Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:37])=[C:14]([C:30]([O:32]C(C)(C)C)=[O:31])[CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:10][C:11]1[NH:12][C:13]2[CH2:37][O:32][C:30](=[O:31])[C:14]=2[CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: CC1=C(C(=O)OC(C)(C)C)C(c2ccccc2)C(C(=O)OC(C)(C)C)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1=C(C(=O)OC(C)(C)C)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In a manner similar to that previously described, 1.14 gram of 80 percent pyridinium bromide perbromide (2.85 millimoles) was added to a cooled to 0° C. solution of 1.00 gram (2.59 millimoles) of di-t-butyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.81 milliliter of pyridine in 20 milliliters of dry chloroform. The resulting mixture was stirred for 30 minutes at 0° C. and then heated at reflux for 90 minutes. Thereafter, the mixture was cooled to room temperature, diluted with 200 milliliters of ethyl acetate and washed successively with 5 percent hydrochloric acid and brine, dried over magnesium sulfate, then filtered to remove the drying agent and the filtrate subjected to reduced pressure to vaporize the solvent and recover 0.90 gram of product as a yellow oil. The oil was chromatographed on 50 grams of silica gel using 1:1 ethyl acetate-hexane as eluant to obtain 250 milligrams (29 percent yield) of white crystalline t-butyl 2-methyl-4 -phenyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product which after recrystallization from diethyl ether and drying at 70° C./0.05 millimeters Hg pressure for 48 hours and 100° C./0.005 millimeters Hg for 24 hours had a melting point of 185°-188° C. Elemental analyses for the product were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(Cl)c1OC
Reactant: NC(=O)c1ccccc1
Product: COc1cc(C(C)=O)cc(Cl)c1OC

Procedure:
3-Chloro-4,5-dimethoxybenzoic acid (1 g) was converted to the benzamide derivative analogously to O3.043, and the latter to the title compound analogously to O2.059. 495 mg of the title compound were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:14]1[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15]1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: O=C(CC(c1ccccc1)c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C
Yield: 60 %

Procedure:
To a solution of 3,3-diphenyl-1-piperazin-1-yl-propan-1-one (2.0 g, 6.79 mmol) and ethyl bromoacetate (0.94 ml, 8.49 mmol) in dry DMF (15 ml) was added K2CO3 (2.7 g, 19.53 mmol) and the mixture was heated to 70° C. overnight. Reaction mixture was cooled and water (32 ml) was added. The product was extracted with ether, dried and evaporated. The residue was purified by column chromatography using hexane:ethyl acetate (1:4) to give the desired product in 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH2:10][S:11][CH3:12].[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.CCCCCC>ClCCCl>[CH3:12][S:11][CH:10]([F:19])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CSCC(=O)c1ccc(F)cc1F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCCl
Solvent: CCCCCC
Product: CSC(F)C(=O)c1ccc(F)cc1F
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a 20 ml solution of 0.5 g (2.5 mmol) of 2',4'-difluoro-2-(methylthio)acetophenone [Compound (2a-1)] in 1,2-dichloroethane, 1.1 g (3.8 mmol) of N-fluoro-2,4,6-trimethylpyridinium triflate ("Onoda Florinate FP-T300", trade name; product of Chichibu Onoda Co., Ltd.) were added at room temperature, followed by stirring at the same temperature for 12 hours. The reaction mixture was added to n-hexane. The insoluble matter so precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 0.50 g of the title Compound (2b-1) was obtained in the form of a light yellow oil (yield: 91.7%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:9]([O:11]C)=[O:10])=O.C([O-])([O-])=O.[K+].[K+].[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:32])[CH3:29]
Reactant: COC(=O)c1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a) and (80a); 236 mg, 1.01 mmol) was dissolved in THF (11 mL) and the resulting solution was charged successively with K2CO3 (1.6 mL of a 2.0 M aq. solution) and ethylchloroformate (258 mg, 2.7 mmol). The reaction was stirred at RT for 48 h, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed with sat. NaHCO3, water (2×), and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. This product was dissolved in 3:1 THF/MeOH (8 mL) and the resultant solution was charged with lithium hydroxide (2 mL of a 1N solution). The reaction was stirred for 14 h, acidified with 1N HCl, and extracted with EtOAc (2×). The organic extracts were combined, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide 3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoic acid. MS found: (M−H)−=276.1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:27]([N:29]([CH2:39][CH2:40][CH2:41][S:42][CH3:43])[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][CH:12]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:27]([N:29]([CH2:39][CH2:40][CH2:41][S:42][CH3:43])[CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Yield: 37.4 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl-N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide (2.42 g.) in hydrogen chloride-dioxane (3.9N, 50 ml.) was stirred for one and one half hours at room temperature, then stripped of volatiles under vacuum. The residue was triturated with ether, the solution was stripped of volatiles under vacuum, and the process was repeated. An aqueous solution of the residue was lyophilized. A solution of the residue in methanol (50 ml.) was stripped of volatiles, affording a white foam (1.960 g.). Part (950 mg.) of the white foam was twice more lyophilized, affording as an amorphous white solid L-tyrosyl-N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide monhydrochloride hemihydrate (675 mg.; [α]D25 +57.0, c=1, methanol), whose free base is the compound of Formula II wherein R2 is CHQ(CH2)nY wherein n is 2, Y is phenyl and Q is hydrogen and R3 is (CH2)mX wherein m is 3 and X is methylthio.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[O:5]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Product: CCS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared using methods analogous to those described in Step A of Example 490 using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and ethanesulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.82-7.74 (m, 1H), 7.64 (d, J=8.3, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m, 1H), 3.12 (q, J=7.4, 2H), 1.37 (s, 12H), 1.32 (t, J=7.4, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:30][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 47115.7 %

