Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:8]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]3)[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[CH3:35]>ClCCl.N1C=CC=CC=1>[CH3:35][C:34]1[CH:33]=[CH:32][C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:42][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:44]3)[O:38][N:37]=2)=[CH:30][C:29]=1[NH:28][C:12]([C:9]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14]
Reactant: O=C(O)c1cnc2ccc(C(F)(F)F)cn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(C(F)(F)F)cn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24a) (50 mg, 0.217 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (19 μL, 0.228 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (47 mg, 0.163 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred at room temperature under Argon for 10 minutes and quenched with water. The crude product was purified by preparative HPLC to yield methyl 3-(3-(4-methyl-3-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F52). 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.90-9.85 (m, 1H), 8.72 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.02-7.99 (m, 1H), 7.86 (dd, J=2.0, 8.0 Hz, 1H), 7.79 (dd, J=2.0, 9.2 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 4.37-4.19 (m, 5H), 3.59 (s, 3H), 2.37 (s, 3H). MS m/z 501.43 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1F
Reactant: Brc1ccc(NCc2cccnc2)cc1
Product: Fc1ccccc1Oc1ccc(NCc2cccnc2)cc1

Procedure:
Using the method of Example 342 using N-(4-bromophenyl)pyridin-3-ylmethylamine and 2-fluorophenol (Aldrich)and purifying via preparative HPLC eluting with 90:10 to 80:20 DCM/ethyl acetate gave N-(4-(2-fluorophenoxy)phenyl)pyrid-3-ylmethylamine. Anal Calcd for C18H15FN2O: C, 73.45; H, 5.14; N, 9.52. Found: C, 73.36; H, 5.22; N, 9.35. MS found 295.1 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(S(=O)(=O)c4ccccc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[CH:3](OC)OC.[Cl:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.O>[Cl:16][C:17]1[C:18]2[N:19]([C:2]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=3)=[CH:3][N:23]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(OC)C(Br)c1ccnc(SC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CSc1nccc(-c2cnc3c(Cl)nccn23)n1

Procedure:
The mixture of 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (from Example 43 supra) (7.5 g, 25.6 mmol), 3-chloropyrazin-2-amine (3.96 g, 30.7 mmol) and p-toluenesulfonic acid (1.594 g, 9.22 mmol) in the mix solvent of acetonitrile/water (120 mL:6 mL) was heated at reflux for 6 hours. The reaction mixture was concentrated and purified by chromatography (dichloromethane:methanol, 20:1) to give 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine as a white solid. (Yield 2.3 g, 32.4%). LC-MS: [M+H]+ 278.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:20]1(=[O:24])[O:23][CH2:22][CH2:21]1>C1COCC1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][CH2:21][C:20]([OH:24])=[O:23])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution in THF of 4-phenylphenol (1.86 g, 10.9 mmol) was added potassium tert-butoxide (1.22 g, 10.9 mmol). Neat β-propiolactone (0.68 mL, 10.9 mmol) was added dropwise. The resulting white suspension was stirred overnight at ambient temperature and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic phase was discarded and the aqueous phase was acidified and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to give 3-(4-phenylphenoxy)propionic acid (0.86 g) as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][CH2:8][CH:9]([OH:12])[CH2:10][F:11].Br[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[F:7][CH2:8][CH:9]([O:12][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10][F:11]
Reactant: OC(CF)CF
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC(CF)CF)OCc1ccccc1
Reaction time: 0.67 h
Yield: 42.7 %

