Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.C(N(CC)CC)C.[O:15]1[CH2:20][CH2:19][CH:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.CCOC(C)=O>C(Cl)Cl>[OH:7][C@H:4]1[CH2:5][CH2:6][N:2]([C:21]([CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[O:22])[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: O=C(Cl)C1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(C1CCOCC1)N1CC[C@H](O)C1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
The (S)-pyrrolidin-3-ol hydrochloride (3.69 g, 29.9 mmol) and triethylamine (6.65 g, 9.16 mL, 65.7 mmol) were put in CH2Cl2 (15 mL). The suspension was cooled at ˜3° C. To this mixture, a solution of tetrahydro-pyran-4-carbonyl chloride (4.67 g, 29.9 mmol) in CH2Cl2 (15 mL) was added slowly. Then the resulting reaction mixture was stirred for 1.5 h at 3-10° C. The reaction mixture was then concentrated to give a powder. To this powder, addition of EtOAc (100 mL). The solid was filtered and washed with EtOAc. The recovered filtrate was then concentrated to give ((S)-3-hydroxy-pyrrolidin-1-yl)-(tetrahydro-pyran-4-yl)-methanone as beige powder. (6.77 g, 98% yield). 1H-NMR (400 MHz, Methanol-d4, 298 K): δ ppm 1.59-2.15 (m, 6H) 2.69-2.86 (m, 1H) 3.43-3.75 (m, 6H) 3.94-4.00 (m, 2H) 4.37-4.48 (m, 1H). LCMS: [M+H]+=199.9, Rt(6)=0.86 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CN(Cc2ccccc2)c2ccccc21
Temperature: 80 °C
Yield: 74.5 %

Procedure:
[2-oxo-3-(3-phenylpropionylamino)-2,3,4,5-tetrahydrobenzo-[b][1,4]diazepin-1-yl]acetic acid methyl ester (104a; 500 mg, 1.31 mmol), calcium carbonate (155 mg, 1.58 mmol), and benzyl bromide (170 μl, 1.44 mmol) were taken into 10 ml of dimethylformamide and heated to 80° C. for 8 hours. The mixture was diluted with 150 ml of ethyl acetate and washed 4 times with 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous, yellow oil that was purified by flash chromatography eluting with dichloromethane/ethyl acetate (8:2) to give 460 mg (75%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.34-7.05 (14H, m), 6.32-6.28 (1H, d), 4.84-4.76 (1H, d), 4.76-4.70 (1H, m), 4.43-4.37 (1H, d), 4.26-4.18 (1H, d), 4.06-4.00 (1H, d), 3.79 (3H, s), 3.45-3.37 (1H, m), 3.02-2.95 (1H, m), 2.90-2.82 (2H, m), 2.5-2.34 (2H, m).
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=2)[C:9]([F:12])([F:11])[F:10])[CH2:4]1.[CH:29]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[C:40]([CH:43]=O)[CH:39]=[CH:38]2)([CH3:31])[CH3:30]>>[F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:43]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[C:33]([O:32][CH:29]([CH3:31])[CH3:30])[CH:34]=[CH:35][CH:36]=5)[N:41]=4)=[N:20][N:19]=3)[CH:14]=2)[C:9]([F:12])([F:10])[F:11])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(CF)CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CCC(CF)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B using tert-butyl 3-(fluoromethyl)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidine-3-ylcarbamate and substituting 8-isopropoxyquinoline-2-carbaldehyde in Step F. LCMS APCI (+) m/z 603 (M+H).
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=NC=C[N:22]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].O[C@@H:37]1CC[N+:39](C)(C(C2C=NC=CN=2)C(=O)N)[CH2:38]1.[Br-].OC1CC[N@@+](C)(CC(=O)NC2N=NC=CC=2)C1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[N:22]=[N:39][CH:38]=[CH:37][CH:26]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](O)C1
Agent: C[N@@+]1(CC(=O)Nc2cccnn2)CCC(O)C1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cccnn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide (Intermediate B) with (R)-3-hydroxy-1-methyl-1-(pyridazin-3-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate F).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][OH:39])[O:18][CH:10]1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:42]([C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Br)=[CH:47][C:46]=1[Cl:53])=[N+:43]=[N-:44].O>CN(C=O)C>[N:42]([C:45]1[CH:52]=[CH:51][C:48]([CH2:49][O:39][CH2:38][C@H:19]2[O:18][CH:10]([S:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:47][C:46]=1[Cl:53])=[N+:43]=[N-:44]
Reactant: OC[C@H]1OC(Sc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(COC[C@H]2OC(Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-benzyl-1-thio-D-glucopyranoside (3) (1.09 g, 2.00 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 96 mg, 2.40 mmol), and the resulting mixture was stirred at room temperature for 15 min. The reaction mixture was cooled to 0° C. and 4-azido-3-chlorobenzyl bromide (592 mg, 2.40 mmol) was added, which was followed by stirring at room temperature for 4 hr. Water (30 ml) was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-benzyl-1-thio-D-glucopyranoside (4) (1.33 g, yield 94%) as slightly yellow crystals.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O>>[F:16][C:13]1[CH:14]=[CH:15][C:8]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:10][C:9]=2[CH:12]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CS
Product: COC(=O)c1cc2cc(F)ccc2s1

