Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([C:37](N1[C@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:38])/[CH:9]=[CH:10]/[C@@H:11]([C:21](N1[C@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:56]CC1.OO.[OH2:60]>>[CH2:1]([C@@H:8](/[CH:9]=[CH:10]/[C@H:11]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:21]([OH:22])=[O:56])[C:37]([OH:38])=[O:60])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Reactant: O
Reactant: C1CCOC1
Agent: OO
Product: CC(C)(C)OC(=O)CC[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 63 %

Procedure:
To a round bottom flask was added tert-butyl (4S,5E,7S)-7-benzyl-8-((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-4-(((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)carbonyl)-8-oxooct-5-enoate (78 mg, 0.10 mmol), THF (0.8 mL) and water (0.25 mL). The reaction was cooled to 0° C. and a solution of H2O2 (50% in water, 0.038 mL, 0.62 mmol) was added to the reaction mixture followed by LiOH monohydrate (13.0 mg, 0.309 mmol). The reaction was stirred at 0° C. for 35 min. The reaction was quenched by the addition of saturated Na2SO3 (0.38 mL) and saturated NaHCO3 (0.38 mL). The mixture was concentrated to remove most of the THF. The mixture was diluted with a small amount of water and extracted with EtOAc (2×) to remove chiral auxiliary. The aqueous phase was then acidified and extracted with EtOAc (2×). The organic extracts were combined, dried over MgSO4, filtered and concentrated to give (2S,5S,E)-2-benzyl-5-(3-tert-butoxy-3-oxopropyl)hex-3-enedioic acid (24 mg, 0.065 mmol, 63% yield) as a colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:62]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:63]([C:71]([NH:73][C@H:74]([C:81](O)=[O:82])[CH2:75][C:76]1[N:80]=[CH:79][NH:78][CH:77]=1)=[O:72])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C(#N)C.C(OCC)(=O)C>[CH:4]1([CH2:3][C@H:2]([NH:1][C:81]([CH:74]([NH:73][C:71]([C@@H:63]([NH:62][C:84](=[O:85])[O:86][C:87]([CH3:89])([CH3:88])[CH3:90])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:72])[CH2:75][C:76]2[N:80]=[CH:79][NH:78][CH:77]=2)=[O:82])[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH:22]([CH3:23])[CH3:24])[CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)[C@@H](CCOc1ccccc1)C[C@H](O)[C@@H](N)CC1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)[C@@H](CCOc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.8 %

Procedure:
174 mg (0.5 mmol) of (2S,3S,5S)-2-amino-1-cyclohexyl-5-isopropyl-7-phenoxy-3-heptanol are dissolved in 8 ml of acetonitrile, the solution is treated with 0.102 ml (0.5 mmol) of Hunig base, 220 mg (0.5 mmol) of BOP and 204 mg (0.5 mmol) of Boc-Phe-His-OH and the reaction mixture is stirred at room temperature for 3.5 hours. Thereafter, the mixture is taken up in ethyl acetate and the organic phase is washed once each time with 1N hydrochloric acid and 2N sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel with a 15:1 mixture of methylene chloride and methanol as the eluting agent yields 226 mg (60%) of t-butyl [(S)-α-[[1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-6-phenoxyhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a resin, MS: 732 (M+ H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.N1CCC[C@H]1C(O)=O>[Cu]I.CS(C)=O>[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: c1ccc(N2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
1-iodobenzene (28.12 g, 137.84 mmol) was added to morpholine (12.0 g, 137.93 mmol). L-Proline (3.12 g, 27.13 mmol) was then added, followed by the addition of CuI (2.6 g, 13.68 mmol) and DMSO (120 mL). The resulting solution was stirred at 90° C. for 4 hours, and then the reaction mixture was then quenched by the addition of 300 mL of iced water. The resulting solution was extracted using dichloromethane (2×200 mL), and the organic layers combined, dried (Na2SO4) and concentrated. The residue was purified by column chromatography using a petroleum ether solvent system. The collected fractions were combined and concentrated to give 10 g (42%) of 4-phenylmorpholine as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.12 g, 21.2 mmol, Aldrich, Cat. 525057) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0° C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 90° C. overnight. Then the reaction mixture was cooled to r.t., quenched with water, and extracted with ethyl acetate. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 30% ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74%). LCMS (M+H)+: m/z=378.4.
Reaction SMILES: [F:1]F.[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.[F-].[Na+]>ClC(Cl)(Cl)F>[F:1][C:7]1[C:6]([Cl:11])=[N:5][C:4]([Cl:3])=[N:9][C:8]=1[Cl:10]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: FF
Agent: [F-]
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Product: Fc1c(Cl)nc(Cl)nc1Cl
Yield: 47.9 %

