Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C(O)C.[CH:21](Br)([CH3:23])[CH3:22]>[OH-].[K+]>[CH:21]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])([CH3:23])[CH3:22]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: CC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(OC(C)C)c1
Reaction time: 1 h

Procedure:
A 22.7 g 0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 100 ml of 1N-potassium hydroxide solution. To this solution 150 ml of ethanol was added and the mixture was stirred for one hour, which was followed by the addition of 12.3 g (0.1 mol) of isopropylbromide. After the addition of the iso-propylbromide, the reaction mixture was warmed and stirred under reflux for 4 hours. After distillation of most of the ethanol, the oily material remaining was extracted with benzene and the residue was distilled to obtain 20.9 g (77.9%) of a red, viscous oil having a boiling point of 186° C/0.08 mm Hg. The product was recrystallized from a mixture of benzene and n-hexane (1 : 1) as white prismatic crystals having a melting point of 92° C. IR cm-1 (KBr-tablet) νNH 3250(S), νCH 2980(S), νCO 1660 (S), 1610(S).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Agent: Cl
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of intermediate from Step B (100 mg, 0.32 mmol) in 2N aqueous NaOH (20 mL) was stirred at reflux temperature for 1.5 h. The solution was cooled in ice bath, neutralized with 2 N aqueous HCl and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (90 mg) as a white solid.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.S(C)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.Cl>CO.ClCCl>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([OH:35])[CH3:34])=[CH:31][CH:32]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: C[C@@H](O)c1ccc(C(F)(F)F)cc1
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To (S)-2-methyl-CBS-oxazaborolidine (Callery, 1M in toluene, 1 eq.) at −45° C. was added BH3.Me2S (1.06 eq.). This solution was stirred for 10 minutes at −45° C. and then placed in a −30° C. cooling bath before the slow dropwise addition of a 1M dichloromethane solution of 4′-(trifluoromethyl)acetophenone. The reaction mixture was allowed to stir for 214 3 hours at −30° C. After completion of the reaction, excess MeOH was added followed by 1N HCl. After warming up to room temperature, the resulting mixture was filtered through a pad of celite pad eluted with 30% EtOAc in hexane. The organic and aqueous layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (20% EtOAc in hexane) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 64.8 %

Procedure:
To a stirred solution of 4-fluorophenol (1.60 g, 14.3 mmol) and sodium hydride (0.34 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) was added a solution of methyl 5-chloro-2-fluorobenzoate (2.70 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) at 0° C. The resulting mixture was heated at 120° C. for 16 h. After cooling to room temperature, the mixture was diluted with ether (300 mL) and washed with water (150 mL×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20:1) to afford 2.60 g (65%) of the title compounds as slight yellow oil: 1H-NMR (CDCl3) δ 7.88 (1H, d, J=2.8 Hz), 7.40 (1H, dd, J=8.8, 2.8 Hz), 7.06–6.85 (5H, m), 3.84 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(COC)OC>[CH2:35]([O:34][C:32]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(OCc1ccccc1)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.7 %

Procedure:
To a solution of 5.0 g (0.014 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole in 50 ml glyme was added 1.7 g (0.015 mole) of potassium t-butoxide. The mixture was cooled and a solution of 5.0 g (0.029 mole) of benzyl chloroformate in 25 ml glyme was added dropwise. The reaction mixture was stirred at room temperature overnight, then poured onto water. The mixture was extracted with ether and the combined ether extracts were washed, then dried and concentrated to give 12.1 g of crystals. The product was purified by chromatography on silica gel, eluting with toluene, to give 2.1 g of colorless crystals (from hexane), mp 110°-111°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=2)=[N:30]1>>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[N:6]3[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])[C:31]([C:43]2[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=2)=[N:30]1
Reactant: O=Cc1ccc(-c2cc3c(Br)cccc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: Cn1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 4-[4-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde and 1-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 564.2.
Reaction SMILES: O=S1(=O)CCCN1C1C(F)=C(C=C([N+]([O-])=O)C=1)C(OC)=O.Cl[CH2:23][CH2:24][CH2:25][CH2:26][S:27]([NH:30][C:31]1[C:32]([F:44])=[C:33]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:34]([O:36][CH3:37])=[O:35])(=[O:29])=[O:28]>>[O:28]=[S:27]1(=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][N:30]1[C:31]1[C:32]([F:44])=[C:33]([CH:38]=[C:39]([N+:41]([O-:43])=[O:42])[CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCCl)c1F
Agent: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCS2(=O)=O)c1F
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCCS2(=O)=O)c1F

Procedure:
Methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2-fluoro-5-nitrobenzoate (D148) was prepared in an analogous manner to the process for methyl 3-(1,1-dioxido-2-isothiazolidinyl)-2-fluoro-5-nitrobenzoate (D147) from methyl 3-{[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D146). [M+H+ NH3]+=350.1, RT=2.79 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15](O)=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[Cl-].[NH4+:29]>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15]([NH2:29])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: Cc1ncsc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1ncsc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 15 %