Procedure:
In a similar manner to Example 9 Method A, methyl thioglycolate (75.2 g) was reacted with 2,5-difluorobenzaldehyde (101.8 g) to give methyl 5-fluorobenzo[b]thiophene-2-carboxylate which was hydrolysed to give 5-fluorobenzo[b]thiophene-2-carboxylic acid which was decarboxylated to give 5-fluorobenzo[b]thiophene (31 g) as an orange oil which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[C:10]([CH2:36][CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:7][P:8]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:43])=[O:25])[CH2:7][P:8]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)S(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(phenoxy)phosphinylmethyl]-glycinate (1.0 g.; 0.002 mol.) dissolved in 10 ml. of methylene chloride at 0° C. was slowly added a solution of metachloroperbenzoic acid (0.4 g.; 0.002 mol.) dissolved in 100 ml. of methylene chloride. The reaction mixture was stirred for one hour and allowed to gradually warm to 25° C. The mixture was washed with 5% sodium hydroxide, dried, then concentrated in vacuo. The resulting oil was extracted into hot petroleum ether and allowed to crystallize for 16 hours to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis-(phenoxy) phosphinylmethyl]-glycinate as a solid having a melting point of 106°-115° C. and the following analysis:
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:19]=2[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([O:28][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:26]=[CH:27][C:19]=2[CH2:18]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc2C1
Product: CCOC(=O)CC1CCCc2cc(OCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound was prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester was used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-acetic acid ethyl ester was used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester and the title compound was isolated as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in hexanes, 13 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield).
Reaction SMILES: N#[C:2]Br.CC(N[C@H]1[C@H](O)O[C@H]([O:15][S:16]([OH:19])(=O)=[O:17])[C@H](O)[C@@H]1O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O)=O.[OH-].[Na+].C1C(N)=CC2C(O[C:46]3([C:56]4C=CC(O)=CC=4[O:54][C:48]4[CH:49]=[C:50](O)[CH:51]=[CH:52][C:47]3=4)[C:38]=2C=1)=O>B([O-])([O-])[O-].[Na+].[Na+].[Na+].O>[CH3:56][C:46]1([CH3:38])[C:47]2([CH2:2][S:16]([OH:19])(=[O:17])=[O:15])[C:48]([CH2:49][CH:50]1[CH2:51][CH2:52]2)=[O:54]
Reactant: Nc1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reactant: CC(=O)N[C@@H]1[C@@H](O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H](OS(=O)(=O)O)O[C@H]1O
Reactant: N#CBr
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2

Procedure:
20 mg cyanogen bromide (CNBr) dissolved in 200 μl deionized water were added to 1 ml of 30 mg/ml chondroitin 4-sulfate (CSA). The pH was adjusted to pH 11 by addition of 5 M NaOH. Activated CSA is applied to a PD-10 column and eluded with 200 mM sodium borate buffer, pH 8.0. CSA fractions were directly dropped into 400 μl of 10 mg/ml fluoresceinamine in 200 mM sodium borate buffer, pH 8.0. The mixture was kept overnight at 4° C. for the coupling reaction. Subsequently, the mixture was concentrated to 1 ml using a SpeedVac concentrator and purified on a PD-10 column and eluded by 50 mM sodium acetate buffer, pH 5.5. Fluoresceinamine-labeled CSA (FL-CSA) fractions were collected and their concentration was determined using the Blyscan glycosaminoglycan assay kit (Biocolor Ltd., Newtown Abbey, Northern Ireland).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>[Pd].C(O)C.O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1ccc2c(c1)OCCC2
Agent: [Pd]
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc2c1OCCC2

