Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cn1cc(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: BrBr
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a stirred solution of 7-methyl-5-(pyridin-2-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (53.6 mg, 0.174 mmol) in anhydrous DMF (1.8 ml) at 0° C. was added bromine (9.85 μl, 0.191 mmol) and the mixture stirred for 5 min. Further bromine (9.85 μl, 0.191 mmol) was added and the mixture stirred for 5 min. The mixture was partitioned between ethyl acetate (5 ml) and an aqueous mixture (3:1:4, water, saturated sodium hydrogen carbonate (aq) solution and 20% w/w sodium thiosulfate (aq) solution, 20 ml). The aqueous phase was separated and extracted with ethyl acetate (3×5 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×5 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (0-5% methanol in ethyl acetate) to afford the title compound (46.8 mg, 70%). LCMS RT=0.74 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:24])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:24])=[O:6]
Reactant: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(1-acetyl-4-piperidyloxy)benzoic acid (0.546 g, 1.86 mmol) in THF (10 ml) was stirred under nitrogen and treated with thionyl chloride (0.27 ml, 0.44 g, 3.7 mmol). The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=4[CH3:26])=[N:15][NH:14][C:13](=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:13]1[C:9]2[NH:10][C:11]3[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=3[C:8]=2[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=2[CH3:26])=[N:15][N:14]=1
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)c1ccc2c(c1)[nH]c1c(Cl)nnc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 110 °C
Yield: 86.7 %

Procedure:
To 7-acetyl-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one (1.88 g, 91.7% pure, 4.75 mmol) at room temperature was added phosphoryl trichloride (350 mL, 3755 mmol), and the mixture was heated at 110° C. for 1 hr. The excess of phosphoryl trichloride was removed under vacuum. The residue was dissolved in ice cold ethyl acetate (900 mL), washed with water (100 mL), saturated NaHCO3 solution (2×100 mL), water (100 mL), and brine (100 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum to dryness to provide the desired product (1.57 g, 4.12 mmol, 86% yield over 2 steps) as a beige solid.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N+:17]([O-:18])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: CC(C)(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 36 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-tert-butylhydroxylamine, the title compound was prepared in 36% yield as the sodium salt, m.p. 117-120° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc(C)c2[nH]c(-c3c(F)cccc3F)nc2c1
Reactant: Fc1cccc(F)c1CBr
Product: Cc1cc(C)c2nc(-c3c(F)cccc3F)n(Cc3c(F)cccc3F)c2c1
Yield: 91.2 %

Procedure:
To 2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (Example 94) (0.50 g, 1.94 mmol) was added 2,6-difluoro-α-bromotoluene (0.52 g, 2.51 mmol, 130 M %). Flash chromatography of the crude product eluting with 2% methanol/CH2Cl2, and recrystallization from hexane gave white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (0.68 g, 1.77 mmol, 91% yield). 1H NMR (200 MHz, CD2Cl2): δ 7.51 (cm, 1H, H4), 7.23 (m, 1H, H4″), 7.11 (m, 1H, H5), 7.05 (cm, 2H, H3′,5′), 6.93 (m, 1H, H7), 6.80 (cm, 2H, H3″, 5″), 5.29 (s, 2H, CH2PhF2), 2.58 (s, 3H, CH3), 2.44 (s, 3H, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN)c(C)c3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NCCOc2c(C)cc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A mixture of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044 mg, 0.211 mmol), and triethylamine (29.4 μL, 0.211 mmol) in CH2Cl2 (812 μL) was stirred at room temperature for 3 h. The mixture was chromatographed directly on silica gel to yield N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization from MeCN/H2O, Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17-7.07 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.91-3.75 (m, 11H), 3.12 (q, J=5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m/z 540 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C([O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:56][C:53]3[CH:52]=[CH:51][C:50]([CH2:49][CH2:48][NH:47][C:46](=[O:57])[OH:45])=[CH:55][CH:54]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (51.1 mg, 0.11 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), [2-(4-AMINO-PHENYL)-ETHYL]-CARBAMIC ACID TERT-BUTYL ESTER (52.3 mg., 0.22 mmol, Chem-Impex) and HATU (77.8 mg, 0.20 mmol) (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 mins, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tent-butyl ester (40.6 mg., 54.2%) as a white lyophilized solid. HRMS (ES+) m/z Calcd C36H40Cl2F2N4O3+H [(M+H): 685.2519. Found: 685.2517.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CNC1CCCCC1)O2
Temperature: 180 °C
Yield: 98 %

