Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23].[I-].[Na+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(CO)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b, 2.5 g) dissolved in NMP (20 mL) was treated with cesium carbonate (7.27 g) and 3-bromo-2,2-dimethylpropan-1-ol (2.75 mL) under nitrogen. The resulting mixture was stirred at 100° C. for 8 h. Further cesium carbonate (1 eq), 3-bromo-2,2-dimethylpropan-1-ol (1 eq) and water (5 mL) were added and the resulting mixture was stirred at 130° C. for 10 h. The incomplete reaction was diluted with water and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was dissolved in NMP (20 mL) was treated with cesium carbonate (7.27 g) and 3-bromo-2,2-dimethylpropan-1-ol (2.75 mL) and sodium iodide (0.167 g) under nitrogen and heated at 130° C. for 10 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by (SiO2 chromatography, elution 60% diethyl ether in isohexane) to afford the subtitle compound (0.93 g) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([SH:20])[CH2:18][CH3:19]>CO>[CH2:17]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: CCCS
Reactant: O=C(O)CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSCCCCCCCCCC(=O)O
Temperature: 69 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
10-bromodecanoic acid (1.0 g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893g, 15.9 mmol) in 1-propanethiol (30 mL) and methanol (30 mL) and stirred at 69° C for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a white crystalline powder. The product was purified by silica column chromatography in 8% ethyl acetate/hexane/0.3% formic acid and recrystallization from hexane to yield 10-(propylthio)decanoic acid (210 mg, 21%), mp 42-43.5° C.; 1H NMR (300 MHz, CDC13) δ 0.96 (t, 3H, J=7.3, CH3) 1.15-1.40 (bm, 10H, methylene envelope), 1.49-1.64 (bm, 6H, CH3CH2CH2SCH2CH2, CH2CH2COOH), 2.32 (t, 2H, J=7.6, CH° COOH), 2.40-2.55 (bm, 4H, CH3CH2CH2SCH2), 10.93 (Br, 1H, COOH); 13C NMR (75.4 MHz, CDCL3) δ 13.64, 23.09, 24.71, 28.96, 29.07, 29.13, 29.24, 29.36, 29.77, 32.16, 34.10, 34.28, 179.98; m/z 247 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O.O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[C:14]([O:13][CH3:12])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ncccc1-c1cnc2ccc(Cl)nn12
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 6.0 g, 25.81 mmol), (2-methoxypyridin-3-yl)boronic acid (3.3 g, 21.58 mmol), cesium carbonate (30 mL of a 2M solution in water, 60 mmol) and 1,4-dioxane (250 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. [1,1′-Bis(diphenyl phosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (1.8 g, 2.16 mmol) was then added and the resulting mixture was again subjected to three further cycles of evacuation backfilling before being heated at 100° C. for 2 hours. Subsequently, the reaction was cooled down, diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was treated with ethyl acetate and the solid formed was filtered, washed with dichloromethane and dried in vacuo to yield the title compound (3.5 g, 62%) as a yellow solid.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:22])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([OH:34])=O)[CH2:8]2)=[CH:3][CH:2]=1.[NH2:46][C@:47]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]1[CH:50]=[CH2:51].P([O-])([O-])([O-])=O.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:21])([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([NH:46][C@:47]3([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]3[CH:50]=[CH2:51])=[O:34])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=CCCCCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (126 mg, 0.198 mmol), (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate (36.8 mg, 0.237 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium phosphate (HATU, 113 mg, 0.297 mmol) in dichloromethane (4 mL) was added N,N-diisopropylethylamine (0. 