Procedure:
Schema 5 illustrates the synthesis of an amino substituted 3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, starting with the reaction of an appropriately halo-substituted phenol with 3-bromopropanol under basic conditions in acetone, yielding the corresponding substituted phenoxypropanol (XI). The propanol is oxidized with Jones reagent in water and acetone, giving an acid, for example, 3-(3-fluorophenoxy)propanecarboxylic acid (XII). The acid is in turn cyclized with phosphorous pentachloride and aluminium chloride in methylene chloride, affording the corresponding 3,4-dihydro-7-substituted-2H-1-benzopyran-4-one (XIII), which is then treated with sodium borohydride in methanol, yielding the appropriate 3,4-dihydro-7-substituted-4-hydroxy-2H-1-benzopyran, for example, 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran (XIV). The 4-hydroxybenzopyran is dehydrated with molecular sieves in the present of p-toluenesulfonic acid, yielding the corresponding 7-fluoro-2H-1-benzopyran (XV). This compound is then hydrogenated in the presence of 5% palladium on carbon in ethanol, yielding 3,4-dihydro-7-fluoro-2H-1 -benzopyran (XVI), which is in turn treated with n-butyllithium and carbon dioxide at -78° C. in tetrahydrofuran, affording the corresponding 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid (XVII). The so-prepared acid is then refluxed with diphenylphosphoryl azide under mild basic conditions in t-butanol, giving the corresponding 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate (XVIII). The carbamate is then converted to the free amine by treating it with trifluoroacetic acid, yielding the 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran intermediate (XIX). The intermediate benzopyran is optionally halogenated in the 5-position by treatment with, for example, N-chlorosuccinimide in N,N-dimethylformamide, yielding the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XX) intermediate. Examples 11 and 12 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [CH:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=O.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:1][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 31.5 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.16 g), molecular sieve 4A (1.1 g), tetrahydrofuran (18 ml), 1-formyl-1-(4-trifluoromethoxyphenyl)cyclopropane (1.08 g), acetic anhydride (0.6 ml) and methyl dichlorofluoroacetate (0.86 g) to yield the title compound (0.45 g, 34%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([O:9]C)=[O:8])[CH2:3]1.O.[OH-].[Li+].CO>O1CCOCC1.O>[CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: C=C1CCC(C(=O)OC)(C(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: C=C1CCC(C(=O)O)(C(C)C)C1
Temperature: 80 °C
Reaction time: 48 h
Yield: 111.9 %

Procedure:
A solution of the methyl 3-methylene-1-isopropylcyclopentanecarboxylate (Step A, 1.21 g, 6.64 mmol) in a mixture of dioxane (4 mL) and water (4 mL) containing 1.114 g (26.56 mmol) of lithium hydroxide monohydrate was homogenized with methanol, and stirred at 80° C. for 48 hrs. The solvent was removed in vacuo, the residue was dissolved in water and the non-acidic components were extracted with diethyl ether (3×30 mL), combined ethers were back-washed with water (1×30 mL). The combined aqueous phases were acidified with 2N HCl and extracted with chloroform (6×30 mL), dried (anhydrous magnesium sulfate) and evaporated to dryness to leave 1.25 g of crude acid. It was used in the next reaction step without any further purification.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([SH:12])[CH3:11].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][CH2:10][CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC

Procedure:
Ethyl 2-bromoisobutyrate (28.6, 0.146 mole), ethanethiol (100 g, 0.161 mole), potassium hydroxide (10.3 g, 0.161 mole), ethyl alcohol. Stirred reaction mixture for two hours at room temperature prior to quenching. Crude yield: 117%; after kugelrohr: 77.8%.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:42])[O:11][C@:12]2([C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]3)[C@:31]3([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]3)[CH2:25][CH2:24]4)[CH2:21][C@@H:20]2[CH3:41])[C:13](=[O:19])[CH2:14][O:15]C(=O)C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(Cl)(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:10](=[O:42])[O:11][C@:12]2([C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]3)[C@:31]3([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]3)[CH2:25][CH2:24]4)[CH2:21][C@@H:20]2[CH3:41])[C:13](=[O:19])[CH2:14][OH:15])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(=O)N[C@H](C)c2ccccc2)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@@H](NC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C)c1ccccc1
Temperature: 25 °C
Reaction time: 24.5 h
Yield: 57.9 %

Procedure:
(11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl (1R)-1-phenylethylcarbamate (42 mg, 0.064 mmol) was dissolved in 1.25 mL of a pre-mixed solution of methanol/chloroform/6N HCl (10:2:1) and stirred at room temperature for 24.5 hours. The solution was then partitioned between ethyl acetate and water and the organic phase was washed with water (twice) and brine and dried over Na2SO4. Filtration and evaporation under vacuum gave a white film which was purified by preparative thin layer chromatography on silica gel, eluting with ethyl acetate/hexane/dichloromethane/methanol (95:95:95:15), to yield 20 mg of (11β,16β)-9-fluoro-11,21-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl (1R)-1-phenylethylcarbamate as a white solid.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]1([C:16]2[CH:17]=[C:18]([OH:23])[C:19](=[CH:21][CH:22]=2)[OH:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:10]1([C:16]2[CH:22]=[CH:21][C:19]3[O:20][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O:23][C:18]=3[CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Oc1ccc(-c2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(-c3ccccc3)ccc2O1

Procedure:
46.1 g of ethyl 2,3-dibromopropionate was added slowly to a mixture of 30 g of 4-phenylcatechol, 66.2 g of potassium carbonate, and 250 ml of acetone. The mixture was refluxed for 18 hours, cooled and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was extracted with hot cyclohexane. The extract was dried (MgSO4) and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was taken up in hexane/methylene chloride. The solution was cooled. The resulting solid (7A) was separated and recrystallized from cyclohexane to give 7, mp: 103°-105° C.