Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].CC(C)=O.[CH3:24][O:25][S:26]([O:29][CH3:30])(=[O:28])=[O:27]>C(OC(=O)C)C.O>[CH3:14][O:13][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].[CH3:24][O:25][S:26]([O:29][CH3:30])(=[O:28])=[O:27]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1c(C)cc([N+](=O)[O-])c(C)c1C
Reaction time: 0.25 h

Procedure:
2,3,6-Trimethyl-4-nitrophenol (2.2 g) and K2CO3 (4.0 g) were added to a flask, to which was slowly added acetone (35 mL), followed by dimethylsulfate (2.09 mL) at room temperature. The suspension was then refluxed for 2.5 hours. After it cooled down, 20 mL water was added and stirred for 15 min. The mixture was taken up by water and ethylacetate and the organic phase was washed with brine, dried and evaporated to give 2-methoxy-1,3,4-trimethyl-5-nitrobenzene as an oil (2.3 g, which still contained 5% dimethylsulfate). 1H-NMR, (300 MHz, CDCl3) δ=7.532, (s, 1H), 3.723, (s, 3H), 2.373, (s, 3H), 2.307 (s, 3H), 2.273 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:21]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:9]=1)=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
6-Nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (8.1 g, 20.5 mmol) was dissolved in DMF (75 mL) at 23° C. under an atmosphere of argon. SnCl2 (12.9 g, 67.7 mmol) was added followed by water (1.7 mL, 92.2 mmol) and the resulting mixture was heated to 50° C. After 4 h, 3N NaOH (45 mL, 135 mmol) was added followed by EtOAc (100 mL). The resulting emulsion was filtered hot through Celite and the bed of Celite was washed with hot EtOAc (3×100 mL). The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to give a solid. The crude material was purified by silica gel chromatography (2:8→7:3 ethyl acetate:hexane), to give 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine as a yellow solid (5.1 g, 68% yield). MS (FAB) [M+H]/z Calc'd 366, found 366.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].Cl[CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[N:4]([CH2:21][C:22](=[O:24])[CH3:23])[C:3]1=[O:19]
Reactant: CC(=O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCn1cnc2c1c(=O)n(CC(C)=O)c(=O)n2C

Procedure:
This compound was prepared by alkylation of 3-methyl-7-(5-oxohexyl)-xanthine with chloroacetone in dimethylformamide in the presence of potassium carbonate at 100° C. for 1.5 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][NH2:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CS(C)=O>[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:17][CH2:16][C:14]1[O:15][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=[CH:18][C:12]=2[CH:13]=1)=[O:24]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 49.5 %

Procedure:
To a dimethylsulfoxide (10 mL) solution of C-(6-benzyloxy-benzofuran-2-yl)-methylamine (300 mg, 1.18 mmol) described in Production Example 1-2-4 were added 2,6-diaminonicotinic acid (181 mg) described in Production Example 1-1-4, 1-hydroxybenzotriazole (319 mg, 2.36 mmol), triethylamine (329 μL, 2.36 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (452 mg, 2.36 mmol) at room temperature, which was stirred at room temperature for 26 hours. To the reaction solution was added water at room temperature followed by extracting with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (227 mg, 60%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:45])=[O:44])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NS(=O)(=O)c4ccccc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (254 mg) synthesized in Example A110(5) in N,N-dimethylacetamide was added benzenesulfonyl chloride (99 μL), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (312 mg, 96%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH2:20])=[C:4]([CH3:21])[N:3]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH:20][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:34])=[CH:31][CH:30]=2)=[C:4]([CH3:21])[N:3]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCNCc1ccc(CC(=O)OC)cc1
Reaction time: 5 h
Yield: 3.1 %