104 mL, 0.594 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with ethyl acetate, washed it with 5% citric acid, 0.1 M NaOH, and brine, dried over MgSO4, filtered, and concentrated. The resulting brown residue was purified by BIOTAGE® column, eluted with gradient 5˜45% ethyl acetate-hexane to afford the desired product (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol, 49.0% yield) as a white film. 1H NMR (500 MHz, MeOD) δ ppm 0.75-0.90 (m, 3 H) 1.24-1.54 (m, 24 H) 1.61 (tt, J=9.00, 4.27 Hz, 1 H) 1.65-1.77 (m, 2 H) 1.86 (d, J=7.32 Hz, 1 H) 1.94-2.11 (m, 2 H) 2.19-2.41 (m, 3 H) 2.41-2.51 (m, 1 H) 2.77 (dd, J=13.12, 7.02 Hz, 1 H) 3.03 (dd, J=12.51, 7.63 Hz, 1 H) 3.94-4.04 (m, 1 H) 4.09-4.24 (m, 3 H) 4.35 (t, J=7.48 Hz, 1 H) 5.07-5.18 (m, 1 H) 5.24-5.36 (m, 1 H) 5.70-5.86 (m, 2 H) 7.30-7.41 (m, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.58-7.75 (m, 6 H). LC-MS (retention time: 3.72 min, method C), MS m/z 774 (M-C2 H4).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[CH:29]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[Br:16])=[O:7].O.[OH-].[Li+].CO.C(O)(=O)C>C1COCC1.O>[Br:16][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[CH:29]=2)=[CH:22][CH:23]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Br)c(C(=O)N[C@@H](Cc2ccc(-c3cc(Br)cn(C)c3=O)cc2)C(=O)O)c1
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (29 mg, 0.05 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (20 mg, 0.47 mmol) in water (1.0 mL). Methanol (0.5 mL) was added to effect a clear solution and the reaction mixture was stirred 18 hr. Acetic acid (0.5 mL) was added, the entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine (22 mg, 79%) as a white solid. HRMS: Obs. Mass 562.9814. Calcd. Mass 562.9817 (M+H).
Reaction SMILES: [Li+].CC(O[Al-](OC(C)(C)C)OC(C)(C)C)(C)C.[C:18]1([C:26](OCC)=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1([CH2:26][OH:27])[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: CC(C)(C)O[Al-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)CC1
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of lithium aluminum-tri-tert-butoxyhydride 1.0M in THF (28.5 mL, 28.5 mmol) is added to a solution of diethyl 1,1-cyclopropanedicarboxylate (2.0 mL, 11.4 mmol) in anhydrous THF (85.0 mL). After stirring the reaction mixture for 4 h, 10 mL of lithium aluminum-tri-tert-butoxyhydride 1.0M solution in THF is added and the solution is stirred overnight. The reaction mixture is diluted with DCM, washed with 1N HCl, saturated NaHCO3 solution and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressure affords 1.60 g of 1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester that is used in the next step without further purification. Yield: 85%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (2H, q, J=4.1 Hz), 1.21-1.33 (5H, m), 2.59 (1H, t, J=6.9 Hz), 3.63 (2H, d, J=7.2 Hz), 4.17 (2H, q, J=7.1 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](I)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][C:21]1(C)[C:25](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.Cl[Pd]Cl.[Fe+2].COCCOC.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:21]([CH3:25])=[CH2:20])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1snc(-c2ccc(CC)cc2)c1C(=O)OCC
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate (200 mg, 0.52 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (130.24 mg, 0.78 mmol, 1.50 equiv), sodium carbonate (164.34 mg, 1.55 mmol, 3.00 equiv), Pd(dppf)Cl2 (37.82 mg, 0.05 mmol, 0.10 equiv), DME/H2O (6 mL). The resulting solution was stirred for 16 h at 95° C. in an oil bath under nitrogen. The resulting solution was extracted with 150 mL of dichloromethane. The organic layer was washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 287.4 mg of ethyl 3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazole-4-carboxylate as brown oil. Mass spectrum (ESI, m/z): Calcd. for C12H19NO2S, 302.4 (M+H). found 302.4.
