Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CN(C)C(=O)C.[C:21](Cl)(=O)[CH2:22][CH3:23]>O>[CH2:22]([C:23]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[N:14]=1)[CH3:21]
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)=NO
Reactant: CCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1nc(Cc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a mixture of N′-hydroxy-2-(4-nitrophenyl)ethanimidamide (6.17 g) and N,N-dimethylacetamide (50 mL) was added propionyl chloride (3.22 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue and xylene (200 mL) was heated under reflux for 15 hrs. with azeotropic dehydration. The reaction mixture was concentrated and the obtained residue was subjected to silica gel column chromatography to give 5-ethyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole as brown crystals (4.40 g, yield 60%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 69-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[C:9]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)[CH:10]=[CH:11][CH:12]2OC3(CCCCC3)[O:15][CH:14]([CH2:23][C:24]([OH:26])=[O:25])[CH2:13]2)=[CH:4][CH:3]=1>C1COCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)[CH:10]=[CH:11][C@@H:12]2[O:26][C:24](=[O:25])[CH2:23][C@@H:14]([OH:15])[CH2:13]2)=[CH:34][CH:35]=1
Reactant: Cn1nnnc1C(C=CC1CC(CC(=O)O)OC2(CCCCC2)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=C[C@H]1C[C@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 26 h
Yield: 16.7 %

Procedure:
A mixture of 4-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-1,5-dioxaspiro[5.5]undecane-2-acetic acid (280 mg, 0.52 mmol) in 20 mL of THF/0.5N HCl (1:1) was allowed to stand at ambient temperature for 26 hours. The solution was partitioned between brine and ethyl acetate. The organic layer was washed with brine (2×), dried (Na2SO4) and concentrated. The resultant foam (126 mg) was dissolved in dry methylene chloride (10 mL) and treated with 1-cyclohexyl-3-(2-morpholinomethyl) carbodiimide metho-p-toluenesulfonate (0.24 g). After 16 hours at ambient temperature, the solution was evaporated under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate as eluent. The appropriate fractions afforded 38 mg (16.6%) of the title compound as a colorless oil which is a racemic mixture of the compound of Example 7.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([F:20])[CH:22]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 94.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 3.0 g (8.6 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.9 g (11 mmol) of 3-fluoro-4-methoxyphenylboronic acid (Example 4, Step 3). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 3.19 g (94%) of 1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 159.2-159.7° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.87 (s, 3H), 6.63-6.85 (m, 3H), 7.16-7.32 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 392 (49), 313 (15), 298 (48), 269 (100), 249 (79). Anal. Calc'd for C20H15F3O3S (0.26 ethyl acetate): C, 60.85; H, 4-0.15; F, 13.71. Found: C, 61.33; H, 3.90; F, 13.40.
Reaction SMILES: [CH2:1]([N:3]1[C@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16]C)=[C:14]([O:18]C)[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2].Cl>CO>[CH2:1]([N:3]1[C@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([OH:16])=[C:14]([OH:18])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2]
Reactant: CCC[C@H]1c2cc(C)cc3c2[C@@H](Cc2ccc(OC)c(OC)c2-3)N1CC
Agent: Cl
Solvent: CO
Product: CCC[C@H]1c2cc(C)cc3c2[C@@H](Cc2ccc(O)c(O)c2-3)N1CC

Procedure:
Proceeding as described in Example 1(g), (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-2-methyl-4-n-propyl-dibenz[cd,f]indole hydrobromide is obtained from the tartrate obtained above under (a). The corresponding hydrochloride melts at above 160° with decomposition; [α]D20 =-94° (c=0.5 in methanol).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CCCBr)cc1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0 °C

