m, 1H), 3.34-3.55 (m, 3H), 2.11-2.28 (m, 1H), 1.99-2.07 ppm (m, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([CH3:16])=[CH2:15])=[N:11][C:10]=1[C:17]([OH:19])=O)=O)(C)(C)C.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]([CH3:16])=[CH2:15])=[N:11][C:10]=1[C:17]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]1)=[O:19]
Reactant: C=C(C)c1nc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: C=C(C)c1nc(C(=O)Nc2cnccc2N2CCC[C@H](N)C2)c(N)s1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(prop-1-en-2-yl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (9 mg). ESIMS m/z=359.3 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:15]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([OH:28])=[CH:20][C:19]=1[C:29]([F:32])([F:31])[F:30])([O-:17])=[O:16]>CC(C)=O>[CH2:7]([O:28][C:21]1[CH:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[C:18]([N+:15]([O-:17])=[O:16])=[C:23]([C:24]([F:25])([F:26])[F:27])[CH:22]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1c(C(F)(F)F)cc(O)cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 13 h
Yield: 94.2 %

Procedure:
Under ice cooling, potassium carbonate (7.23 g, 52.3 mmol) and benzyl bromide (5.45 mL, 45.8 mmol) were added to a solution of 4-nitro-3,5-bis(trifluoromethyl)phenol (12.0 g, 43.6 mmol) in acetone (250 mL). After stirring at 50° C. for 13 hours, the reaction mixture was filtered and the insoluble matter was washed with acetone. To the residue obtained by distilling the filtrate under reduced pressure, ethyl acetate and water were added to allow it to separate into layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from hexane-acetone, whereby 15.0 g (yield: 94.3%) of 4-benzyloxy-2,6-bis(trifluoromethyl)nitrobenzene was obtained as pale yellow needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][C:15]=2[O:14]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:22]3[O:23][CH2:13][O:14][C:15]=3[CH:16]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Temperature: 25 °C