Procedure:
To a solution of the product from step (ix) (57 mg) in THF (5 mL) was added (4-formylphenyl)acetic acid methyl ester (51 mg) and acetic acid (0.011 mL). The resulting mixture was stirred for 5 h, sodium triacetoxyborohydride (90 mg) was added and the resulting solution stirred at rt for 16 h. TEA (0.013 mL) was added and the reaction mixture stirred for a further 2 h. The solvents were evaporated, the residue redissolved in MeOH and purified by RPHPLC to afford the title compound 2.7 mg.
Reaction SMILES: Cl.[NH:2]1[CH2:11][C@H:9]([OH:10])[CH2:8][C@H:3]1[CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.O1CCCC1.CC(C)=O.C(OCC)(=O)C>[C:25]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=[CH:27][C:28]([C:29]([N:2]2[CH2:11][C@H:9]([OH:10])[CH2:8][C@H:3]2[CH2:4][C:5]([OH:7])=[O:6])=[O:30])=[CH:32][CH:33]=1
Reactant: O=C(O)C[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of commercial L-beta-homohydroxyproline hydrochloride (245 mg, 1.35 mmol), triethylamine (1.13 ml, 8.09 mmol) in water (0.8 ml) and tetrahydrofuran (2 ml) at 0° C. under argon, was added dropwise a solution of 4-phenylbenzoyl chloride (438 mg, 2.02 mmol) in tetrahydrofuran (1 ml). The reaction mixture was allowed to warm to room temperature and was stirred 18 hours. It was then diluted with acetone-ethyl acetate (1-2) and washed with HCl 1N. The organic phase was dried (MgSO4) and concentrated to afford a mixture of desired product and 4-phenylbenzoyl acid. A small quantity of acid could be obtained by precipitation with ethyl acetate.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29]/[CH:30]=[CH:31]/[CH2:32][C:33]([O:36][Si](CC)(CC)CC)([CH3:35])[CH3:34])[CH2:12][C@@H:11]([O:44][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29]/[CH:30]=[CH:31]/[CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH2:12][C@@H:11]([OH:44])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.1 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxymethyl}androsta-5,7,16-triene (550 mg, 0.726 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (7 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and purified by column chromatography (using ethyl acetate:dichloromethane=4:1 and then ethyl acetate) to give the titled compound (238 mg, 79%) as a colorless foam.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:35])[CH3:34])=[CH:15][C:16]3[NH:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:18][C:17]=3[CH:27]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1>[OH:5][C:3]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:35])[CH3:34])=[CH:15][C:16]3[NH:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:18][C:17]=3[CH:27]=2)=[CH:8][CH:7]=1)([CH3:1])[CH3:4]
Reactant: CC(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(C(C)(C)O)nc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.1 ml of methyl lithium (1.0 M diethyl ether solution) was added to a tetrahydrofuran (1.5 ml) solution of 15.0 mg of 1-(2-(6-(6-acetyl-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 341, at −78° C., and the reaction liquid was stirred at −78° C. for 30 minutes. The reaction liquid was poured into aqueous saturated ammonium chloride solution, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=7.5/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1>CN(C)C=O>[C:87]([O:86][C:84]([N:81]1[CH2:80][CH2:79][CH:78]([NH:77][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH2:32][CH3:33])[CH:24]=2)[CH2:83][CH2:82]1)=[O:85])([CH3:90])([CH3:89])[CH3:88]
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a mixture of 0.0905 g (0.196 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 6 mL of dimethylformamide was added 0.0418 g (0.310 mmole) of 1-hydroxybenzotriazole, 0.1146 g (0.302 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1484 g (1.148 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0624 g (0.299 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.1081 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-221) as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH2:12]([C@H:15]1[O:17][C@@H:16]1[CH2:18][OH:19])[CH2:13][CH3:14].O>C1COCC1.[Cl-].[Na+].O.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[O:11][C@@H:15]([CH2:12][CH2:13][CH3:14])[C@H:16]([OH:17])[CH2:18][OH:19]
Reactant: CCC[C@H]1O[C@@H]1CO
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](Oc1cc(Cl)cc(Cl)c1)[C@H](O)CO
Temperature: 75 °C
Yield: 26 %

