Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.C1C(=O)N([Br:27])C(=O)C1.CCCCCCC>S(Cl)(Cl)=O.C(#N)C.O>[Br:27][CH:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Product: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Solid tricyclo[3.3.1.13,7]decane-1-acetic acid (Formula N) (288 grams; 1.48 mole) was suspended in thionyl chloride (465 mL) in a 3-necked round bottomed flask, equipped with a condenser. Dimethylformamide (DMF; 0.3 mL was added and the suspension was stirred at room temperature for 1.5 hours. Completion of the reaction was checked by gas chromatography. Solid NBS (307 g) was then added portionwise to the reaction mixture and the reaction mixture was heated to 60° C. The reaction was stirred for 3 hours while maintaining the temperature at 60 to 65° C. Monitoring by gas chromatography was performed to ensure the completion of the reaction. Heptane (900 mL) was added to the reaction mixture. Excess thionyl chloride was distilled off at 78-80° C. Water was then added cautiously (violent reaction) to quench the reaction (total volume 1050 mL). Heptane (500 mL) and water (600 mL) were then added and the aqueous layer was separated from the organic layer. The organic layer was washed with additional water (600 mL) and the aqueous layer was again separated from the organic layer. Additional water (150 mL) was added to the organic heptane layer and the heptane was distilled off from the aqueous layer. Specifically, 70 mL of water co-distilled with heptane. After distilling off the heptane, tetrahydrofuran (THF; 1200 mL) was added to the aqueous layer and the resulting mixture was stirred vigorously at room temperature for 16 hours for slow hydrolysis. Monitoring via gas chromatography indicated the presence of some unreacted acid chloride. Addition water (150 mL) was then added to speed up the hydrolysis and the reaction was monitored by gas chromatography to ensure completion. The THF was then distilled off yielding a biphasic (water and oil) reaction mixture. Seeds were then added and the reaction was allowed to reach room temperature so that a heavy solid comes out. Water (250 mL) and acetonitrile (500 mL) were added to keep the suspension stirrable as the suspension was stirred for 2 hours at room temperature. The solid was then filtered off and washed with acetonitrile (2×250 mL). This filtrate contained the first crop of α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O); 264 grams with AP 95 in 66% yield after drying in vacuo at room temperature. The mother liquor (113 gram residue) was then triturated the residue with water and acetonitrile (250 mL/250 mL) for 1-2 hours at room temperature. The reaction was then filter and the solid dried to obtain a second crop of α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O); 64 grams with AP 90 in 16% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Sn](CCCC)CCCC)CCC.Cl[C:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])([CH3:23])[CH:21]=[O:22]>C1(C)C=CC=CC=1>[O:22]1[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])([CH3:23])[CH:21]1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(Cl)(C=O)c1ccc(Cl)cc1Cl
Agent: CCCC[Sn](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2Cl)OC1n1ccnc1
Yield: 43.7 %

Procedure:
A mixture of tri-n-butyltin imidazole (9.28 g), 2-chloro-2-(2,4-dichlorophenyl)propionaldehyde (4.75 g) and toluene (100 ml) was heated under reflux for 5 hours. After cooling, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The oily residue was purified by chromatography over silica gel to give 1-[1,2-epoxy-2-(2,4-dichlorophenyl)propyl]imidazole (2.35 g, yield 43.7%) as an oil. The product was dissolved in ether, and the ether solution was neutralized by adding fuming nitric acid to give crystals of 1-[1,2-epoxy-2-(2,4-dichlorophenyl)propyl]-imidazole nitrate, which were recrystallized from methanol.
Reaction SMILES: [C:1]1([N:7]=[C:8]2[CH2:17][CH2:16][N:15]3[CH:10]([CH2:11][CH2:12][CH:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCOC(C)=O.CC(C)=O>CO>[NH:7]([CH:8]1[CH2:17][CH2:16][N:15]2[CH:10]([CH2:11][CH2:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N=C2CCN3CC(c4ccccc4)CCC3C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: c1ccc(NC2CCN3CC(c4ccccc4)CCC3C2)cc1