Procedure:
Under N2, Mg powder (21.15 g, 0.87 gram-atom) was added to a 5 1, 3-neck flask fitted with a mechanical stirrer, condenser, and septum inlet. The Mg was covered with dry THF (200 cc), stirring was begun and a trace of iodine was added followed by about 20 cc then dropwise addition of a solution of 1-bromo,3-(3,4-dimethoxyphenyl)propane (222 g, 0.857 mole) from which all traces of water had been removed in dry THF (1150 cc) at a rate to maintain gentle reflux over a period of 2.5 hours. The resulting dark grey solution was stirred and refluxed for 45 minutes and then cooled to 0° C. With stirring a solution of dried 3,4-dimethoxybenzaldehyde (149.5 g, 0.899 mole) in dry THF (150 cc) was added dropwise over 1 hour at 0° C.-3° C. The resulting mixture was stirred overnight at room temperature, cooled to 0° C., and treated over 1/2 hour at 0°-5° C. with saturated NH4Cl solution (100 cc). The nitrogen atmosphere was discontinued at this point. After standing at room temperature for several hours, the mixture was filtered and the solids were air-dried overnight. The filtrate was evaporated in vacuo to a syrup. The solids were extracted with CH2Cl2 (500 cc) by stirring for a few hours and filtering. The filtrate was combined with the syrup from above and the mixture was diluted with CH2Cl2 (1:1) The organic solution was washed with H2O (3 ×500 cc), dried (Na ), and evaporated in vacuo to a light orange syrup; yield: 300 g (>100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH2:22])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][S:33]([C:25]2[O:24][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH:26]=2)(=[O:34])=[O:35])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Yield: 40 %

Procedure:
Following General Procedure B, the title compound (380 mg, 54%) was prepared from tert-butyl(4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate (640 mg, 1.72 mmol) and 1-benzofuran-2-sulfonyl chloride (372 mg, 1.72 mmol) in pyridine (5 ml).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[C:13]([C:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[I-].[Li+].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:22][C:27]1[C:4]([C:5]#[N:6])=[C:23]([NH:10][C@H:9]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[N:12]3[C:8]=2[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:8])[CH:24]=[CH:25][CH:26]=1
Reactant: c1ccncc1
Reactant: O=C([O-])c1cccc2ncc(-c3cncc(F)c3)n12
Agent: [I-]
Agent: [Li+]
Product: C[C@H](Nc1cccc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1cncc(F)c1

Procedure:
A solution of methyl 2-((1S)-1-(6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(5-fluoro-3-pyridinyl)imidazo[1,2-a]pyridine-5-carboxylate (0.060 g, 0.139 mmol) and lithium iodide (0.056 g, 0.416 mmol) in pyridine (0.73 mL) was stirred at 100° C. for 6 h. Volatiles were removed under reduced pressure to afford (S)-2-(1-((3-amino-2-cyanophenyl)amino)ethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylic acid as a dark residue. LC-MS (ESI) m/z 419.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 83.8 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (119 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (220 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC#Cc1nn(Cc2ccccc2)c2ccccc12

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (84 mg, 54%); 1H NMR δ (CDCl3): 7.9 (d, J=8.02 Hz, 1H), 7.4-7.19 (m, 8H), 5.5 (s, 2H), 2.48 (t, J=7.22 Hz, 2H), 1.65 (p, J=7.18 Hz, 2H), 1.5-1.32 (m, 4H), 0.94 (t, J=7.21 Hz, 3H); LCMS m/z: 302.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:25])[C:22]([O:27][CH3:28])=[O:26])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: COC(=O)C(C)O
Reactant: Oc1ccc(Oc2ccc(Cl)cc2F)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2F)cc1

