Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>O>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:17]2[C:16]=1[N:15]=[C:3]([C:2]([F:13])([F:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[NH:20][C:18]2=[O:19]
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1cccc(Cl)c1N
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Cl)cccc12
Temperature: 115 °C
Yield: 92.1 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (51 mg, 0.24 mmol) and 2-amino-3-chloro-benzamide (34 mg, 0.20 mmol) were combined with polyphosphoric acid (1.0 g) and the mixture was heated at 115° C. for 20 h with vigorous stirring. The mixture was allowed to cool to rt and then water (3 mL) was added, resulting in a precipitate that was separated washing with DCE (2×8 mL). The combined DCE extracts were washed with brine (3 mL) and separated using Biotage Phase Separators. The organic fraction was concentrated using a Savant Speed Vac to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4(3H)-one as an off-white solid (60 mg). LCMS (ESI) m/z 326 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].N1[CH:27]=[CH:26]C=CC=1.[OH2:28]>C(OC(=O)C)(=O)C>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:26](=[O:28])[CH3:27])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O
Reactant: c1ccncc1
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCNS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (1 g) was dissolved in acetic anhydride (25 mL). Pyridine (5 mL) was added and the mixture stirred for 3 hours at 50° C. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL), dried (Na2SO4) and evaporated to give the title compound as an amorphous solid. δC (CDCl3, 62.9 MHz): 21.0, 25.7, 26.3, 42.8, 63.8, 127.3, 127.6, 127.8, 128.0, 129.1, 138.4, 139.3, 145.6 and 171.2.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].O.[NH2:23][NH2:24]>CO>[CH3:19][N:17]1[CH:18]=[C:14]([C:11]2[CH:12]=[C:13]3[C:5]([C:3]([NH:23][NH2:24])=[O:4])=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:15]=[N:16]1
Reactant: NN
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c3c2)cn1
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)NN)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of the trichloroethanone 3 prepared above are suspended in 150 ml of methanol, and 34 ml of hydrazine hydrate are slowly added dropwise at 5-10° C. When the addition is complete, the mixture is stirred at RT for a further 1 h. Half of the liquid components are subsequently removed in vacuo, and the residue is cooled to 0° C. The precipitating crystals are filtered off with suction and washed with methanol. The residue is subsequently dried at 80° C. in vacuo, giving 5.4 g of the hydrazide 4. HPLC-MS: Rt=1.263 min; [M+H+]: 257.1
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.P(Cl)(Cl)([Cl:18])=[O:17].[ClH:21].[C:22]1([CH3:28])[CH:27]=[CH:26]C=[CH:24][CH:23]=1>>[ClH:18].[Cl:21][CH2:24][CH2:23][C:22]1[C:28](=[O:17])[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[N:15][C:27]=1[CH3:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: Cc1ccccc1
Agent: Cl
Product: Cc1nc2c(O)cccn2c(=O)c1CCCl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 3-benzyloxy-2-aminopyridine (formula-2) (100 grams), toluene (3.5 L) and phosphorusoxychloride (139 ml) was heated to 50° C. 3-acetyldihydrofuran-2(3H)-2-one (218 grams) (formula-3) was added to the reaction mixture, heated to 95° C. and stirred for 18 hrs. The solvent was distilled off under reduced pressure to obtain a residue which was cooled to 40° C. and toluene (500 ml) was added to it. A solution of concentrated hydrochloric acid (600 ml) was added to the reaction mixture, heated to 60° C. and stirred for 6 hrs. The reaction mixture was cooled to 0° C. A solid crystallized out which was filtered, washed with toluene and dried at 50° C. to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:23]([Si](C)(C)C)#[CH:24]>CN(C=O)C.CCOC(C)=O.[Cu]I>[C:23]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)#[CH:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)nc2)ccn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
A solution of tert-butyl (5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.70 g, 2.18 mmol) in DMF (5 mL) was sparged with Ar, treated with ethynyltrimethylsilane (0.64 g, 6.55 mmol), TEA (1 mL), copper(I)iodide (0.042 g, 0.22 mmol) and trans dichlorobis(triphenylphosphine)palladium(0) (0.15 g, 0.22 mmol) and heated at 75° C., under Ar, overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and washed with EtOAc and water. The layers of the filtrate were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was dissolved in MeOH (20 mL), treated with K2CO3 (0.7 g), stirred at RT for 2 h, then concentrated to dryness. The residue was treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford tert-butyl (5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.29 g, 43%). 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1 H), 8.41 (d, J=5.6 Hz, 1 H), 8.18 (d, J=2.8 Hz, 1 H), 7.88 (d, J=9.2 Hz, 1 H), 7.66 (m, 1 H), 7.07 (d, J=2.4 Hz, 1 H), 6.95 (m, 1 H), 4.34 (s, 1 H), 1.46 (s, 9 H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC(C(N[C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=O)=CC=2)C1)=O.[C@H:73]1([NH:83][C:84]([C@H:86]2[N:90](C(OCC3C=CC=CC=3)=O)[CH2:89][C:88]([C:101]([O:103][CH3:104])=[O:102])=[CH:87]2)=[O:85])[C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH2:76][CH2:75][CH2:74]1>>[C@H:73]1([NH:83][C:84]([C@H:86]2[NH:90][CH2:89][C@@H:88]([C:101]([O:103][CH3:104])=[O:102])[CH2:87]2)=[O:85])[C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH2:76][CH2:75][CH2:74]1