Procedure:
The crude anil (IV) (7.2 g.) was dissolved in MeOH (100 ml.), cooled in an ice bath and then NaBH4 (3.6 g.) added portionwise. The mixture was refluxed for 1 hr. and cooled. The solvent was removed and the residue treated with EtOAc/H2O. The EtOAc extracts were combined, dried over MgSO4 and solvent removed in vacuo. Yield, 6.7 g. The TLC showed two spots (most likely two isomers). The mixture was run through a HPLC using EtOAc/acetone (5:1). The mixture was not easily separated and the main portion (4 g.) was still a mixture. The mixture was carried through the rest of the synthesis. Also obtained was the fast component pure (0.7 g.) and the slow component pure (0.4 g.)
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]2[O:4][N:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(O)c2c(C)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2c(C)noc2c1
Yield: 34.7 %

Procedure:
3,6-dimethyl-1,2-benzisoxazol-4-ol (Intermediate 19, 345 mg) was dissolved in acetonitrile (10.0 ml) and then 1-fluoro-4-nitrobenzene (298 mg, 2.11 mmol) and potassium carbonate (877 mg, 6.34 mmol) were added. The reaction mixture was stirred and heated at reflux overnight. After removal of the volatiles, the residue was purified by silica gel chromatography eluting with a gradient cHex/EtOAc from 100/0 to 50/50 to afford the title compound (208 mg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[CH:16])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[C:16][C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[CH:31][CH:30]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: Fc1ccccc1CNc1ccc(I)cc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COC(=O)[C@H](CC#Cc1ccc(NCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Yield: 28.1 %

Procedure:
To a stirred solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 365 mg, 1.60 mmol), prepared with analogous procedure to that described hereinabove, N-[(2-fluorophenyl)methyl]-4-iodoaniline (D63, 630 mg, 1.92 mmol) and diethylamine (0.82 ml, 585 mg, 8 mmol) was added CuI (30 mg, 0.08 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol). After stirring at room temperature for 5 h ethyl acetate was added and the solution was extracted with sat. ammonium chloride solution. The organic layer was dried (Na2SO4), filtered and evaporated. The resulting crude material was purified by flash chromatography using a cyclohexanes, ethyl acetate gradient (5%40%) on silica gel to afford the title compound (192 mg, 28%); UPLC: 0.88 min, MS: (ES/+) m/z: 427 [MH]+, C24H27FN2O4 requires 426.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]Cl)[N:37]=1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:18][C:12]2[CH:11]=[C:10]3[C:15]([C:6]([NH:5][C:4]4[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=4[F:2])=[N:7][CH:8]=[N:9]3)=[CH:14][C:13]=2[O:16][CH3:17])[N:37]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1csc(NC(C)=O)n1
Yield: 25.2 %

Procedure:
Using an analogous procedure to that described in Example 27, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg 1.14 mmol), (prepared as described for the starting material in Example 22), and 2-acetamido-4-chloromethylthiazole (381 mg, 1.68 mmol) were combined to give 7-((2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline (135 mg, 25%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])(=[O:21])[C:18]([CH3:20])=[CH2:19]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(Cl)(Cl)Cl>[C:17]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCNC(=O)Oc1cccc(OC(=O)c2ccccc2)c1
Yield: 90.7 %

Procedure:
A mixture of 65 grams (0.30 mol) of resorcinol monobenzoate, 50 grams (0.32 mol) of isocyanatoethyl methacrylate, 1.05 grams of dibutyltin dilaurate and 400 ml. of chloroform was heated under reflux for 4 hours. The solvent was then removed by vacuum stripping and the residue was recrystallized from a mixture of ethyl acetate and hexane. There was obtained 100.5 grams (87% of theoretical) of the desired 3-benzoyloxyphenyl 2-methacryloxyethylcarbamate having a melting point of 57.5°-61.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([N:28]2[CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27]2)=[O:26])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: c1ccc2c(c1)CNC2
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
As described in example 1E, 76 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 2,3-dihydro-1H-isoindole to give 75 mg of [4-(1,3-dihydro-isoindole-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H29N3O5+H 464.5; found 464.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1I)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:15]([Cu])#[N:16]>CN(C=O)C.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2ccccc2c1C#N
Temperature: 80 °C