Reaction SMILES: [C:1]([C:6](C(OCC)=O)([CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3]CC)=[O:2].[CH:24]1[C:25](/[CH:40]=[N:41]/[OH:42])=[CH:26][CH:27]=[N+:28]([CH2:30][N+:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[N:38]/[OH:39])=[CH:33][CH:32]=2)[CH:29]=1.[Br-:43].[Br-].[OH-].[K+].C(C(C(O)=O)(C)CCCCCC1C(=O)CCC=1)(O)=O.C1C(/C=N/O)=CC=[N+](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-]>>[C:1]([CH:6]([CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([OH:3])=[O:2].[CH:26]1[C:25](/[CH:40]=[N:41]/[OH:42])=[CH:24][CH:29]=[N+:28]([CH2:30][N+:31]2[CH:32]=[CH:33][C:34](/[CH:37]=[N:38]/[OH:39])=[CH:35][CH:36]=2)[CH:27]=1.[Br-:43].[Br-:43]
Reactant: CCOC(=O)C(C)(CCCCCC1=CCCC1=O)C(=O)OCC
Agent: CC(CCCCCC1=CCCC1=O)(C(=O)O)C(=O)O
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Product: CC(CCCCCC1=CCCC1=O)C(=O)O

Procedure:
Saponification of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime (Example 96) with potassium hydroxide by the method of Example 20 is productive of 2-(6,6-dicarboxyheptyl)-2-cyclopentenone methoxime, decarboxylation of which in the manner of Example 63 provides the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)=[O:14]
Reactant: COC(=O)C=COc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1coc2ccccc12
Temperature: 110 °C
Yield: 39 %

Procedure:
A stirring solution of 2.43 g (9.45 mmol) of 3-(2-Bromo-phenoxy) acrylic acid methyl ester, prepared as in Intermediate 17, 1.98 g (7.56 mmol, 0.8 equiv) of triphenylphosphine, 794 mg (9.45 mmol, 1.0 equiv) of NaHCO3, and 848 mg (3.78 mmol, 0.4 equiv) of palladium (II) acetate in 25 mL of DMF is heated to 110° C. for 16 h. After cooling to RT, the reaction mixture is diluted with 100 mL of Et2O and extracted with H2O (1×100 mL), dried (MgSO4), and the solvents removed in vacuo. Purification of the crude material by silica gel flash column chromatography afforded 650 mg of the title compound as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ8.22 (s, 1H), 8.06 (m, 1H), 7.55 (m, 1H), 7.37 (m, 2H), 3.95 (s, 3H); Rf =0.50 in hexane/EtOAc 5/1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: C1COCCN1
Product: c1cc(N2CCC3(CC2)OCCO3)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 8 and morpholine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12]NN=2)[CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].N1C(C)=CC(C)=CC=1C.O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:20][C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[Cl:16])=[N:12][N:11]=2)[CH:5]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1cccc(-c2nn[nH]n2)c1
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: COc1ccccc1
Product: COC(=O)c1cccc(-c2nnc(-c3ccccc3Cl)o2)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
3-(2H-Tetrazol-5-yl)-benzoic acid methyl ester (204 mg, 1 mmol) (prepared by the method of Tanaka et al, J. Med. Chem., 1998, 41(13), 2406) and 2-chlorobenzoyl chloride (175 mg, 1 mmol) were combined in anisole (10 mL) at room temperature and 2,4,6-collidine (121 mg, 1 mmol) in anisole (1 mL) was added. The reaction mixture was heated at 100° C. for 1 hour followed by 120° C. for 15 minutes, monitoring the evolution of gas by balloon [volume of gas evolved was measured by positive displacement of water, total =22 mL]. Cooled reaction mixture to room temperature, and concentrated to dryness in vacuo. The residue was subjected to flash column chromatography on silica with gradient dilution 5% to 40% ethyl acetate/heptane. 3-[5-(2-Chlorophenyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid methyl ester was isolated as a colorless powder (229 mg, 73%). 1H NMR [CDCl3]: δ 8.79 (s, H); 8.36 (d, H); 8.25 (d, H); 8.14 (d, H); 7.72-7.57 (m, 2H); 7.57-7.41 (m, 2H); 4.00 (s, 3H). MS(Ion spray): 315 and 317 (M++1).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NC(CO)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)c1ccc(F)c(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6 g, 15.0 mmol) in CH2Cl2 (15 mL) and 20% (by wt.) NaOH (15 mL) was added a solution of chloroacetyl chloride (1.32 mL, 16.5 mmol) in 15 mL of CH2Cl2 at −10° C. dropwise under argon atmosphere. After the addition was complete, the reaction mixture was stirred for 15 min and then it was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with a solution containing 10 mL of brine and 5 drops of concentrated HCl. The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo to give a white solid. It was further purified with flash column chromatography on silica gel with 1:1 hexane/EtOAc followed by EtOAc as the eluting system. 