Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)([CH3:3])[CH3:2].[C:10]([CH2:12][C:13]1([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[N:37](COCC[Si](C)(C)C)[CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=2)[CH2:14]1)#[N:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CC(N)C.C([O-])(O)=O.[Na+].C(N)CN>CN(C=O)C>[C:10]([CH2:12][C:13]1([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[NH:37][CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:14][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:25])=[N:21][CH:22]=2)[CH2:16]1)#[N:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: NCCN
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (19 μL, 0.11 mmol) was added to a mixture of 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid (19.4 mg, 0.0365 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.044 mmol) and 2-propanamine (3.2 mg, 0.055 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was treated with methylene chloride (1.3 mL) and TFA (1.3 mL). The mixture was stirred at room temperature for 1.5 h., and concentrated under reduced pressure. The residue was dissolved in methanol (1.3 mL), and treated with ethylenediamine (0.086 mL, 1.3 mmol). The resulting mixture was stirred at room temperature for 2 h, and then purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=442.1. 1H NMR (400 MHz, DMSO-d6): δ 12.19 (br, 1H), 8.99 (s, 1H), 8.66 (d, J=1.4 Hz, 1H), 8.47 (s, 1H), 8.32 (d, J=5.7 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (d, J=1.4 Hz, 1H), 7.67 (dd, J=3.2, 2.7 Hz, 1H), 7.54 (d, J=5.5 Hz, 1H), 7.09 (dd, J=3.5, 2.7 Hz), 4.82 (d, J=10.0 Hz, 2H), 4.56 (d, J=10.0 Hz, 2H), 4.10 (m, 1H), 3.79 (s, 2H), 1.17 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1.Cl>CC#N>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C:7]2[C:20]3[C:19](=[CH:18][CH:17]=[C:16]([S:15][CH3:14])[CH:21]=3)[NH:22][C:8]=2[CH3:9])=[CH:4][CH:3]=1
Reactant: CSc1ccc(NN)cc1
Reactant: CC(=O)COc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: CSc1ccc2[nH]c(C)c(Oc3ccc(Cl)cc3)c2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(4-Chloro-phenoxy)-propan-2-one (2.66 g) was added to a stirred solution of [4-(methylthio)phenyl]-hydrazine hydrochloride (2.5 g) in MeCN (15 ml)/HCl (0.5M, 15 ml) at RT. The reaction was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction was partitioned between ethylacetate/water, the organics were separated, washed with aq sodium hydroxide (1 M), dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-20% ethylacetate/iso-hexane. The resulting hydrazone was dissolved in THF (80 ml). Sodium bicarbionate solid (1.04 g) was added followed by phosphorus trichloride (0.41 ml) dropwise, and the reaction stirred at RT for 2 h. Further phosphorus trichloride (1.20 ml) was added dropwise, and the reaction stirred at RT for 16 h. The reaction was quenched with water. The mixture was extracted with ethylacetate, the organics washed with aq. sodium hydrogencarbonate, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-10% ethylacetate/iso-hexane. Yield 0.45 g.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Yield: 61 %

Procedure:
The general method described in Step 8 of Example 1 was used to oxidize 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (3.54 g, 11.4 mmol) with DMSO (1.33 g, 17.1 mmol), oxalyl chloride (1.59 g, 12.5 mmol), and triethylamine (3.45 g, 34.1 mmol) to provide 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.15 g) as a dark solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][CH:30]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 38.2 %

Procedure:
Into a solution of methyl 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g) in THF/methanol (10/5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 2 days. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid until the pH was adjusted to 2-3, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (425 mg) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27]COC)=[N:11][C:12]([NH2:16])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.Cl.[OH-].[OH-].[Pd+2]>[NH2:16][C:12]1[N:11]=[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=1
Reactant: COCOCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N)nc(CCCCCCCCCCO)c1O

Procedure:
To a stirred solution containing 133 mg (0.48 mmol) of 5-(benzyloxy)-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidin-2-amine in 10 mL of methanol were added two drops of concentrated HCl and the mixture was stirred at reflux for 16 h. To the mixture were added 10 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/N). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (13×3 cm). Elution with 17:3 dichloromethane-methanol afforded the expected product as white solid: yield 68 mg (69%); mp: 103-104° C.; silica gel TLC Rf 0.20 (17:3 dichloromethane-methanol); 1H NMR (methanol-d4) δ 1.29-1.35 (m, 12H), 1.50 (quint, 2H, J=6.8 Hz), 1.64 (quint, 2H, J=7.6 Hz), 2.37 (s, 3H), 2.71 (dd, 2H, J=7.6, 7.6 Hz) and 3.51 (t, 2H, J=6.4); 13C NMR (methanol-d4) δ 16.42, 25.50, 27.07, 29.00, 29.02, 29.08, 29.13, 29.25, 30.72, 32.22, 61.56, 138.97, 153.46, 157.60 and 160.84; mass spectrum (APCI+), m/z 282.2170 (M+H) (C15H28N3O2 requires 282.2182).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].I[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[C:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccccc1C(=O)OC
Yield: 101 %