Procedure:
To a solution of 2 g 3-Iodo-1H-indole-2-carboxylic acid methyl ester in 10 ml DMF and 20 ml THF, 1.5 g CuCN, 434 mg Et4NCN and 461 mg DPPF were added and the mixture was purged with argon for 15 min. Then, 254 mg Pd2(dba)3 were introduced and the reaction was heated to 80° C. for 5 h. Finally, 10 ml saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with DCM. After subsequent removal of the solvent under reduced pressure the residue was purified by chromatography on silica gel with ethylacetate as eluent. The fractions containing the product were evaporated to yield a white solid. Yield: 1.2 g.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[S:20])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C1CCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 86.3 %

Procedure:
To a solution of 1,5,6,7-tetrahydro-indol-4-one (4.51 g, 33.36 mmol) in dry THF (300 mL) was added Lawesson's reagent (3.495 g, 33.36 mmol) at 0° C. as a solid, in portions. The reaction mixture was warmed to RT and stirred for 35 min. The reaction mixture was then poured into saturated NaHCO3, the product extracted into Et2O, dried over MgSO4, filtered, evaporated, and dried under vacuum overnight. The product was purified by filtration through SiO2 using 30% EtOAc/hexane, evaporated to dryness, and dried under vacuum for 1 h to provide 1,5,6,7-tetrahydro-indole-4-thione (4.354 g, 86.3% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 2.75 g (53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([OH:23])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:24][CH3:25])[C:15]=2[CH3:26])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47]I.Cl>O1CCCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][I:27])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:24][CH3:25])[C:15]=2[CH3:26])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(O)cccn23)ccc1N
Reactant: ICCOCCOCCOCCOCCOCCOCCI
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCCOCCOCCOCCOCCOCCOCCI)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
12 ml (6.0 mmol) of potassium hexamethyldisilylamide (0.5 M solution in toluene) at −20° C. under nitrogen is added, dropwise, to the solution of 2.0 g (5.64 mmol) of methyl 2-amino-5-[(8-hydroxy-1-methoxy-2-methyl-indolizin-3-yl)carbonyl]benzoate (described in stage F of Example 1) in 56 ml of tetrahydrofuran. The formation of a red precipitate is observed. The mixture is allowed to return to ambient temperature and 18.5 g (33.9 mmol) of 1,20-diiodo-3,6,9,12,15,18-hexaoxaicosane are added (Example R1). The solution is stirred at ambient temperature for 18 hours. The reaction medium is poured into a solution of hydrochloric acid (1 M) and the mixture is extracted with an ethyl acetate/tetrahydrofuran mixture. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (gradient of dichloromethane/methanol: 100/0 to 90/10). 2.3 g (53%) of a yellow oil are obtained.
Reaction SMILES: Cl.Cl.[C@H:3]12[CH2:9][C@H:6]([NH:7][CH2:8]1)[CH2:5][N:4]2[C:10]([C@@:12]1([C:26]2([OH:30])[CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:15][C@@H:14]([NH:17][C@@H:18]2[C@H:23]([O:24][CH3:25])[CH2:22][O:21][CH2:20][CH2:19]2)[CH2:13]1)=[O:11].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:30][C:26]1([C@:12]2([C:10]([N:4]3[CH2:5][C@@H:6]4[CH2:9][C@H:3]3[CH2:8][N:7]4[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]=3)=[O:11])[CH2:16][CH2:15][C@@H:14]([NH:17][C@@H:18]3[C@H:23]([O:24][CH3:25])[CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)[CH2:29][CH2:28][CH2:27]1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3)(C2(O)CCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)n2)(C2(O)CCC2)C1