Procedure:
To a stirred solution of 3β-hydroxyandrost-5-en-17-one (0.81 g) in CH2Cl2 (7.4 mL) cooled at 0° C., a solution of mCPBA (0.77 mg) in CH2Cl2 (13.6 mL) was added dropwise. After 0.5 h at 0° C. and 0.5 h at room temperature, a 10% aqueous solution of Na2SO3 was added. The mixture was neutralized by addition of 5% NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give 3β-hydroxy-5α,6α-epoxyandrostan-17-one (0.64 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (d, 1H), 3.52 (m, 1H), 2.87 (d, 1H), 2.44-0.56 (m, 19H), 1.00 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:7][C:6]=1[O:27][CH3:28].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:12][O:11][C:10]1[CH:9]=[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:5]=1[C:4](=[O:29])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1c(OC)cc(OCCOc2ccc3ccccc3c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(OCCOc2ccc3ccccc3c2)cc(OC)c1C(=O)C(=O)O
Yield: 93.2 %

Procedure:
A solution of 2,6-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.45 g of purified 2,6-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 154° C. with decomposition. Analysis Calculated for C22H20O7 : C, 66.66; H, 5.09.
Reaction SMILES: [CH:1]#[C:2][CH:3](O)[CH2:4][CH3:5].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH2:2]([C:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:4]=1[CH3:5])[CH3:1]
Reactant: C#CC(O)CC
Reactant: Nc1ccccc1
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CCc1c(C)[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 7.5 h
Yield: 111.2 %

Procedure:
1-Pentine-3-ol (0.757 g, 9 mmol), aniline (0.559 g, 6 mmol), Ru3(CO)12 (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 140° C. for 7.5 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby a 9.3:1 mixture of 2-ethyl-3-methyl indole and 3-ethyl-2-methyl indole (1.06 g; 6.67 mmol; yield, 95%) was obtained.
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C@H:11]([OH:14])[CH2:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>ClCCl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[F:21][C:17]1[CH:16]=[C:15]([C@H:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C@H:11]([OH:14])[CH2:12][OH:13])[CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A mixture of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol (2.00 g, 6.96 mmol) and activated manganese dioxide (20.0 g, 230 mmol) in dichloromethane (30 mL) was stirred at 20° C. for 3 hours. The mixture was diluted with ethyl acetate (15 mL), filtered through a pad of silica gel, and concentrated. The crude product was purified by Biotage chromatography (FlasH40i, silica, 0-70% EtOAc/hexane) to give 1.40 g (71%) of (2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as a colorless oil. MS (ESI) m/z 286.0 ([M+H]+). HRMS: calcd for C17H16FNO2+H+, 286.1238; found (ESI, [M+H]+), 286.1239.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)[CH3:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:22][CH:23]=1)[CH3:17])(=[O:47])=[O:48]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(c2ccc(OCCN3CCCC3)cc2)C(C)c2ccc(OC3CCCCO3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
To a solution of [4-(2-pyrrolid in-1-yl-ethoxy)-phenyl]-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-amine (0.050 g, 0.12 mmol) in 0.4 mL methylene chloride was added triethylamine (0.05 mL, 0.36 mmol) and 2-mesitylenesulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 3 days. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred at room temperature for 45 minutes. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford 0.071 g of the crude title compound of Step A which was used without further purification. MS 593.2 (M+1)+
Reaction SMILES: [CH:1]([O:3][CH2:4][N:5]1[C:8](=[O:9])[CH2:7][C@H:6]1[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:2].[H][H]>CO.[Pd]>[CH:1]([O:3][CH2:4][N:5]1[C:8](=[O:9])[CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:2]
Reactant: O=COCN1C(=O)C[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=COCN1C(=O)C[C@H]1C(=O)O
Yield: 94.1 %