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.23 g; 0.01 mole), the methanesulfonate of S methyl lactate (18.22 g; 0.1 mole, minimum of 90% optical purity), and potassium carbonate (1.4 g; 0.01 mole) in DMSO (75 ml) was stirred at room temperature for 18 hours. After this period, the mixture was poured into water (500 ml) then extracted into ether (3×100 ml). The ether extracts were dried (MgSO4), and the solvent evaporated. The residue was purified by preparative HPLC using 8:2 hexane-ethylacetate as the eluent. The first peak to elute (after the solvent front) was collected and the solvent evaporated. This gave 2.3 g (17%) of a light yellow oil whose 1H and 19F NMR (CDCl3) were consistent with the assigned structure. This material possessed an optical rotation of +24.68° as measured at 25° C. The refractive index was 1.5466. Attempts to measure the optical purity using the optically active NMR shift reagent tris-[3-(trifluoromethylhydroxymethylene)-d-camphorateo]europium (III) were not successful. Based upon the optical purity of the starting lactate the optical purity is estimated to be between 75 and 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(OC)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-Amino-5-methoxy-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.60 (s, 3H), 3.72 (s, 3H), 6.55 (d, 2H, J=8.8 Hz), 6.78 (d, 1H, J=2.8 Hz), 7.07 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.28-7.37 (m, 4H), 7.42 (d, 2H, J=6.8 Hz), 7.54 (m, 1H), 7.72 (d, 1H, J=8.8 Hz), 9.05 (s, 1H). MS: m/z 398.3 (M++1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:11]=[CH:10][C:8](O)=[CH:7][C:6]=1[OH:12])=O.[C:13]1([CH:20]=[CH:19][CH:18]=[C:16](O)[CH:15]=1)O>CS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:20]2[CH:19]=[CH:18][CH:16]=[CH:15][C:13]=2[O:12][C:6]2[C:5]1=[CH:11][CH:10]=[CH:8][CH:7]=2
Reactant: Oc1cccc(O)c1
Reactant: O=C(CCl)c1ccc(O)cc1O
Agent: CS(=O)(=O)O
Product: ClCC1c2ccccc2Oc2ccccc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A mixture of 4.91 g (51.84 mmol) of chloroacetic acid, 4 mL (54.84 mmol) of thionyl chloride and one drop of DMF was stirred at 90° C. for 3 hours. The resulting solution was cooled and evaporated to remove excess thionyl chloride, hydrogen chloride and sulfur dioxide to yield crude chloroacetyl chloride as a colorless oil, pure enough to use in the next step without further purification. To a stirred suspension of 8.01 g (60.07 mmol) of anhydrous aluminum chloride in 10 mL of nitrobenzene were added 2 mL of chloroacetyl chloride and 2.37 g (21.52 mmol) of resorcinol at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 16 hours, poured into ice (ca. 20 mL), hydrolyzed by conc. HCl (10 mL), diluted with water (20 mL) and chloroform (50 mL) and separated. The organic layer was dried over MgSO4, evaporated and purified by column chromatography (75 g of SiO2, 20% ethyl acetate-hexane) to yield 2.57 g (13.77 mmol, 64.0% yield) of 4-(2-chloroacetyl)resorcinol. A mixture of 167.2 mg (0.896 mmol) of 4-(2-chloroacetyl)resorcinol and 109.0 mg (0.990 mmol) of resorcinol in methanesulfonic acid (0.5 mL) was stirred at 85° C. for 1 hour. To the resulting deep red solution, ice (ca. 10 mL) was added to precipitate a product as a black gummy material which eventually became reddish brown fine powder after scratching with a spatula. The precipitate was collected by filtration, washed with water and dried over P2O5 under vacuum to yield 196.6 mg (0.754 mmol, 84% yield) of 9-chloromethylxanthene as a reddish brown solid. 1H NMR (D2O+K2CO3) δ 7.66 (1H, d, J=9 Hz). 6.60 (1H, dd, J=9 & 2 Hz), 6.30 (1H, d, J=2 Hz), 4.82 (2H, s); MS (ES, positive) 261.4, 263.4; UV (KMOPS, pH 7.2) λmax (ε) 515 nm (41,200 M−1cm−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:35]([N:37]([CH2:40][CH2:41]Cl)[CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:35]([N:37]([CH2:40][CH2:41][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:10])[CH2:38][CH3:39])[CH3:36]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 49.6 %