Procedure:
Sodium tert-butoxide (0.923 g, 9.60 mmol) in DMF (20 mL)/THF (12 mL) mixture was cooled down to 0° C. and set under N2 atmosphere. 1,3-Difluoropropan-2-ol (0.717 mL, 9.25 mmol) was added via syringe and stirred for 40 min then benzyl 2-bromoacetate (1.373 mL, 8.73 mmol) was added dropwise via syringe and the mixture was stirred at rt for 16 hours. Ethyl acetate and sat NaHCO3 solution were added and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by silica gel chromatography (heptane/EtOAc gradient) to afford the title compound (0.91 g, 43% yield).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[N:33](=[CH:41][CH2:42]Cl)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl>>[N:33]1([CH2:41][CH2:42][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCC=NCCCCCCCl
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:19]C(C)(C)[N:17]([C:22](=[O:26])[CH:23]([F:25])[F:24])[C@@H:16]3[CH2:27][F:28])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[NH2:35]>CN(C)C=O>[F:25][CH:23]([F:24])[C:22]([NH:17][C@H:16]([CH2:27][F:28])[C@H:15]([OH:19])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][NH:35][C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:26]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: Cn1ccnc1N
Solvent: CN(C)C=O
Product: Cn1ccnc1NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
A solution of 1-{(4S,5R)-5-[4-(6-chloromethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (25 mg, 0.06 mmol) and 1-Methyl-1H-imidazol-2-ylamine (30 mg, 0.3 mmol) in dimethyl formamide (2 ml) is heated at 75° C. for 16 h. The reaction mixture is concentrated to dryness, dissolved in CH2Cl2 (1 ml) and treated with trifluoroacetic acid (0.5 ml) and water (0.1 ml). The mixture is shaken at ambient temperature for 2 hours and then concentrated to dryness. The crude product is purified by preparative HPLC to give the title compound (7 mg): 1H NMR (400 MHz, DMSO-d6) 2.50 (s, 3H), 3.51 (s, 2H), 4.24-4.36 (m, 1.5H), 4.37-4.46 (m, 0.5H), 4.51-4.59 (m, 0.5H), 4.63-4.71 (m, 0.5H), 4.87-4.92 (m, 1H), 5.31 (s, 2H), 6.22 (t, 1H), 7.05-7.10 (m, 2H), 7.40-7.52 (m, 3H), 7.66-7.74 (m, 2H), 8.09-8.16 (m, 1H), 8.86 (s, 1H), 9.63-9.69 (m, 1H). m/z M+H 434.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)[N:7]=1)=[O:5])C.[CH:24]([OH:27])([CH3:26])[CH3:25]>>[CH:24]([O:27][C:20]1[N:19]=[CH:18][C:17]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:6]([C:4]([OH:3])=[O:5])=[N:7]2)=[CH:22][CH:21]=1)([CH3:26])[CH3:25]
Reactant: CC(C)O
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(Cl)nc2)n1
Product: CC(C)Oc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Yield: 81 %

Procedure:
The general procedure of Referential Example 125 was repeated through use of the 1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester (1.05 g) prepared in Referential Example 123-3) and isopropanol, to thereby give the title compound as a powder (840 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C@@H:6]3[CH:20]4[CH2:26][CH2:25][N:23]([CH2:24][C@@H:5]3[C:4]=2[CH:3]=1)[CH2:22][CH2:21]4.CO.C(=O)=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C@H:6]3[CH:20]4[CH2:26][CH2:25][N:23]([CH2:24][C@H:5]3[C:4]=2[CH:3]=1)[CH2:22][CH2:21]4
Reactant: Cc1ccc2c(c1)[C@H]1CN3CCC(CC3)[C@H]1N2CCc1ccc(C)nc1
Agent: O=C=O
Solvent: CO
Product: Cc1ccc2c(c1)[C@@H]1CN3CCC(CC3)[C@@H]1N2CCc1ccc(C)nc1

Procedure:
Individual enantiomers of the racemic mixture of Example 158 (150 mg, 0.43 mmol) were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, flow rate 40 mL/minute) to afford the title compound as the first-eluting enantiomer: 1H NMR (500 MHz, methanol-d4) δ ppm 1.46-1.56 (m, 1H), 1.81-1.90 (m, 1H), 1.90-1.99 (m, 1H), 2.19 (s, 3H), 2.25-2.41 (m, 2H), 2.48 (s, 3H), 2.62 (dd, J=14.0, 11.6 Hz, 1H), 2.71-2.87 (m, 4H), 2.90-3.04 (m, 1H), 3.10-3.22 (m, 3H), 3.35-3.44 (m, 1H), 3.45-3.53 (m, 1H), 3.82 (dd, J=8.5, 5.2 Hz, 1H), 6.39 (d, J=7.9 Hz, 1H), 6.78 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.62 (dd, J=7.9, 2.1 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H); MS (APCI) m/z 348 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3F)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:32])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]23[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=[C:26]2[O:32][C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]3=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCCC1(c1ccc(OCc2ccccc2)cc1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: Fc1cccc2c1C1(c3ccc(OCc4ccccc4)cc3)CCCCC=C1O2
Temperature: 90 °C