Procedure:
6.5 g (0.0250 mol) of 8-t-butyl-2-chloromethyl-1,4-dioxaspiro[4.5]decane and 4.5 g (0.0450 mol) of cyclohexylamine are dissolved in 50 ml of 95% ethanol in the presence of 5.65 g (0.040 mol) of K2CO3 and 0.42 g (0.0025 mol) of KI in an autoclave. The mixture is heated to 180° C. for 8 hours with stirring. After returning to room temperature, the reaction medium is poured into 500 ml of water and extracted with 200 ml of CH2Cl2. The organic phase is dried over magnesium sulphate and concentrated under vacuum. The brown oil is used directly in the following step (yield: 98%; NMR analysis).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
(Examplary Compound 8). The title compound was prepared according to the procedure of Scheme I-A, starting from 3,5-bis(benzyloxy)benzoic acid chloride and 3-(trifluoromethyl)aniline in THF solution. White solid, yield 0.250 g (69%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.47 (s, 1H); 8.24 (s, 1H); 8.06 (d, J=8.3 Hz, 1H); 7.60 (t, J=8.0 Hz, 1H); 7.51-7.32 (m, 11H); 7.25 (s, 2H); 6.95 (s, 1H); 5.18 (s, 4H). Anal: Calcd. for C28H22F3NO3: 70.43; H, 4.64; N, 2.93. Found: C, 70.58; H, 4.67; N, 2.91.
Reaction SMILES: [NH2:1][C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](O)=O)=[N:12]1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=2)=[N:12]1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: CCOC(=O)C(N)=NO
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2cc(C)n(C)n2)n1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (95%, 3.78 mmol, 0.530 g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were suspended in DCM (70 ml) under nitrogen atmosphere. The mixture was stirred at RT for a day. The solvent was evaporated and pyridine was added to the residue. The resulting mixture was refluxed for 6 h and stirred at RT overnight. Pyridine was evaporated and the residue diluted with DCM and water. The phases were separated and the water phase was extracted four times with DCM. The combined organics were washed with aqueous HCl solution, saturated NaHCO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.285 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.43 (t, 3H), 2.30 (s, 3H), 4.23 (s, 3H), 4.49 (q, 2H), 6.96 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].[Cu][C:14]#[N:15].O>CS(C)=O>[CH3:12][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:14]#[N:15]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N#C[Cu]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1C#N
Yield: 60 %

Procedure:
1 mol of 2,6-dichloro-3-nitrotoluene in 1 l of dimethyl sulfoxide was stirred at 150° for 5 hours with 1 mol of copper (I) cyanide. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic phase was evaporated and the residue was purified by chromatography on silica gel. There was obtained 2-methyl-3-chloro-6-nitrobenzonitrile (yield 60%), m.p. 97°-98°.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)/[C:17](=[CH:18]/[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: C1CCNC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\N2CCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of wortmannin (30.0 mg, 70.0 μmol) in CH2Cl2 (200 μL) was added pyrrolidine (7.0 μL, 84 μmol) in CH2Cl2. The reaction mixture was stirred at room temperature for 1 h. The solvent and excess thiol were removed in vacuo and the product was purified by chromatography on SiO2 (hexanes/ethyl acetate 9:1, then 1:1) to give PX-867 (30.0 mg, 60.6 μmol, 86%) as an orange oil. The product was analyzed by several experimental methods and shown to be of the correct structure and of high purify as: [α]D −390 (c 0.0073, CH2Cl2, 23° C.); IR (KBr) 3337, 1740, 1684, 1617, 1570, 1261, 1221, 1099, 1018 cm−1; 1H NMR δ 8.29 (s, 1H), 6.72 (s, 1H), 6.07 (dd, 1H, J=6.9,4.8 Hz), 4.47 (dd, 1H, J=7.0, 1.9 Hz), 3.80-3.70 (m, 2H), 3.25 (s, 3H), 3.25-3.14 (m, 2H), 3.02-2.90 (m, 2H), 2.69 (br s, 1H), 2.58 (dd, 1H), J=19.1, 8.4 Hz), 2.39 (dd, 1H, J=14.6. 7.8 Hz), 2.32-2.08 (m, 2H), 2.06 (s, 3H), 1.99-1.95 (m, 5H), 1.84 (dd, 1H, J=14.5, 4.2 Hz), 1.56 (s, 3H), 0.86 (s, 3H); 13C NMR δ 217.5, 178.9, 169.9, 164.9, 153.9, 151.3, 137.6, 137.1, 129.2, 89.4, 82.1, 73.3, 67.7, 59.3, 55.2, 49.2 (2 C), 42.6, 42.4, 37.8, 36.3, 25.6 (2 C), 24.5, 22.4, 21.0, 16.3; MS (EI) m/z (rel. intensity) 499 (M+, 1), 439 (2), 365 (7), 167 (35), 149 (100); HRMS (EI) calculated for C27H33NO8 499.2206; found 499.2191.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:5][N:4]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1noc(-c2cccnc2)c1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2cccnc2)c1Cl
Yield: 64 %