Procedure:
Pent-1-yne (5.6 mL, 57.2 mmol) was added to methyl 2-iodobenzoate (5.6 mL, 38.2 mmol), copper(I) iodide (1.0 g, 5.72 mmol) and Pd(PPh3)4 (1.3 g, 1.14 mmol) in DMF (5 mL) and Et3N (1 mL) at RT for 3 hrs. The reaction was partitioned between Et2O and 0.1 M HClaqueous. The resulting organic phase was washed with 0.1 M HClaqueous, NaHCO3aqueous and brine. Organic phase was then anhydrified over Na2SO4 and dried under reduced pressure to give methyl 2-(pent-1-ynyl)benzoate (7.8 g) as a dark oil. The crude will be used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]2[S:29][CH:28]=[C:27]([CH3:30])[N:17]2[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:30][C:27]1[N:17]2[C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:14]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:13])[N:15]=[C:16]2[S:29][CH:28]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3ccncc3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccncc3)c(=O)n12

Procedure:
A mixture of 6-bromo-9H-purine (0.064 g, 0.32 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.046 g, 0.16 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.32 mmol) in ethanol (0.5 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the product as the free base. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.1.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:8]2[C:9]3[N:45]=[C:43]([NH:42][C:32]4[CH:33]=[CH:34][C:35]([N:36]5[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]5)=[C:30]([O:29][CH3:28])[CH:31]=4)[N:44]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CN(C)C=C1CCCC(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(Cl)c(Cl)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(3,4-dichloro-phenyl)-cyclohexanone (119 mg, 0.40 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (148 mg, 0.40 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (92 mg, 48%). MS ISP (m/e): 480.0 [(M+H)+]. mp 167-169° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(OC)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Methyl 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoate was dissolved in isopropanol (20 mL), and 1 mol/L aqueous sodium hydroxide solution (30 mL) was added. The mixture was stirred at 70° C. for 3 h, and completion of the reaction was confirmed by HPLC. After cooling the reaction mixture to room temperature, activated carbon (Sirasagi A) (1.0 g) was added. After stirring, the mixture was filtered using powder cellulose (KC FLOCK). The reaction container and the filter were washed with isopropanol (5 mL)/water (5 mL) solution, and combined with the filtrate. Water (20 mL) and hexane (20 mL) were added to the obtained filtrate and, after stirring, the organic layer was removed. The aqueous layer was washed again with hexane (20 mL). The aqueous layer was ice-cooled, methylisopropylketone (50 mL) was added while adding 2 mol/L hydrochloric acid solution (10 mL) dropwise at 10° C. After the addition, the mixture was stirred at room temperature and the aqueous layer was discarded. The organic layer was washed twice with 10% brine (20 mL). After washing, the solvent was evaporated under reduced pressure to give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid (4.8 g, yield 81%, from methyl 5-bromo-2,4-dimethoxybenzoate obtained in Step 2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of 3-(3-tert-butoxycarbonylaminophenyl)propanol (3.24 g, 12.9 mmol), methanesulfonylchloride (1.63 g, 14.2 mmol), triethylamine (1.44 g, 14.2 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(3-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as a colorless oil (3.50 g, 82%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[N+](C1C=CC=CC=1N)([O-])=O.FF.C1(N)C=CC=CC=1N>C(OCC)(=O)C.C(O)(=O)C.C(Cl)(Cl)Cl.[Fe].O>[F:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]([F:18])([F:17])[CH:14]([F:15])[F:16]
Reactant: Nc1cc(F)c(OC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: FF
Agent: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(OC(F)(F)C(F)F)cc1N
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
4.7 Grams of 5-fluoro-2-nitro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the o-nitroaniline compound (VI) containing fluorine as the substituent X] was dissolved in a mixed solvent of 15 ml of ethyl acetate and 15 ml of acetic acid. The resulting solution was dropwise added to a suspension of 4.8 g of iron powders in a mixed solution of 3 ml of acetic acid and 30 ml of water while maintaining the temperature at 40° C. Thereafter, stirring was continued for 15 minutes at 40° C. to 50° C. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with chloroform as an eluent to obtain 3.9 g of 4-fluoro-5-(1',1',2',2'-tetrafluoroethoxy)-1,2-benzenediamine [i.e. the o-phenylenediamine compound (IV) containing fluorine as the substituent X]. 