Reactant: COC(=O)C1=C[C@@H](C(=O)N[C@@H]2CCCc3ccccc32)N(C(=O)OCc2ccccc2)C1
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: COC(=O)[C@@H]1CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Yield: 96.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound T of Example 1, (S)-1-benzyl 3-methyl 5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1H-pyrrole-1,3(2H,5H)-dicarboxylate (156 mg, 0.36 mmol) was converted to the title compound (105 mg, 97%). MS (ESI+) m/z 303.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](COCC[Si](C)(C)C)[CH:8]=[CH:7]2.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:24]1[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:23]=1
Reactant: Cc1cccc2ccn(COCC[Si](C)(C)C)c12
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from 7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (prepared by SEM protection of 7-methyl-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM protecting group with TBAF. Yield: 190 mg (51%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][OH:25].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([NH:22][CH2:23][CH2:24][OH:25])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCO)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of (3S)-4-benzyloxy-3-tert-butoxycarbonylamino-2-butanone (4.3 g) in dry MeOH (20 ml) was added to a solution of 2-aminoethanol (2.0 g) and AcOH (1.8 g) in dry MeOH (20 ml). NaBH3CN (1.4 g) was added and the mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between AcOEt and aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The organic layer was mixed with 1N HCl (50 ml) and the mixture was stirred vigorously for 1 hour. The organic layer was separated, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo to give 4.1 g of (2R, 3RS)-O-benzyl-2-tert-butoxycarbonylamino-3-(2-hydroxyethylamino)butanol as an oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH:14]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH3:15]>CN(C=O)C>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=1[C:9]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:19][CH:20]=1)=[O:10]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cc(F)ccc2N)cc1
Temperature: 70 °C

Procedure:
To a suspension 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.06 g, 5.90 mmol) in DMF (5 mL) was added 4-sec-butylphenylamine (1.95 mL, 11.8 mmol) at room temperature. The suspension was heated at 70° C. for 2 days, and cooled to room temperature. The reaction mixture was poured into crushed ice (150 mL), and extracted with dichloromethane. The organic layer was dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash column chromatography on a Biotage (40 M silica column), using a gradient of hexane:ethyl acetate (9:1 to 8:2) mixture as eluent to afford 2-amino-N-(4-sec-butylphenyl)-5-fluorobenzamide. Yield: 1.16 g (69%).
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([I:9])=[CH:7][N:8]=1>O.CO>[NH2:2][C:3]1[C:4]([C:10]([NH2:1])=[O:12])=[N:5][C:6]([I:9])=[CH:7][N:8]=1
Reactant: COC(=O)c1nc(I)cnc1N
Reactant: N
Solvent: CO
Solvent: O
Product: NC(=O)c1nc(I)cnc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
30 ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate in 150 ml of methanol. The reaction medium is stirred at 25° C. for 48 hours. After evaporation of the solvents, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 12.50 g of 3-amino-6-iodopyrazine-2-carboxamide (88%) in the form of a beige solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:8]2[N:9]([C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][N:21]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH:4]([CH3:6])[CH3:5].[H][H].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[CH2:3]([C:7]1[C:8]2[N:9]([C:19]([CH:22]([CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][N:21]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)Cc1nnc2c(CC(C)C)nc(-c3ccccc3)cn12
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccnc1)c1nnc2c(CC(C)C)nc(-c3ccccc3)cn12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (202 mg) was added to a solution of ethyl 8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-ylacetate (1.35 g) in DMF (10 ml) with stirring at 0° C. under an atmosphere of argon. When evolution of hydrogen had ceased (approximately 15 minutes), a solution of 3-chloromethylpyridine hydrochloride (722 mg) in DMF (5 ml) was added dropwise over 5 minutes. The mixture was stirred at 0° C. until hydrogen evolution ceased and then at ambient temperature for 2 hours. The mixture was added to ice-cold 0.5 M hydrochloric acid (60 ml). The solution was washed with ether (50 ml) and then basified by addition of solid sodium hydrogen carbonate. The resulting emulsion was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), followed by saturated sodium chloride solution (50 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (3:97 v/v), to give ethyl 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionate (B), as a white powder (1.1 g), m.p. 110°-111° (after trituration with ether); NMR (CDCl3): 1.1 (d, 6H), 1.2 (t, 3H), 2.6 (m, 1H), 3.3 (d, 2H), 3.75 (ddd, 2H), 4.2 (q, 2H), 4.5 (t, 1H), 7.2 (dd, 1H), 7.5 (m,3H), 7.6 (m, 1H), 7.9 (m, 2H), 7.9 (dd, 1H), 8.2 (s, 1H), 8.4 (dd, 1H), 8.6 (d, 1H).