Procedure:
A mixture of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (320 mg, 0.65 mmol), 2-[(N,N-diethyl)amino]ethyl chloride hydrochloride (579 mg, 3.26 mmol) and potassium carbonate (451 mg, 3.27 mmol) in ethyl acetate (5 mL) and water (5 mL) was at room termperature overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to afford N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester (190 mg, 49%) as an amorphous white solid. ES-HRMS m/e calcd for C29H34Cl2N4O5 (M+H) 589.1978, found 589.1980.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:23][OH:24])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:12]1)[CH2:23][OH:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamic acid tert-butyl ester. (0.46 g, 1.24 mmol) in dichloromethane (6 ml) is treated with trifluoroacetic acid (2 ml) and the reaction mixture stirred for 1 hour at ambient temperature. The solvent is evaporated and the residue dissolved in water. The resulting aqueous solution is basified with saturated aqueous NaHCO3 and extracted into dichloromethane. The dichloromethane is dried over MgSO4 and evaporated to afford (S)-2-amino-4-[3-(4-chlorophenoxy)-azetidin-1-yl]-butan-1-ol as a clear oil. [MH]+ 271.0
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CO>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CCCCOC(=O)Nc1ccc(C)c(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.7 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (800 mg, 2.14 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (390 μL, 4.29 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with methanol (20 mL), anhydrous sodium carbonate (1.0 g, 9.43 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL)/tetrahydrofuran (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (880 mg, 93%) as a pale-yellow powder.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:7]2.[Cl:25]CCl>CN(C=O)C.Cl[Cu]>[Cl:25][C:2]1[CH:3]=[C:4]([O:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:7]2
Reactant: ClCCl
Reactant: CC(c1ccc(Cl)cc1)N1Cc2cc(OC(F)F)cc(I)c2C1=O
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)N1Cc2cc(OC(F)F)cc(Cl)c2C1=O
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A solution of the 7-iodo-2-[1-(4-chloro-phenyl)-ethyl]-5-difluoromethoxy-2,3-dihydro-isoindolone (0.122 g, 0.26 mmol) in DMF (5 mL) was treated with CuCl (0.130 g, 1.31 mmol) and stirred at 140° C. for 1-2 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded 7-Chloro-2-[1-(4-chloro-phenyl)-ethyl]-5-difluoromethoxy-2,3-dihydro-isoindolone (0.05 g, 52%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.66 (d, 3H), 3.94 (d, 1H), 4.27 (d, 1H), 5.74 (q, 1H), 6.54 (t, 1H), 7.17 (s, 1H), 7.26 (s, 1H), 7.31 (m, 4H). GC-MS: m/z 371 (M)+, 356 (M−15)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N:28]1([CH2:37][C:38](O)=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:28]1([CH2:37][C:38]([O:10][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH2:8][C:7]2[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=2[Cl:1])=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cn1ccc2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.615 g, 1.463 mmol), 2-(1H-indol-1-yl)acetic acid (0.282 g, 1.610 mmol), EDC (0.842 g, 4.39 mmol), and DMAP (0.268 g, 2.195 mmol) in DCM (20 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous NaHCO3 and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM/MeOH from 99/1 to 98/2) to afford (S)-4-(2-(2-(1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.615 g, 1.065 mmol, 72.8% yield). MS/ESI+ 577.2 [MH]+; [αD]=+5.500, c=0.44, DCM; 1H NMR (300 MHz, DMSO-d6) d ppm 8.52 (s, 2H), 7.48-7.63 (m, 1H), 7.27 (d, 1H), 7.13-7.19 (m, 2H), 7.10 (td, 1H), 7.00-7.05 (m, 1H), 6.99 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.45 (dd, 1H), 6.02 (dd, 1H), 5.23 (d, 1H), 5.05 (d, 1H), 3.84 (d, 2H), 3.42 (dd, 1H), 3.20 (dd, 1H), 1.13-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.29-0.46 (m, 2H).