Procedure:
KHMDS (0.2 mL, 0.5 M in toluene) was added to a solution of 2-(4-(benzyloxy)phenyl)-2-(2,6-difluorophenyl)cycloheptanone (50 mg) in toluene (3 mL) and DMPU (1 mL). The reaction mixture was heated at 90° C. for 2 h (TLC indicated some conversion of the starting material). Additional heating for 1 h gave no further conversion of the starting material according to TLC. The organic phase was washed with water (10 mL), brine, dried (Na2SO4) and concentrated in vacuo. Work-up by flash chromatography (eluent heptane dichloromethane 1:1) afforded the title compound 22 in a yield of 20 mg. 1H-NMR (400 MHz, CDCl3): δ ppm 7.49-7.46 (m, 2H), 7.50-7.34 (m, 5H), 7.10-7.00 (m, 1H), 6.96-6.91 (m, 2H), 6.61-6.59 (m, 1H), 6.53-6.48 (m, 1H), 5.73 (dd, J=5, 9 Hz, 1H), 5.02 (s, 2H), 3.07-3.02 (m, 1H), 2.00-1.20 (m, 8H).
Reaction SMILES: F[C:2](F)(C1C=CC(F)=CC=1)C1N=C(NC2C=C(C)NN=2)C2C(=CC(F)=CC=2)N=1.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=2)[N:33]=[C:32]([C:41]([F:50])([F:49])[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[N:31]=1>>[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([CH3:2])=[CH:37][CH:38]=2)[N:33]=[C:32]([C:41]([F:49])([F:50])[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[N:31]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccc(F)cc3n2)cc1
Reactant: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Product: Cc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Yield: 13 %

Procedure:
2-(Difluoro(4-fluorophenyl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine was obtained according to the procedure described in Example 20 for preparation of 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, substituting 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline in Example 20 with 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazoline (13% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.50 (s, 3H), 6.30 (s, 1H), 7.34 (t, 2H), 7.47 (m, 1H), 7.71-7.66 (m, 3H), 8.56 (d, 1H), 10.59 (s, 1H), 12.20 (bs, 1H); LC-MS (ESI) m/z 384 (M+H)+.
Reaction SMILES: [C:1]([N:4]([O:42][CH3:43])[C:5]1([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36])(=[O:3])[CH3:2].Cl.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>O1CCOCC1>[OH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([N:4]([O:42][CH3:43])[C:1](=[O:3])[CH3:2])([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:6](=[O:36])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:25][C:19]=2[S:18](=[O:34])(=[O:35])[N:17]=1
Reactant: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A mixture of the product of Example 39A (16 mg, 0.026 mmol) and 4 N HCl in dioxane (0.26 mL) was stirred at room temperature for 4 h and then concentrated in vacuo. The resulting residue was taken up in dichloromethane (1 mL) and triethylamine (36 μL, 0.3 mmol) and methanesulfonyl chloride (10μL, 0.13 mmol) were then added. The reaction solution was stirred at room temperature for 2 h. The solution was then washed with aqueous 1 N HCl (2×0.5 mL), dried (Na2SO4), and concentrated in vacuo. The residue was then dissolved in methanol (1 mL) and treated with excess of K2CO3 for 30 min. The mixture was diluted with ethyl acetate (3 mL) and filtered. The filtrate was washed with aqueous 1 N HCl (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (1%→3%→5% methanol/dichloromethane) afforded the title compound as a yellow solid (8 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.38-0.56 (m, 1H), 0.60-0.73 (m, 6H), 0.91-1.09 (m, 1H), 1.17-1.39 (m, 2H), 2.01 (s, 3H), 2.11-2.32 (m, 1H), 3.03 (s, 3H), 4.05 (s, 3H), 7.32-7.62 (m, 7H), 8.05 (d, J=7.72 Hz, 1H), 10.05 (s, 1H), 14.46 (s, 1H); MS m/z 591.1 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[CH2:14][NH2:15].C(N(C(C)C)CC)(C)C.C(OCC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:15][CH2:14][C:13]1[CH:16]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=1[F:17])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)NCc1cc(Br)ccc1F
Yield: 91.8 %