Procedure:
Add sodium hydroxide (1N, 9 mL) to a stirred solution of 3,5-dichlorophenol in THF (9 mL) followed by a solution of (R,R)-(3-propyl-oxiranyl)-methanol in THF (5 mL). Heat the reaction mixture at 75° C. overnight, cool to room temperature, add water, brine and dichloromethane, and separate the layers. The aqueous layer is extracted with dichloromethane, the combined organic extracts are washed successively with 1N sodium hydroxide and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Analysis of the crude reaction mixture by 1H NMR reveals a ˜2:1 mixture of the C-3:C-1 adducts. Purification of the crude residue on silica gel eluting with 0-25% EtOAc/hexanes gives the major title compound (332 mg, 26%). 1H NMR (DMSO-d6): 0.86 (dd, 3H, J=4, 4 Hz), 1.21-1.48 (m, 2H), 1.52-1.72 (m, 2H), 3.28-3.45 (m, 2H), 3.60-3.67 (m, 2H), 4.37-4.44 (m, 1H), 4.69 (dd, 1H, J=6, 6 Hz), 4.88 (d, 1H, J=5 Hz), 7.01-7.10 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(F)c3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Yield: 50.2 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-methanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (200 mg, 0.296 mmol) and 1.0 N aqueous sodium hydroxide (2.96 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-methanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (92 mg, 50%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C32H36F2O8S (M+Na)+ 641.1991, found 641.1988.
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH2:8][CH:9]=1)(=[O:3])[CH3:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:32]1[NH:35][C:34](=[O:36])[C@@H:33]1[C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C.[Br-].[Zn+2].[Br-].O.C(N(CC)CC)C>[CH2:13]([O:12][C:10]([N:7]1[CH2:6][CH:5]=[C:4]([C:1](=[O:3])[CH2:2][C@H:32]2[NH:35][C:34](=[O:36])[C@@H:33]2[C@H:37]([O:39][Si:40]([C:43]([CH3:44])([CH3:46])[CH3:45])([CH3:42])[CH3:41])[CH3:38])[CH2:9][CH2:8]1)=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1CC=C(C(C)=O)CC1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CC=C(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 4 h
Yield: 65.1 %

Procedure:
To a solution of 4-acetyl-1-allyloxycarbonyl-1,2,3,6-tetrahydropyridine (1.33 g) and triethylamine (1.06 ml) in dichloromethane (50 ml) was added trimethylsilyl trifluoromethanesulfonate (2.2 ml) at 0° C. After stirring for 4 hours, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.82 g) and zinc bromide (1.86 g) in ethyl acetate (10 ml) was added to the mixture, and the resultant mixture was stirred for 1 hour at 0° C. The reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (200 ml). After adjusting pH to 4 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (40 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-3:7, V/V) to give (3S,4R)-4-[2-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.80 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>O1CCOCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)=[S:47])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CNC(=O)c1ccc2[nH]c(=O)oc2c1)CN1CCC(Cc2ccccc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC(CNC(=S)c1ccc2[nH]c(=O)oc2c1)CN1CCC(Cc2ccccc2)CC1
Yield: 79.1 %

Procedure:
2-Oxo-2,3-dihydrobenzoxazole-6-carboxylic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide (686 mg, 1.31 mmol) and Lawesson's reagent (530 mg, 1.31 mmol) in dioxane (5 mL) were heated under reflux conditions for 2 hours. The solvent was removed, and the product was purified by chromatography (silica gel, 0-50% EtOAc in heptane) to give 2-oxo-2,3-dihydrobenzoxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide (559 mg, 79%): as a green gum:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:55][C@@H:56]([CH3:76])[C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:72]CC)[O:69]CC)=[O:58]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][C@@H:56]([CH3:76])[C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:69])([OH:72])[OH:75]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)N)OCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)C(=O)NCCOCCOCCP(=O)(O)O)NC(=O)CCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 26, step 8) and (S)-diethyl (2-(2-(2-(2-aminopropoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 30, step 2) by following the procedure described for example 28, step 3-5. 1H NMR (DMSO-d6): δ 9.38 (br s, 1H), 8.14 (t, 2H), 4.18-4.25 (m, 1H), 3.92-4.00 (m, 1H), 3.06-3.67 (m, 15H), 2.92 (dd, 2H), 2.79 (dd, 2H), 2.59-2.73 (m, 4H), 2.07 (t, 2H), 1.65-1.75 (m, 2H), 1.42-1.50 (m, 4H), 1.21-1.28 (m, 35H), 0.85 (t, 6H). LRMS [M+H]=811.5.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(N(CC)CC)C.[Pd].[Cu]I>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[CH2:15][C:14]#[C:13][CH2:12][CH2:11][OH:16]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Product: OCCC#CCc1cc(F)c(F)cc1F

Procedure:
A mixture of 1-bromo-2,4,5-trifluorobenzene (5.0 g, 23.7 mmol), 4-pentyn-1-ol (2.4 ml, 26 mmol), palladium bis(triphenylphosphine chloride (5 mg), copper (I) iodide (5 mg) in triethylamine (30 ml) was refluxed under argon for 10 hours. On cooling, the mixture was acidified with dilute hydrochloric acid and was extracted with ethyl ether. Evaporation of the extracts gave an oil, which was purified by chromatography on a silica column using 60% ethyl ether/hexane to give the title alcohol.