Procedure:
10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 30.4 mg (15% yield) of the title compound.
Reaction SMILES: Br.Br.[NH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:30])C=O>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[O:16][CH3:17])[C:6]1=[C:4]([CH3:5])[N:3]=[C:26]([NH:27][C:30]3[C:6]([CH3:4])=[CH:15][CH:10]=[CH:11][C:12]=3[CH3:13])[N:7]1[CH2:8][CH2:9]2
Reactant: COc1cc2c(cc1OC)C(C(C)N)=NCC2
Reactant: CN(C)C=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1OC)-c1c(C)nc(Nc3c(C)cccc3C)n1CC2

Procedure:
2.9 g 2,6-dimethylphenylisocyanide dichloride is added to a suspension of 5 g of 1-(1-aminoethyl)-3,4-dihydro-6,7-dimethoxyisoquinoline dihydrobromide in 100 ml dimethylformamide. 3.6 g of anhydrous potassium carbonate are then added. The suspension is stirred and warmed at 60° for 6 hours. The potassium carbonate is filtered off and washed with dimethylformamide. The washings and filtrate are concentrated in a vacuum, and the residue is chromatographed on silicagel using CHCl3 /CH3OH (95:5) as eluant to give the title compound as the free base; M.Pt. 234°-236°.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@@H:3]([C@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][N:6]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:4].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C:87](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78].[Li+].[OH-]>CCO.O.CO.C(Cl)(Cl)Cl>[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=2)[C:87]([NH:1][C@@H:2]([CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[C@H:3]([OH:4])[C@H:5]2[CH2:9][C@@H:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][NH:6]2)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3ccccn3)CN2)C1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
Step 12 (B): (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step 12 (A), 39.2 mg, 0.072 mmol) in EtOH (3 mL) was added a solution of LiOH (35 mg, 1.44 mmol) in H2O (0.75 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 34.5 mg (93% yield) of the title compound as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 2.12-2.31 (3H, m), 2.44 (1H, m), 2.64 (1H, dd, J=6, 12 Hz), 2.80 (1H, m), 2.99-3.09 (2H, m), 3.30-3.38 (2H, m), 4.98 (1H, s), 5.36 (1H, m), 6.60-6.73 (3H, m), 6.79-6.86 (2H, m), 7.11-7.39 (9H, m), 7.45-7.47 (1H, m), 7.58 (1H, m), 8.06 (1H, m). HPLC retention time: 1.55 min (method A). MS (ESI) (M+H)+ 516.24.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4ethylphenyl)5(pent-1-enyl)pyridine (Example 131) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 22 H), 2.28 (m, 2 H), 2.73 (q, J=7.5 Hz, 2 H), 3.35 (m, 1 H), 3.45 (m, 1 H), 4.35 (s, 2 H), 7.10 (d, J=8.0 Hz, 2 H), 7.18-7.34 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C25H37NO 368; found 368 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane). mp 87-88° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:9][O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1C(=O)OC
Temperature: 55 °C

Procedure:
Add methyl 4-bromobutyrate (54.4 mL, 0.437 mol) to a mixture of 2-tert-butoxycarbonylamino-4-chloro-benzoic acid methyl ester (96.15 g, 0.337 mol) and Cs2CO3 (274.10 g, 0.841 mol) in DMF (1.3 L). Heat the suspension at 55° C. overnight. Remove DMF under vacuum. Dilute the organics with ethyl acetate (1.5 L) and water (1.5 L). Separate the organic layer and extract the aqueous with ethyl acetate (2×0.5 L). Combine the organics and wash with half saturated potassium bicarbonate (1 L), water (2×0.5 L) and brine (0.5 L). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. This provides the title compound as a yellow oil crude (141.8 g):
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:4][CH2:3][CH2:2]2.C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24][CH:25]=O)=[O:21].C(O)(=O)C>C(OCC)C.C(OCC)(=O)C.CCCCCC>[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24]/[CH:25]=[C:7]1/[C:6](=[O:9])[CH:5]2[CH:1]([CH2:8]/1)[CH2:2][CH2:3][CH2:4]2)=[O:21]
Reactant: COC(=O)CCCC=O
Reactant: O=C1CCC2CCCC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
(E)-2-[(mixture of 3α and 3β)-tert-Butyldimethylsilyloxyoct-1-enyl]bicyclo[3,3,0]octan-6-one (290 mg), prepared as described in Reference Example 19 or 26 and predominantly in the 2β-configuration, was dissolved, with stirring, in anhydrous diethyl ether (5 ml) at -78° C. in an argon atmosphere, and the solution was then treated with a freshly prepared solution of lithium diisopropylamide in diethyl ether (1.1 ml; 0.9M) at -78° C. and the mixture was stirred at -78° C. for 10 minutes. The mixture was then treated with 4-methoxycarbonylbutanal (208 mg) at -78° C. and stirred for a further period of 10 minutes. The reaction mixture was then treated with a solution of glacial acetic acid (100 mg) in diethyl ether (0.1 ml) at -78° C., and was then warmed to 20° C. The mixture was then diluted with ethyl acetate (25 ml), washed with aqueous ammonium chloride solution (2M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting oil (480 mg) was dissolved with stirring in dry benzene (5 ml) and then was treated with methanesulphonyl chloride (124 mg) and then, dropwise, with a solution of triethylamine (101 mg) in benzene (0.5 ml) at 20° C. The mixture was stirred for 1 hour at 20° C. and then was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (1.0 ml) and the resulting mixture was stirred for a further period of 1.5 hours at 20° C. The mixture was concentrated in vacuo to give a residue which was subjected to chromatography on a silica gel column using a mixture of hexane and ethyl acetate (1:9 v/v) as eluant, to give 6-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxyoct-1-enyl]3-[(E)-4-methoxycarbonylbutylidene]-bicyclo[3,3,0]octan-2-one (92.4 mg), predominantly in the 6β-configuration, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-prosta-5,13-dienoate.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH2:9]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])[CH3:10]>C(O)C>[CH2:17]([C:11]1[C:12](=[O:13])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[N:1][C:9]=1[CH3:10])[CH3:19]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: NC1=NCCCCC1
Solvent: CCO
Product: CCc1c(C)nc2n(c1=O)CCCCC2
Yield: 61 %