1H-NMR (CDCl3): δppm 6.40-6.70(2H), 5.90(1H, tt, J=54, 3 Hz), 3.30(4H, broad).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([NH2:50])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:50][CH:48]1[CH2:47][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:49]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 98.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 90 mg, 0.209 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (115 μL, 1.043 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (53.9 mg, 0.313 mmol), and BOP (166 mg, 0.376 mmol). This was stirred overnight before EtOAc was added. The solution was washed with brine, 1N HCl, and sat. NaHCO3 solution. The organic layer was dried and concentrated to give single enantiomer tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (120.6 mg, 0.206 mmol, 99% yield): LCMS=586.4 [M+H]+. A portion of this tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (118 mg, 0.202 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL). This was stirred for 1 h and then concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B% over 10 min, product retention time=10.5 min, 20 mL/min, 220 nM) to give single enantiomer N-(azetidin-3-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (30 mg, 0.046 mmol, 22.60% yield): LCMS=486.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.25 (2 H, m), 7.65-7.78 (4 H, m), 7.54-7.65 (3 H, m), 5.18 (1 H, s), 4.71 (1 H, t, J=7.81 Hz), 4.16-4.32 (4 H, m). HPLC Peak RT=8.3 min (Analytical Method A).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[S:49]1[CH:53]=[CH:52][C:51]([C:54]2[N:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)=[CH:50]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:60][C:57]2[CH:56]=[N:55][C:54]([C:51]3[CH:52]=[CH:53][S:49][CH:50]=3)=[CH:59][N:58]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1cnc(-c2ccsc2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccsc3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A solution of triphenylphosphine (149.0 mg, 0.568 mmol) in methylene chloride (8 mL) cooled to 0° C. was treated with N-bromosuccinimide (103.0 mg, 0.579 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 150.0 mg, 0.453 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-thiophen-3-yl-pyrazin-2-ylamine (168.0 mg, 0.948 mmol) followed by pyridine (0.16 mL, 1.978 mmol). The resulting reaction mixture was stirred at 25° C. for 1.5 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 to 2/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophen-3-yl-pyrazin-2-yl)-propionamide (105.6 mg, 47.5%) as a pale yellow foam: mp 96–102° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H24ClN3O3S2 (M+H)+ 490.1021, found 490.1023.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]2)=[CH:2]1.N1C=CC=CC=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1C=CC=CC=1>[CH:28]1([C:34]([NH:21][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:17][CH2:16]2)=[O:20])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(NC(=O)C1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
To a suspension of 1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea (0.35 g) in dry benzene (2 ml) was added anhydrous pyridine (0.12 g) and then cyclohexanoyl chloride (0.18 g). After refluxing the mixture for 2 for hours, the title compound was filtered off, washed, dried and converted in ethanolic hydrogen chloride to the hydrochloride (0.52 g) m.p. 236.3° C.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=3)[N:10]=[C:9]([C:26]#[N:27])[C:8]=2[N:28]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CS(C)=O>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:10]=[C:9]([C:26]#[N:27])[C:8]3[N:28]=[C:5]([CH:4]=[CH:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[NH:6][C:7]=3[CH:12]=2)=[CH:14][C:15]=1[C:22]([F:25])([F:24])[F:23])[CH3:21]
Reactant: C1COCCN1
Reactant: CCOc1ccc(-c2cc3[nH]c(C=CCCl)nc3c(C#N)n2)cc1C(F)(F)F
Solvent: CS(C)=O
Product: CCOc1ccc(-c2cc3[nH]c(C=CCN4CCOCC4)nc3c(C#N)n2)cc1C(F)(F)F

Procedure:
A solution of 2-(3-chloro-propenyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (23 mg, 0.05 mmol), morpholine (16.1 mg, 0.15 mmol) in DMSO (500 uL) was heated to 120° C. for 5 minutes. The mixture was purified using ion exchange chromatography to afford the title compound.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[C:1]1([S:7][CH2:8][CH2:9][O:10][C:13]2[CH:12]=[CH:11][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCSc1ccccc1
Reactant: Oc1ccc2c(c1)CCCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: c1ccc(SCCOc2ccc3c(c2)CCCC3)cc1

Procedure:
5.1 g (0.033 mol) of 2-phenylthioethanol, 3.7 g (0.025 mol) of 5,6,7,8-tetrahydro-β-naphthol and 7.9 g (0.03 mol) of triphenylphosphine were dissolved in 60 g of diethyl ether and a solution of 5.2 g (0.03 mol) of diethyl azodicarboxylate in diethyl ether was added dropwise to the solution at room temperature.