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:47]C(=O)OC(C)(C)C)[CH:12]=[C:13]([C@@H:15]2[C@@:26]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C:18]3([CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]3)[NH:17][C@H:16]2[C:37](=[O:46])[NH:38][C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)[CH:14]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:47][C:11]1[CH:12]=[C:13]([C@@H:15]2[C@@:26]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C:18]3([CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH2:19]3)[NH:17][C@H:16]2[C:37]([NH:38][C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[O:46])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cc(Cl)cc(NC(=O)OC(C)(C)C)c1)[C@]21C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cc(N)cc(Cl)c1)[C@]21C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4N hydrochloric acid/1,4-dioxane solution (1.16 ml, 4.64 mmol) was added to a 1,4-dioxane (6 ml) solution of the compound (321 mg, 0.47 mmol) obtained in Step 3 above and the resulting mixture was stirred at room temperature for 24 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography [methanol:ethyl acetate=1:4 (v/v)] to give 248 mg (91%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][NH:9]2)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([O:43][CH3:44])=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:38]=1>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][CH2:10][N:9]2[S:39]([C:37]1[CH:38]=[C:33]([Cl:32])[CH:34]=[CH:35][C:36]=1[O:43][CH3:44])(=[O:40])=[O:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)NCCN2C(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester (300 mg, 0.98 mmol) was dissolved in dichloromethane (20 mL) and pyridine (2 mL). N,N-Diisopropylethylamine (127 mg, 0.98 mmol) and 5-chloro-2-methoxy-benzensulfonyl chloride (300 mg, 1.24 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude compound was purified by flash chromatography, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester as a light yellow gum, 435 mg (87%), δH (300 MHz; CDCl3) 8.17 (1H, s), 8.05 (1H, s), 7.82 (1H, d), 7.74 (1H, d), 7.46 (1H, dd), 6.82 (1H, d), 4.35 (2H, q), 3.93 (2H, m), 3.71 (2H, m), 3.56 (3H, s), 1.48 (9H, s), 1.39 (3H, t).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnn(C)c(=O)c2)cc(C)c1I
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-iodo-3,5-dimethylphenyl)-2-methylpyridazin-3(2H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 14): tR=1.18 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I([O-])(=O)(=O)=[O:32].[Na+]>CO.O>[CH2:1]([S:13]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCS(=O)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (0.340 g, 0.76 mmol) in methanol (15 ml) was treated with a solution of sodium periodate (0.165 g, 0.77 mmol) in water (3 ml) and the resulting mixture was stirred at 22° C. for 18 h. The solid formed was filtered and washed with methanol. This filtrate was then concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic phase was then dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 1:1) to give 0.335 g (90%) of 4-[4-[2-(dodecylsulfinyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone as a white solid. By 1HNMR this product was a 6:4 mixture of trifluoromethyl ketone and hydrated trifluoromethyl ketone. The pure hydrate precipitates from ethyl acetate-hexane: m.p. 98-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[N:9][C:10]=1[Cl:11].[CH3:14]I>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[N:9][C:10]=1[Cl:11])[CH3:14]
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Reactant: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of KH (30%, 13.3 g, 125 mmol) in THF (200 mL) at 0° C. was added (4,6-Dichloro-pyrimidin-5-yl)-acetic acid methyl ester (20.0 g, 90.0 mmol) and MeI (290.0 g, 8.8 mL, 141.0 mmol) in THF (200 mL) slowly. After addition, the mixture was stirred at room temperature for 30 min, and then heated to reflux for 1 hour. After cooling to 0° C., the mixture was quenched with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phase was combined and dried. After removal of the solvent, the residue was subject to column chromatography, eluted by hexane/ethyl acetate (5:1) to give 2-(4,6-Dichloro-pyrimidin-5-yl)-propionic acid methyl ester (17.6 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 4.39 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 3.73 (s, 3H), 1.57 (d, J=7.21 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]=1[C:14]([OH:16])=[O:15].[CH:42]1C=CC=CC=1.[N+](=C)=[N-].CN(N=O)C(N)=O>C(O)(=O)C.C(OCC)C>[OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]=1[C:14]([O:16][CH3:42])=[O:15]
Reactant: C[C@H](O)CCC1OCCOC1CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Reactant: c1ccccc1
Agent: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1c(/C=C/CCCC2OCCOC2CC[C@H](C)O)cc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of 48 g. of 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoic acid in 300 ml. of benzene is added a stoichiometric excess of diazomethane in 250 ml. of diethyl ether. The diazomethane is freshly prepared from N-methylnitrosourea. The solution becomes light yellow and is stirred for 15 minutes after the addition of the diazomethane. Acetic acid is then added to the mixture to decompose the excess diazomethane, and the solvents are removed to provide 48.8 g. of light yellow oil. The oil is purified by chromatography on 1250 g. of SilicAR, CC-7, an absorbent silica gel obtainable from Mallinckrodt Chemical Works, using a chloroform solvent. About 41 g. of a colorless oil of methyl 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoate are obtained. This oil analyzes as containing 72.92 wt. % carbon and 7.24 wt. % hydrogen, as compared to theoretical values of 73.17 wt. % carbon and 7.32 wt. % hydrogen.