Procedure:
0.5 mol of fluorine in the form of a 30% by volume mixture with helium was introduced into a suspension of 36.7 g (0.2 mol) of 2,4,6-trichloropyrimidine, 21 g of sodium fluoride (0.5 mol) and 250 ml of trichlorofluoromethane, at a temperature of -78° C. The rate of introduction was 0.15 mol of fluorine per hour. After the introduction, the reaction mixture was filtered and 19.3 g of pure 5-fluoro-2,4,6-trichloropyrimidine were obtained from the filtrate by distillation over iron filings. This corresponds to a yield of 48% of theory. The boiling point of the isolated product was 80°-87° C. at 10 mbar. The reaction mixture also contained more highly fluorinated pyrimidine derivatives.
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:1]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc2c1CCCN2
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Oc2cccc3c2CCCN3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 0.15 g (1.01 mmol) 1,2,3,4-tetrahydro-quinolin-5-ol in 10 ml dichloromethane were added 0.17 g (1.40 mmol) phenylboronic acid, 0.25 g (1.36 mmol) copper(II) acetate, a spatula end of 4 Å molecular sieves and 0.57 ml (4.52 mmol) triethylamine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 34 mg (17%) of the title compound as a pink oil. MS (ISP): 226.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure C. Mp: 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.69 (m, 6 H), 3.25-3.28 (m, 6 H), 3.82 (s, 2 H), 4.14 (s, 2 H), 6.20 (d, J=5.5 Hz, 1 H), 6.38 (s, 1 H), 6.76 (d, J=11.7 Hz, 1 H), 7.00 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 7.32 (s, 1 H), 7.46-7.55 (m, 2 H), 7.83-7.92 (m, 3 H), 8.20-8.21 (m, 1H), 8.36 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1ccc(Br)nc1
Product: COc1cc(-c2ccc(C)cn2)ccn1
Yield: 42.2 %

Procedure:
2-Bromo-5-methylpyridine (2.93 g, 17.0 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.34 g, 14.2 mmol) were reacted according to Example 31 (step a) to provide the title compound (1.2 g, 42%) as a brown solid: ESI MS m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:14]=1[NH:15][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 15.8 %

Procedure:
Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(Cl)Cl>[C:4]1([N:7]=[C:8]2[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][O:18]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(N=C2OCC3CCCCN23)cc1
Reaction time: 12 h

Procedure:
3 g Phenyl isocyanide dichloride in 10 ml methylene chloride was treated at room temperature with a solution of 5.4 ml triethylamine and 1.7 g 2-hydroxymethylpiperidine in 20 ml methylene chloride. After 12 hours at room temperature, the mixture was washed with water, the organic phase was dried over magnesium sulphate, the solvent was distilled and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][C:19]([O-:21])=[O:20].[CH3:22]N(C)C=O>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CN(C)C=O
Reactant: O=C([O-])CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CN1CCN(c2ccc(C#N)cc2)CC1

Procedure:
2 g of 1-(4-cyanophenyl)-piperazine are stirred in 20 ml of dry dimethylformamide at ambient temperature with 0.51 g of a 50% sodium hydride/oil suspension. Whilst cooling in a water bath, 1 ml of bromoacetate is added. Then the mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are dried and the solvent is removed under reduced pressure. The residue remaining is chromatographed with methylene chloride/methanol (98:2) over silica gel. The product is triturated with ether, suction filtered and washed with petroleum ether. Yield: 1.6 g (58% of theory), Melting point: 92°-96° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of Boc-D-cyclohexylglycine (10 g, 39 mmol) in DCM (200 mL), N,O-dimethylhydroxyamine HCl salt (4.6 g, 46 mmol), HOBT (7 g, 51 mmol), and TEA (11 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 10 g, 51 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added. The resulting solution washed with aqueous citric acid solution, aqueous NaHCO3 solution, and aqueous NaCl solution. The organic layer was separated, dried with MgSO4, and then evaporated to yield [cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+:19]=[N-:20])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](COS(C1C=CC(C)=CC=1)(=O)=O)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+:19]=[N-:20])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Yield: 96 %

