Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([OH:10])=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([O:10][CH3:20])=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(O)c([N+](=O)[O-])cn1C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)c([N+](=O)[O-])cn1C
Yield: 88.6 %

Procedure:
A mixture of ethyl 1-methyl-4-nitro-3-hydroxypyrrole-2-carboxylate (0.071 g, 0.3315 mmol), dimethyl sulfate (0.055 g, 0.436 mmol) and anhydrous potassium carbonate (0.5 g, 3.90 mmol) in dry acetone (20 mL) was refluxed under a nitrogen atmosphere for 22 h. Potassium carbonate was removed by filtration and the filtrate was evaporated under reduced pressure to afford an orange crystalline solid. Excess dimethyl sulfate was destroyed by treating the residue with aqueous ammonia (1 mL). Water (2 mL) was added and the residue was extracted with ether (30 mL). The combined ether extracts were washed with aqueous sodium hydroxide solution and water. Removal of ether under reduced pressure afforded a cream residue. The residue was dissolved in CH2Cl2 (25 mL), dried with anhydrous Na2SO41 filtered and evaporated under reduced pressure to yield a cream microcrystalline solid (0.067 g, 89%). Recrystallization from acetone/hexane afforded colorless needles, mp 145-147° C.; 1H NMR (300 MHZ, CDCl3) d 1.40 (t, J=7.2 Hz, 3H, CH3—CH2—), 3.90 (s, 3H, CH3—N—), 3.95 (s, 3H, CH3O—), 4.36 (q, J=7.0 Hz, 2H, CH3—CH2—), 7.47 (s, 1H, H-5); 13C NMR (100 MHZ, CDCl3) d 14.22, 38.92, 60.67, 63.02, 114.73, 125.76, 127.79, 146.18, 160.09; MS (EI, 70 eV) m/z (relative intensity) 229 (M+1, 3), 228 (M+, 30), 211 (12), 183 (12), 167 (20), 153 (25), 152 (100), 141 (7), 109 (12), 84 (8), 67 (6), 53 (31), 42 (17), Calcd for C9H12N2O5: 228.20. HRMS (M+H): Calcd for C9H13N2O5 [M+H+]: 229.0824, Found 229.0834. Anal. Calcd for C9H12N2O5: C, 47.37; H, 5.29; N, 12.27. Found. C, 47.44; H, 5.36; N, 12.28. TLC (ethyl acetate/Hexane, 1:3) Rf 0.23.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]([CH2:15][OH:16])[CH2:13]O)=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.CN(C)C([S-])=S.[Zn+2].CN(C)C([S-])=S>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:13][O:16][CH2:15]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccc(C(CO)CO)cc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CN(C)C(=S)[S-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(C3COC3)cc2n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 21.7 %

Procedure:
To a solution of 2-(2-methylquinolin-7-yl)propane-1,3-diol (0.100 g, 0.46 mmol) and PPh3 (0.241 g, 0.921 mmol) in toluene (10 mL) was added zinc(II) dimethylcarbamodithioate (0.211 g, 0.690 mmol) and DEAD (0.145 ml, 0.921 mmol). The resulting mixture was stirred at ambient temperature for 30 hours. The solvent was removed under reduced pressure, and water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 25 CV)) to give 2-methyl-7-(oxetan-3-yl)quinoline (0.020 g, 0.100 mmol, 22% yield) as a solid.
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][O:14]CC2C=CC=CC=2)[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.C[Si](I)(C)C.C(N(CC)CC)C.Cl>ClCCl.CO>[C:4]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][OH:14])[C:1](=[O:39])[C:2]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOCc2ccccc2)cc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-benzyloxy-4-aza-octane (9.5 g, 17.1 mM) and trimethylsilyl iodide (2.7 mL, 10% excess) in dry dichloromethane is stirred overnight at room temperature under nitrogen. Triethylamine (3 g) is added, and stirring is continued for 1 hour at room temperature. Following the addition of more dichloromethane, the reaction mixture is washed with 1N HCl (twice), aqueous NaHSO3 (twice), brine (twice), and dried (Na2SO4). The solvents are removed by evaporation to yield an oil. This oil is dissolved in methanol and 1 mL of a 9N solution of HCl in methanol is added. The mixture is evaporated and stripped twice with CCl4 to provide an oil, which upon scratching with ether/petroleum ether yields 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane as slightly violet crystals: 6.8 g (85%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([N:62]([CH3:64])[CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([N:62]([CH3:63])[CH3:64])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)N(C)C
Yield: 88.1 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 2.00 g, 4.35 mmol), dimethyl sulfoxide (0.87 ml, 12.2 mmol), oxalyl chloride (0.56 ml, 6.5 mmol), triethylamine (3.03 ml, 21 8 mmol), 2-(diethylphosphono)-N,N-dimethylacetamide (1.17 g, 5.22 mmol) and 60% sodium hydride (174 mg, 4.35 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with hexane-ethyl acetate 1 1) to give the title compound (2.02 g, 88.1% yield)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.Br[CH2:14][CH2:15]Br.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:11]([O:10][C:8]([C:7]1([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH2:15][CH2:14]1)=[O:9])[CH3:12]
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1nc(C)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2nc(C)cs2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
Ethyl 2-(4-methylthiazol-2-yl)acetate (1 g, 5.4 mmol, Eq: 1.00) was dissolved in DMF (5 mL). 1,2-dibromoethane (1.62 g, 744 μL, 8.64 mmol, Eq: 1.60) and Cs2CO3 (4.4 g, 13.5 mmol, Eq: 2.50) were added. The reaction mixture was stirred 48 h at RT. The reaction mixture was poured into 0.5 M aqueous HCl (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield 1.14 g (73.6%) of a light yellow liquid. MS (ESI): m/z=212.0 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:37](=[O:38])[C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])#[N:27]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C#N