Procedure:
4-Chloro-3-hydroxy-5-(3-pyridyl)isoxazole (0.49 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.54 g, 63%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=C[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(#[N:48])C.O>>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=[N:48][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Sulfonic acid, 11, was synthesized in a manner similar to Compound 25 described below, using compound, 57a, as the starting material: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])[O:3][C:2]2=O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(O)(=O)C>[CH2:9]([N:16]1[C:4](=[O:7])[CH:5]2[CH:1]([CH2:6]2)[C:2]1=[O:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-oxabicyclo[3.1.0]hexane-2,4-dione (23-1) (20 g, 0.179 mol) was dissolved in acetic acid (100 mL), and benzylamine (28.8 g, 0.269 mol) was added dropwise under cooling in a water bath, after the completion of addition, the temperature was raised to reflux and stirred overnight. The reaction mixture was cooled to room temperature, poured into 1 L of water to precipitate large amount of white solid, filtered, and the filter cake was recrystallized from isopropanol to give Compound 23-2 (27 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10](I)[CH:9]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)cc1-n1nccn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (12.0 g, 37 mmol) was added portionwise to a rt solution of commercially available 4-chloro-2-iodobenzoic acid (5.22 g, 18.5 mmol) in DMF (25 mL) followed by 1H-1,2,3-triazole (1.61 mL, 27.8 mmol) and Cu(I)I (210 mg, 1.1 mmol). The resulting blue suspension was stirred at 120° C. for 30 min, then the rxn mixture was quenched with 2M aq. HCl and filtered through a celite plug before being extracted with DCM (3×). The combined org. layers were dried (Na2SO4), filtered and evaporated in vacuo to give the crude product that was purified by FC (Biotage SP1: eluting with DCM/MeOH 95:5+0.1% AcOH) to give the title compound A-1-1 as a brown solid. LC-MS A: tR=0.66 min; [M(35Cl)+H]+=224.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH3:24])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH3:43][O:44][C:45](=[O:48])[CH2:46][NH2:47]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:47][CH2:46][C:45]([O:44][CH3:43])=[O:48])=[O:21])=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
A mixture of 3.9 g (0.012 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid, 6.5 g (0.039 mole) of diethyl phosphorocyanidate and 6.6 ml (0.047 mole) of triethyl amine in 500 ml of N,N-dimethylformamide (dried over 4H molecular sieves overnight) was stirred at room temperature for five hours. A mixture of 1.8 g (0.014 mole) of glycine methyl ester, hydrochloride, 2 ml (0.014 mole) of triethylamine and 10 ml of N,N-dimethylformamide was added to the suspension and the mixture was stirred at room temperature for another two hours. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 48° C. The solid residue was dissolved in 200 ml of ice water and neutralized with saturated sodium carbonate solution to pH 8. The solid was collected and washed with 100 ml of water. Recrystallization from acetonitrile gave 2.6 g of the product as a pale yellow solid, mp 255° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)N(C)C)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenylpiperidine-4-carboxylic acid dimethyl-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: COCCN
Product: COCCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 88.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 49 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.