Procedure:
A procedure similar to that used to prepare compound 160 was used except (3S,5S)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acid tert-butyl ester 168 (4.155 g, 9.74 mmol) was used as a reactant to give 169 as an oil (2.77 g, 96%). MS (APCI) m/z 270 (M+−27, 30%, —N2), 214 (M+−87, 100%, -tBu, —N2).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(NC(C)C)(C)C.[Li].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>O1CCCC1.CCCCCC.O1CCCC1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(CC(=O)OCC)cc1
Reactant: CC(C)C(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCCCCc1ccc(C(C(=O)OCC)C(=O)C(C)C)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
6.0 g (24 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 130 mL of dry tetrahydrofuran under a nitrogen atmosphere and cooled to −60° C. After addition of 31.8 mL (36.2 mmol) of 1.14 M solution of lithiumdiisopropylamine in hexane/tetrahydrofuran, the solution was warmed to 0° C. and stirred for 1 hours. The reactuion solution was cooled to −60° C. again and stirred with 3.6 g (34 mmol) of isobutyryl chloride at −60° C. to room temperature for 15 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (150 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (0:100 to 1:9) as the eluent to give 5.39 g of the desired product as a pale yellw oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([O-:33])=[O:32].[K+].O>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([N+:31]([O-:33])=[O:32])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)cc(Br)c1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n1-c1cc(Cl)cc(Br)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of 1,3-dihydro-1-(5-chloro-3-bromo-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (1 g, 2.5 mmol) in glacial acetic acid (5 ml) was under stirring on an ice bath added acetic anhydride (2.5 ml) and two drops of concentrated sulfuric acid. When the starting material had gone into solution, an ice cold solution of potassium nitrate (0.3 g, 3 mmol) in concentrated sulfuric acid (1 ml) was added, and the mixture was stirred for 15 minutes. The reaction mixture was poured into water, the crystalline product was collected by filtration and the acetate was hydrolysed by reflux in ethanol (50 ml) and 4M sodium hydroxide (5 ml) for one hour. The reaction mixture was acidified by addition of 4M hydrochloric acid and water was added until starting precipitation. The mixture was cooled and the crystals were collected by filtration yielding the title compound as slightly yellow crystals, M.p. 262°-264° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)([O-:13])=[O:12].CC([O-])=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:9]=[O:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 65 %

Procedure:
POCl3 was added to DMF at 0-10° C. after which 50 ml of CCl4 was added at room temperature. A solution of 4.5 g (24 mmol) 1a in 50 ml of CCl4 was added slowly to the reaction mixture at about 10° C. during 1 hour. The reaction mixture was refluxed for 15 min. and a solution of 50 g of NaOAc, 3H2O in 50 ml of H2O was added and refluxing was continued for 15 min. The mixture was cooled, extracted with ether and dried over Na2SO4. 8.0 g (65%) of 2a was isolated by column chromatography using EtOAc:petroleum ether as eluent.
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[NH2:22][C:23](=[N:41][OH:42])[C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][N:28]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:29]>>[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:16][N:41]=[C:23]([C:24]3[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=3)[CH2:27][N:28]([CH3:29])[CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:22]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[ClH:1].[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:42][N:41]=[C:23]([C:24]3[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=3)[CH2:27][N:28]([CH3:29])[CH2:30][C:31]([OH:33])=[O:32])[N:22]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3]
Reactant: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Agent: Cl
Product: CCC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)O)c3)no2)cc1COC
Product: CCC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
Tert-butyl N-(3-{5-[4-(2-ethylpiperidin-1-yl)-3-(methoxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}benzyl)-N-methylglycinate was prepared following the general procedure 3 starting from Intermediate 9 and Intermediate 21. It was hydrolyzed following general procedure 8 to afford the title compound as a white powder. LC/MS (Method B): 479.4 (M+H)+, 477.4 (M−H)−. HPLC (Method A) Rt 2.74 min (Purity: 98.5%).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)([CH3:3])[CH3:2].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:9][CH:8]=1
Reactant: CC(C)Sc1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Sc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a solution of 2-(isopropylthio)thiazole (260 mg, 1.63 mmol) in DMF (2 mL) was added N-bromosuccinimide (435.8 mg, 2.45 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a yellow oil (390 mg, 100% yield). LCMS (Conditions C): Tr 3.67 min.; (M+H)': 237.86 (30%), 239.86 (30%), 195.86 (100%), 197.86 (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([CH3:18])[CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[SH:30][CH:31]([C:38](=O)[CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)Cl>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[S:30][CH:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:38]([CH3:39])=[N:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[C:5]2=3)=[C:12]([CH3:18])[CH:11]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)CC(S)C(C)=O
Reactant: Cc1cc(Cl)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CC1SC(c2ccc(Cl)cc2C)c2c(C)nn(C)c2N=C1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (0.58 g, 5.22 mmol, Oakwood Chemicals), 4-chloro-2-methylbenzaldehyde (0.81 g, 5.22 mmol, Ark Pharm) and p-TSA (0.10 g, 0.52 mmol) in acetonitrile (10.5 mL) was added ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol) and stirred at about 90° C. for about 18 h. The reaction mixture was cooled to ambient temperature and saturated NaHCO3 (15 mL) and DCM (20 mL) were added. The organic layer was separated and the aqueous layer was back extracted using DCM (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:50) to afford ethyl 2-(4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate (0.85 g, 1.97 mmol, 37%). LC-MS (Table 1, Method g) Rt=2.66, 2.63 min, m/z 406 (M+H)+.