Procedure:
A mixture of DIPEA (1,145 ml, 6.55 mmol) and (S)-pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.567 g, 2,114 mmol) in DCM was added to a mixture of (R)-2-(tert-butoxycarbonylamino)propanoic acid (0.4 g, 2.114 mmol) and HATU (0.804 g, 2.114 mmol) in DMF. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography with a gradient DCM to DCM-MeOH (95-5). (0.47 g, 83%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([CH3:19])([CH3:18])[CH2:11][N:12]1[CH2:17][CH2:16]C[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]1CCNCC1>>[CH3:18][C:10]([CH3:19])([CH2:11][N:12]1[CH2:17][CH2:16][N:22]([CH3:21])[CH2:14][CH2:13]1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: CN1CCNCC1
Reactant: CC(C)(CN1CCCCC1)C(=O)OCc1ccccc1
Product: CN1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1

Procedure:
The procedure for benzyl-2,2-dimethyl-3-piperidin-1-ylpropanoate was followed except for replacing piperidine with 1-methylpiperazine. Purification via silica gel chromatography (5% EtOAc in hexane) afforded the title compound as a yellow oil. MS (ES+): m/z: 291.20 (100) [MH+]. HPLC: tr=2.08 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=1.18 (s, 6H), 2.09 (s, 3H), 2.23-2.33 (m, 4H), 2.39-2.50 (m, 6H), 5.11 (s, 2H) 7.31-7.36 (m, 5H)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-(4-Fluorobenzoyl)propionic acid (250 g, 1.28 mole) was added in portions to stirred fuming nitric acid (1000 ml) maintained at -15° C, the mixture was stirred an additional 30 minutes and then poured into ice-water (3000 ml). The product was collected, washed with water, and recrystallised from propanol to give 3-(4-fluoro-3-nitrobenzoyl)propionic acid (175 g, 56%, m.p. 136° C). (Found: C, 49.98; H, 3.34; N, 5.69. C10H8FNO5 requires: C, 49.80; H, 3.34; N, 5.81%)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: CC(C)(O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 72.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.105 g, 0.35 mmol) was reacted with 1-(4-aminophenyl)-2-methylpropan-2-ol (0.086 g, 0.53 mmol) to afford the title compound (0.100 g, 73%) as a white solid. MW=392.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.90-7.88 (m, 1H), 7.75-7.72 (m, 1H), 7.46-7.39 (m, 2H), 7.23-7.14 (m, 5H), 4.28 (s, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.64 (s, 2H), 2.08 (quin, J=7.5 Hz, 2H), 1.08 (s, 6H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([OH:4])=[O:3].[Na].Br[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1.CNCCNC>CS(C)=O>[F:14][C:9]1[CH:8]=[C:7]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: CS(=O)O
Reactant: Oc1ccc(Br)cc1F
Agent: CNCCNC
Agent: [Na]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(O)c(F)c1
Yield: 70 %