Procedure:
A solution of 93 mg (0.20 mmol) of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-3-(1-hydroxycyclobutyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol dihydrochloride, 91 mg (0.49 mmol) of 2-chloro-6-trifluoromethylpyridine, and 0.14 mL (0.80 mmol) of diisopropylethylamine in 0.5 mL of DMSO was heated at 80 C for 18 h, then cooled and partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using as the mobile phase acetonitrile-water containing 0.05% TFA. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-2.52 (m, 16H) 3.26-3.54 (m, 8H) 3.53-3.92 (m, 4H) 4.02 (dd, J=11.8, 4.3 Hz, 1H) 4.22 (d, J=13.0 Hz, 1H) 5.01 (d, J=14.3 Hz, 2H) 6.47 (d, J=8.5 Hz, 1H) 6.93 (d, J=7.5 Hz, 1H) 7.56 (t, J=8.0 Hz, 1H). HRMS calculated for C27H37N4O4F3: 539.2845; found: 539.2894.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[OH:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>CO>[NH2:26]/[C:6](/[C:5]1[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: O=C(c1ccc(F)cc1)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccc(F)cc1
Yield: 63 %

Procedure:
Prepared as in Example 1 from 2-(4-fluorobenzoyl)-benzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 63% of theory. Yellow, felt-like crystals; M.p. 158° C. (methanol).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[C:17]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](I)=[N:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[Br-].[CH2:35]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41][Zn+])=[CH:39][CH:38]=1)[CH3:36].O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([CH2:35][CH3:36])=[CH:38][CH:39]=2)=[N:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2ccccc21
Reactant: CCc1ccc(C[Zn+])cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)cc1

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (0) (167 mg) and tri(2-furyl)phosphine (135 mg) in tetrahydrofuran (20 ml) was stirred at room temperature for 5 minutes under argon atmosphere. Thereto were added 1-t-butoxycarbonyl-3-iodo-1H-indazole (2.0 g) and the above 4-ethylbenzylzinc bromide (N,N-dimethylformamide solution) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-92:8) to give 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.37 g) as colorless oil. APCI-Mass m/Z 337 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH3:11][C:12]([C:14]([CH3:16])=[CH2:15])=[CH2:13].[Cr](O)(O)(=O)=O.OS(O)(=O)=O>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[C:5]2[C:6]([C:7](=[O:9])[CH:8]=1)=[CH:15][C:14]([CH3:16])=[C:12]([CH3:13])[CH:11]=2
Reactant: COC1=CC(=O)C=CC1=O
Reactant: C=C(C)C(=C)C
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COC1=CC(=O)c2cc(C)c(C)cc2C1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Methoxy-p-benzoquinone (0.50 g) and 2,3-dimethyl-1,3-butadiene (0.63 ml) were added to 23.0 mL of glacial acetic acid. The mixture was heated at 45° C. for 18.5 hrs. A chromic acid solution consisting of 1.85 g of Na2Cr2O7.2H2O, 1.16 mL water, and 0.09 mL of concentrated H2SO4 was then added, and the temperature was kept at approximately 67° C. for 1 hour. The product was precipitated by the addition of ice water, washed several times with cold water, and then dried over P2O5. A 71% yield (0.557 g) of 2-methoxy-6,7-dimethyl-1,4-naphthoquinone was obtained.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:34][CH2:35][C:36]([O:38]C)=[O:37].O.[OH-].[Li+]>C1COCC1.O>[C:28]1([S:25]([NH:24][C@H:11]([C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C:8]2[CH:7]=[CH:6][C:5]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[C:4]([CH:9]=2)[C:3]([OH:40])=[O:2])(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(=O)[C@H](Cc2ccc(OCC(=O)O)c(C(=O)O)c2)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
5-[(2S)-2-Benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester Step H (17 mg, 0.30 mmol) is stirred in 3:2 THF/H2O (3 mL) at RT. Lithium hydroxide monohydrate (20 mg, 0.5 mmol) is added and the reaction is stirred overnight. The mixture is partitioned between EtOAc (15 mL) and 2N HCl (15 mL). The organics are washed with saturated NaCl (1×15 mL), filtered and concentrated to afford the title compound (compound 1), 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-carboxymethoxy-benzoic acid; 1H NMR (400 MHz, CDCl3) δ7.65 (d, 2H), 7.51 (m, 1H), 7.38 (m, 3H), 7.20 (d, 1H), 7.01 (d, 2H), 6.80 (d, 2H), 6.68 (d, 1H), 4.73 (s, 2H), 4.17 (m, 2H), 3.94 (m, 1H), 3.78 (s, 3H), 2.99 (dd, 1H), 2.91 (dd, 1H); MS (ES−) m/z 541 (M−1).