2-Chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide was obtained as a white solid (2.6 g, 69.5% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][NH2:35])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.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:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][NH:35][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][N:6]=[C:5]3[Cl:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccccc2CN)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2CNc2ccc3c(=O)[nH]nc(Cl)c3c2)CC1
Temperature: 90 °C
Yield: 10.5 %

Procedure:
A mixture of 6-bromo-4-chloro-2H-phthalazin-1-one (140 mg, 0.54 mmol), 4-(2-Aminomethyl-phenyl)-perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (150 mg, 0.49 mmol), Pd2(dba)3 (45 mg, 0.049 mmol), BINAP (92 mg, 0.15 mmol) and NaOt-Bu (138 mg, 1.47 mmol) in DMA (10 mL) was purged with nitrogen for 10 min. The mixture was heated at 90° C. for 5 h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25 mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (25 mg, 11%) m/z (M+H)=484.72.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20](C(Cl)=O)[CH:19]=[CH:18]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:26][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)Cl)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product obtained in Step D (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice bath. After adding sodium azide (24 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0° C. for 2 hours. The organic phase is separated off, washed with water (2×5 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with saturated sodium hydrogen carbonate solution (2×5 ml) and is concentrated under reduced pressure. The residue is then taken up in methanol (20 ml); water (80 ml) and then potassium carbonate (30 mmol) are added. After stirring at ambient temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml and is then extracted 3 times with ether (3×50 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: [CH:1]([C@@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[C:5](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:6])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.S(=O)(=O)(O)O>O1CCCC1.O1CCCC1.O>[CH:1]([C@@H:4]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:25][CH:26]=1)[CH2:5][OH:6])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
With stirring at 0° C., a solution of 8.63 g of 3-[2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propanoyl]-4(R)-benzyl-oxazolidin-2-one in 40 ml of tetrahydrofuran is added dropwise to a suspension of 2.41 g of LiAlH4 in 160 ml of tetrahydrofuran. The reaction mixture is stirred for a further 4 hours at 0° C. and then, at 0° C., 5 ml of ethyl acetate, 30 ml of a mixture of tetrahydrofuran/water=1:1 and then 80 ml of 2N sulfuric acid are added in succession thereto. The suspension is extracted with ethyl acetate and the extracts are concentrated by evaporation and purified by FC (700 g of silica gel, eluant: dichloromethane). The title compound is obtained: Rf (dichloromethane)=0.34; m.p.=49°-51° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9]([O-:11])=[C:8](C(OC)=O)[C:7]=1[CH2:16][CH3:17])=[O:5])[CH3:2].[Na+].[Cl-].[K+].CC(O)=O.C([O-])(O)=O.[Na+]>O.C1(C)C=CC=CC=1>[CH2:16]([C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[CH:8]=1)[CH3:17]
Reactant: CCOC(=O)C1=C(CC)C(C(=O)OC)=C([O-])C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(=O)C=C1CC
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A 5 L round bottom flask was charged with sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate (316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction was heated at reflux for about 6 h then cooled to ambient temperature and added dropwise to NaHCO3 (8% w/v aqueous, 3.5 L). The resulting biphasic mixture was extracted with MTBE (2×1.5 L). The combined organic layers were washed with brine (1 L), dried over anhydrous MgSO4 and concd under reduced pressure to give 191 g of crude material that was purified by vacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): 1H NMR (CDCl3) δ 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).