Procedure:
5.6 g. of 7-amino-3,4,5,6-tetrahydro-2H-azepine and 7.5 g. of ethyl 2-ethyl-acetoacetate are boiled in 50 ml. ethanol for 3 hours. The ethanol is then evaporated at reduced pressure. The residual oil is dissolved in 20 ml. of 10% hydrochloric acid and shaken out twice with 10 ml. ethyl acetate. The aqueous layer is neutralized with sodium hydrogen carbonate and shaken out with 3×10 ml. chloroform. The combined chloroform layer is dried over calcinated sodium sulphate and evaporated. The residual colorless oil is fractionated at reduced pressure. 6.3 g. (61%) 3-ethyl-2-methyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine are obtained. Boiling point: 156°-160° C./2 mmHg.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]2[CH2:13][S:12][C:11]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=4[NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:10]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41].O>ClCCl>[Cl:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=1)[NH:15][C:14]([C:11]1[S:12][CH2:13][C@@H:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:3]3)[N:10]=1)=[CH:22]2
Reactant: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
The compound (85 mg, 0.19 mmol) prepared in Example 115 was dissolved in dichloromethane (10 ml). Diisopropylethylamine (0.13 ml, 0.75 mmol) and acetyl chloride (0.013 ml, 0.19 mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39 mg, Yield 42%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([OH:14])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:15]([OH:17])=[O:16])(=O)[CH3:2].CC1OC2C=CC(C(O)=O)=C(C(O)=O)C=2N=1>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[CH3:2][C:1]1[O:14][C:13]2[CH:12]=[CH:11][C:7]3[C:8]([O:17][C:15](=[O:16])[C:6]=3[C:5]=2[N:4]=1)=[O:10]
Reactant: CC(=O)Nc1c(O)ccc(C(=O)O)c1C(=O)O
Agent: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2o1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c3c(ccc2o1)C(=O)OC3=O
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A 4:1 mixture of 3-acetamido-4-hydroxyphthalic acid and 2-methyl-4,5-benzoxazoledicarboxylic acid in acetic anhydride and concentrated sulfuric acid (0.10 mL) is stirred for 18 hours at 110° C., cooled and filtered. The white solid filter cake is air dried to give the title product, 5.39 g (77.1%), identified by NMR and IR spectral analyses.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:33](=[O:36])[NH:34][N:35]=4)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:37]>CO.O1CCOCC1>[ClH:37].[ClH:37].[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:33](=[O:36])[NH:34][N:35]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(c2n[nH]c(=O)o2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 250 mg of tert-butyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate in 4 ml of methanol was added 4 ml of 4 M hydrogen chloride in 1,4-dioxane at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and concentrated in vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:28]([CH:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:38](=[O:39])[NH:37][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH3:29])=[O:10])=[CH:19][CH:20]=1
Reactant: CCC(N=C=O)c1ccccc1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N(C(=O)NC(CC)c2ccccc2)[C@@H]1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of compound 59 (41 mg, 0.15 mmol), triethylamine (83 uL, 0.60 mmol), α-ethyl-benzyl isocyanate (29 mg, 0.18 mmol) in methylene chloride (1.2 mL) was stirred overnight. TLC analysis indicated the completion the reaction. Removal of solvents gave the crude material, which was purified by preparative TLC plate (15% EtOAc in hexanes), yielding 38.2 mg of compound 60 (59%): LC-MS purity: 98.1%; 1HNMR (300 MHz, CDCl3): 0.95 (t, 3H), 1.92 (m, 2H), 2.69 (m, 2H), 3.30 (m, 1H), 3.83 (s, 3H), 4.22 (d, 1H), 4.85 (q, 1H), 5.18 (m, 4H), 5.80 (m, 1H), 6.85 (br, d, 1H), 7.45 (m, 9H). Anal. C25H28N2O5, Mol. Wt.: 436.5. Found: ESI-MS: 437.1 (M+H)+.