Procedure:
Add ethyl chloroformate (0.24 mL, 2.49 mmol) to a solution of 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol). After 3 h dilute the reaction with diethyl ether and wash twice with 1 N hydrochloric acid and once with an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a colorless oil (0.527 g, 92%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:4][OH:5].[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1)[CH2:4][O:5][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)[C@H](COCCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 6.7 %

Procedure:
(2R)-3-Methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (50 mg, 0.201 mmol), which is the compound obtained in Step 1 of Example 2, phenethylbromide (0.22 mL, 2.01 mmol) and tetrabutylammonium hydrogensulfate (catalytic amount) were added to a mixed solvent of benzene(1 mL) and 50% aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 days. After work-up according to a conventional method, the mixture was purified by purification step A to give the title compound (4.76 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5].Cl[C:14]1([C:25]2[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[NH:16][C:15]1=[O:24].C1COCC1.CCN(C(C)C)C(C)C>ClCCl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:14]1([C:25]2[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[NH:16][C:15]1=[O:24])=[O:5]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.67 g, 3.44 mmol) was added to a solution of the intermediate from step B in a mixture of dichloromethane (10 ml), THF (2 ml) and DIPEA (1.6 ml). The reaction mixture was stirred at room temperature for 18 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 0.58 g of the more polar diastereomer, 0.2 g of the less polar diastereomer and 0.4 g of a mixture of diastereomers (ratio about 1:1).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:17].CN(C=O)C>ClCCl>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC)c(C(=O)O)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a mixture of 2-fluoro-3,6-dimethoxybenzoic acid (4.8 g, 24 mmol) in anhydrous dichloromethane (75 mL) at 0° C., SOCl2 (14.2 g, 120 mmol) was slowly added followed by DMF (0.1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to give 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g). To a solution of ethyl 2-(3-methoxyphenyl)acetate (4.7 g, 24 mmol) in anhydrous THF (40 mL) at −78° C., LiHMDS (1.0 M in THF, 36 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min and a solution of 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g, 24 mmol) in anhydrous THF (60 ml) was added dropwise. The reaction mixture was stirred for additional 2 h at −78° C. and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (7.8 g).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[OH-].[Na+].[Br-].[NH4+].[I-].[NH4+].[N+]([O-])([O-])=O.[Ag+:23]>C(OCCCC)(=O)C.O>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:23]
Reactant: CCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCCCCCCC(=O)[O-]

Procedure:
A solution prepared by dissolving 11 g of capric acid in 100 ml of butyl acetate was mixed with a solution prepared by dissolving 1.8 g of sodium hydroxide in 150 ml of water and, further, 0.25 g of ammonium bromide and 0.02 g of ammonium iodide were added thereto, followed by stirring with a homogenizer at 1500 rpm to emulsify the system. While stirring, an aqueous solution prepared by dissolving 8.5 g of silver nitrate in 50 ml of water was added thereto to yield both silver halide and silver caprate. This reaction system separated into two phases when allowed to stand. An aqueous phase, one of the two phases, was removed, and the remaining butyl acetate phase containing silver caprate and silver halide (silver caprate: ca. 1/20 mol, AgX: ca. 2.5×10-3 mol) was dispersed in a 15 wt% isopropanol solution of polyvinyl butyral to prepare a polymer dispersion of the silver salts. This solution was referred to as dispersion K.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10]N1C(=O)CCC1=O>CN(C=O)C>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:9])=[C:4]([F:8])[CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of 2,6-Difluorophenol (10.0 g, 76.86 mmoles) in DMF (60 mll), N-bromosuccinimide (13.68 g, 76.86 mmoles) was added at 0° C. and stirred at RT for 20 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow liquid (15.1 g, 93% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.49 (s, 1H), 7.35 (d, J=6.2 Hz, 2H).