Procedure:
In 20 ml of methanol was dissolved 1.05 g of compound (16) and 100 mg of 10% Pd-C was added to the solution followed by catalytic hydrogenation at ambient temperature under atmospheric pressure of hydrogen. The catalyst was filtered off and the solvent was removed by distillation under reduced pressure to obtain 650 mg of (S)-1-formyloxymethyl-4-oxo-2-azetidinecarboxylic acid (17).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:56](=[O:61])[CH2:57][CH2:58][O:59][CH3:60]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][C:56](=[O:61])[CH2:57][CH2:58][O:59][CH3:60])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COCCC(=O)Nc1ccccc1O
Product: COCCC(=O)Nc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.458 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.32 g of N-(2-hydroxyphenyl)-3-methoxypropionamide are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (1:1 EtOAc-heptane); Rt=5.70.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl.[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][O:42][CH2:43][CH2:44][NH2:45]>CN(C=O)C.C(O)C>[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:17](=[O:19])[C@H:12]([C:13]([CH3:14])([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COCCOCOCCN
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCO
Product: COCCOCOCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Benzyloxycarbonyl-L-tert-leucine (2.01 g, 7.6 mmol) was dissolved in DMF (20 ml), cooled in an ice bath and stirred during the addition of pentafluorophenol (2.83 g, 15.4 mmol) and EDC (2.95 9, 15.4 mmol). The mixture was stirred at 0° C. for for 1 hour then at room temperature for a further 2 hours. The solution was cooled back to 0° C., a solution of O-(2-methoxyethoxymethyl) ethanolamine in ethanol, prepared in StepG, was added and the reaction was allowed to stirovernight at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in diethyl ether (50 ml), and the solution was washed successively with 1M sodium carbonate (2×30 ml),1M hydrochloric acid (2×30 ml) and brine (30 ml). The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil whichwas purified by column chromatography (silica gel, gradient elution with 50-75% ethyl acetate in hexane). Yield: 1.79 g (67%). 1H--NMR; δ(CDCI3), 7.34 (5H, m), 6.54 (1H, m), 5.60 (1H, m), 5.11 (2H, m), 4.62 (2H, s), 3.93 (1H, d, J=9.3 Hz), 3.70 (4H, m), 3.57 (3H, m), 3.44(3H, s), 3.41 (1H, m) and 1.00 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([Si:22]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC(O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 151.7 %

Procedure:
To a 0° C. mixture of 3-(t-butoxycarbonylamino)-2-hydroxypropanol (22.5 g, 118 mmol), imidazole (8.8 g, 130 mmol) and DMF (450 ml) was added triisopropylsilyl chloride (25 mL, 118 mmol). The reaction was warmed to room temperature and stirred for 3 h. The reaction was concentrated to a slurry, CH2Cl2 was added, and the mixture filtered. The filtrate was washed with water (2×) and concentrated. The reaction was repeated. The combined crude product was chromatographed with SiO2 (hexanes to 30% EtOAc/hexanes) to give the title compound (62.2 g, 76%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(=O)(O)[O-].[Na+].[C:27](=[O:34])([S:31][CH2:32][CH3:33])[O:28][CH2:29]I>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCCl>[C:27](=[O:34])([S:31][CH2:32][CH3:33])[O:28][CH2:29][O:15][C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: CCSC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.050 mole) is added to a stirred solution of sodium bicarbonate (0.100 mole) and tetrabutylammonium hydrogen sulfate (0.050 mole) in water (100 mL) at ambient temperature. After 10 minutes 1,2-dichloroethane (100 mL) is added and then after 30 minutes O-iodomethyl S-ethyl carbonothioate (0.050 mole) in 1,2-dichloroethane (25 mL) is added over 15 minutes. The mixture is stirred for 1 hour at ambient temperature. The organic layer is separated, washed with water (50 mL), dried (magnesium sulfate), and the solvent is evaporated. The residue is stirred with diethyl ether (100 mL), insoluble material is filtered off and washed with diethyl ether. The combined ether phases is evaporated, and the residue may be crystallized to give O-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl) S-ethyl carbonothioate (1005). See eg., Folkmann, et al., Synthesis, 1159 (1990), Method D.
Reaction SMILES: [BH4-].[Na+].Cl.[NH2:4][C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)([CH3:9])[C:6](O)=[O:7].B(F)(F)F.O(CC)CC>C1COCC1>[NH2:4][C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)([CH3:9])[CH2:6][OH:7]
Reactant: CC(N)(C(=O)O)c1cccc(Br)c1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)(CO)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
NaBH4 (38 g, 1.125 mol) was added at room temperature to a slurry of 2-amino-2-(3-bromo-phenyl)-propionic acid hydrochloride (105 g, 375 mmol) in dry THF. At 0° C. BF3—O(C2H5)2 (158 g, 1.125 mol) was added dropwise. The mixture was allowed to warm to room temperature, stirred for three days, quenched with 1M aqueous NaOH solution, concentrated in vacuo to remove the THF and extracted with EtOAc (3×300 ml). The organic phase was washed with 1M aqueous NaOH solution, dried with sodium sulfate and concentrated in vacuo to yield the title compound, which was used in the next reaction step without further purification.