Procedure:
A solution of 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine (3.29 g) in dichloromethane (30 ml) is charged with 3,4-methylenedioxybenzylamine ("A") (3.02 g). Triethylamine (1.52 g) is added, and the mixture is stirred at room temperature. The solvent is removed, and the usual workup yields 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(=O)O[CH2:16][CH2:15][O:14]1>[I-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:16][CH2:15][OH:14])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C1OCCO1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CCOC(C)=O
Product: O=C(OCCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture of p-nitrobenzoic acid (33.4 g, 0.2 mole), ethylene carbonate (19.4 g, 0.22 mole) and tetraethylammonium iodide (9.6 g, 0.036 mole) was heated at 140° C. for 45 minutes. On cooling, the mixture was dissolved in ethyl acetate (500 ml) and washed with water (3×) and saturated sodium chloride. The organic solution was dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was shown to be a mixture of the desired product and a small amount of the diester product, bis-(4-nitrobenzoyl)-ethylene glycol, by TLC (silica gel, ethyl acetate as mobile phase; Rf 's=0.5 and 0.7, respectively). The mixture was therefore chromatographed on silica gel, eluting first with benzene and then with chloroform to give hydroxyethyl p-nitrobenzoate (31 g) as a pale yellow solid, m.p. 77°-78° C., which was homogeneous by TLC.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:18]=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[N:2]([CH2:3][C:4]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:5])[C:24]([CH3:25])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(=O)CCC(=O)c1ccnc(Cl)c1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A slurry of benzyl 2-aminoacetate hydrochloride (922 mg, 4.57 mmol), 1-(2-chloropyridin-4-yl)pentane-1,4-dione (968 mg, 4.57 mmol), and solid sodium bicarbonate (961 mg, 11.4 mmol) in dichloromethane (15.2 mL) was heated to 45° C. for 14 hours. A significant amount of starting material was observed after 14 hours by LC/MS, so the reaction was heated to 65° C. The reaction was allowed to stir (with occasional monitoring by LCMS) at this temperature for 11 days. The reaction was then allowed to cool down to room temperature and poured onto water and extracted with dichloromethane (3×50 mL), dried (sodium sulfate), filtered, and concentrated to a dark orange residue. Purification was achieved by column chromatography (Luknova 80 g, 20 mL/min) using 5 to 45% ethyl acetate in hexanes over 60 minutes. The product, benzyl 2-(2-(2-chloropyridin-4-yl)-5-methyl-1H-pyrrol-1-yl)acetate was isolated as a light orange oil (890 mg, 2.61 mmol, 57% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.23 (d, 1H), 7.36-7.40 (m, 5H), 7.21 (m, 1H), 7.02 (dd, 1H), 6.37 (d, 1H), 6.07 (d, 1H), 5.25 (s, 2H), 4.64 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared in analogy to example 8 from 4-nitro-3-(trifluoromethyl)-phenol and 3-Fluoro-benzylbromide. Yield=85%. Yellowish solid. MS (ISP): m/e=333.2 (M++NH4).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:9]=1)C>O.C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:27])=[O:5])=[CH:9][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=1[Cl:26]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Sodium hydroxide (0.72 g) in water (40 ml) was added to the product from step (v) (3.6 g) in THF (40 ml) and stirred at RT overnight. The reaction was quenched with 2M HCl, extracted with EtOAc, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from EtOAc/isohexane to give the subtitle compound (2.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH3:27])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ccnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e 442.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 2-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[Br:25])=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: Cc1cccc(Br)c1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C)cccc1Br
Yield: 64 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-bromo-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 64% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-bromo-6-methylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 563.0138. Calcd. mass, 563.0140 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][C@H:8]([NH2:7])[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (420 mg, 0.91 mmol) in DCM (6 mL) was added TFA (3 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (284 mg, 86%). LCMS (Method B): RT 2.16 min [M+H]+ 363.20.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:23]([C:33]([F:36])([F:35])[F:34])=[N:24][N:25]([CH:28]([CH3:32])[C:29](O)=[O:30])[C:26]=1[CH3:27]>>[Cl:21][C:22]1[C:23]([C:33]([F:35])([F:34])[F:36])=[N:24][N:25]([CH:28]([CH3:32])[C:29]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:30])[C:26]=1[CH3:27]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Agent: Cl
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 2-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]propanoic acid (282 mg). After chromatographic purification, this gives 2-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}propan-1-one (165 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[I:11]I>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:11])=[CH:4][C:3]=1[F:10]
Reactant: II
Reactant: COc1ccc(F)c(Br)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1I
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 equiv) in DCM (5.0 L) was added silver trifluoromethane sulfonate (686.0 g, 2.68 mol, 1.1 equiv, Angene) and the reaction mixture was stirred for 20 mins. Iodine (678.0 g, 2.68 mol, 1.1 equiv) was added to the reaction and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and filtered through celite. The celite bed was washed with DCM (2×1.0 L) and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to get 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%), as off-white solid. TLC solvent system: 100% hexanes. Product's Rf: 0.6. MS (ESI, positive ion) m/z: 331.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=7.2 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.[CH2:24]([O:31][C:32](ON1C(=O)CCC1=O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([O:31][C:32]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (5.04 g, 23.2 mmoles) was suspended in chloroform (80 mL) and N,N-diisopropylethylamine (4.10 mL, 23.5 mmoles) and N-(benzyloxycarbonyloxy)succinimide (6.48 g, 26.0 mmoles) were added. The reaction mixture was stirred at room temperature for 4 hours, during which time all solids dissolved. The reaction mixture was then extracted with 1N aqueous hydrochloric acid (100 mL), water (75 mL), and saturated aqueous sodium chloride (50 mL). The chloroform solution was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a white solid. The product was crystallized from ethyl acetate:hexanes to afford 6.17 g (84% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (m.p. 91°-92° C., open capillary, uncorrected).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[C:10]=[S:11]>>[Br:1][C:2]1[C:3]([NH:8][C:10]([NH:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[S:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=S
Reactant: Nc1ncccc1Br
Product: COc1ccccc1NC(=S)Nc1ncccc1Br

Procedure:
1-(3-Bromo-pyridin-2-yl)-3-(2-methoxy-phenyl)-thiourea was prepared from 3-bromo-pyridin-2-ylamine (5.0 g, 29.0 mmol) and 1-isothiocyanato-2-methoxy-benzene (4.0 mL, 29.0 mmol) in a manner analogous to Step 19a. The reaction product was isolated as a yellow solid (8.46 g, 86%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 13.62 (br s, 1H), 8.75-8.65 (m, 2H), 8.21 (dd, J=5.1, 1.5 Hz, 1H), 7.91 (dd, J=8.0, 1.6, Hz, 1H), 7.21 (dt, J=7.9, 1.5 Hz, 1H), 7.06-7.00 (m, 1H), 6.98-6.94 (m, 1H), 6.91 (dd, J=7.9, 5.0 Hz, 1H), 3.93 (s, 3H). MS=340 (MH)+.