Procedure:
A stirred mixture of sodium methane sulfinic acid (51.0 g, 4.009 equivalents), 4-bromo-2-fluorophenol (23.8 g, 1.000 equivalent), copper(I) trifluoromethanesulfonate benzene complex (6.28 g, 0.1001 equivalents), N,N′-dimethylethylenediamine (DMEDA, 2.2 g, 0.2003 equivalents), and dimethylsulfoxide (DMSO, 104 g) was heated under nitrogen at 130°-135° C. for 18 hours. Substantially all of the DMSO solvent was then removed from the reaction mixture by rotary evaporation at 1 torr with a 120° C. oil bath. To the brown oily distillation residue were added ethyl acetate (90 g) and water (100 g). After the resulting mixture had been heated and agitated to facilitate dissolution of the reaction mixture in the two liquid phases, it was filtered through a coarse sintered glass filter funnel containing a Whatman filter paper disc and 30 g of Celite. Addition of concentrated aqueous HCl (20 g) to the filtrate lowered the pH of the aqueous phase to less than 3. The phases were separated, and the aqueous phase was extracted two more times with ethyl acetate (90 g each). The combined organic phases were extracted with three 100-gram-portions of 1 M aqueous NaOH to extract the sodium salt of the phenoxide product into the aqueous phase. The aqueous phases were combined, acidified with cooling and concentrated aqueous HCl (40 g) to a pH less than 3, and then extracted with four 90-gram-portions of ethyl acetate to return the product as the free phenol to the organic phase. The organic phases were combined, dried over magnesium sulfate (15 grams), filtered, and concentrated by rotary evaporation at reduced pressure to provide product (4) (16.6 g, 70% yield) as a clear orange to brown oil, which solidified on standing.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cncnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cncnc43)cc2o1
Temperature: 135 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A mixture of 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (106 mg, 0.34 mmol), (1R,2R)-2-aminocyclohexanol (77 mg, 0.51 mg) and DIEA (132 mg, 1.02 mmol) in DMA (3 mL) was stirred at 135° C. for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:6 petroleum ether/ethyl acetate to give crude product, which was washed with 10:1 petroleum ether/ethyl acetate to afford (1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (68 mg, 48.57%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.16 (d, J=1.2 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H) 5.51 (s, 2H), 4.66 (d, J=4.2 Hz, 1H), 3.34 (br s, 2H), 1.90 (br s, 2H), 1.60 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 365 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.CCN(C(C)C)C(C)C.[NH2:57][C@H:58]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[OH:62]>C1COCC1.CN1C(=O)CCC1>[C:67]([O:66][C:64](=[O:65])[C@@H:58]([NH:57][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:12][CH:11]=1)[CH2:59][CH2:60][C:61]([OH:63])=[O:62])([CH3:70])([CH3:68])[CH3:69]
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)O)s1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(12-carboxydodecyl)-thiophene-2-carboxylic acid tert-butyl ester (31 mg, 0.0 78 mmol) was treated with TSTU (28.2 mg, 0.094 mmol) and DIPEA (0.016 mL, 0.094 mmol) in THF (1.3 mL) for 2½ hours at room temperature under nitrogen. The solvent was removed in vacuo and the mixture added NMP (1 mL) and H-Glu-OtBu (31.3 mg, 0.154 mmol) and DIPEA (0.027 mL). The mixture was stirred overnight at room temperature. The mixture was separated between diethyl ether (10 mL) and 10% aqueous NaHSO4 (2×10 mL) and the organic phase isolated and solvent removed in vacuo to give the crude (S)-2-[13-(5-tert-Butoxycarbonylthiophen-2-yl)-tridecanoylamino]-pentanedioic acid 1-tert-butyl ester which was subsequently in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=2[CH3:45])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=2[CH3:45])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (350 mg, 82%).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][NH:13][NH2:14]>CO>[CH3:12][N:13]1[CH:4]=[CH:5][C:6]([C:7]([F:10])([F:9])[F:8])=[N:14]1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CNN
Solvent: CO
Product: Cn1ccc(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a mixture of 18 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and 50 ml of methanol was added 5.7 ml of methylhydrazine, and the mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and subjected to distillation under reduced pressure (60° C./15 mmHg) to obtain 8.71 g of 1-methyl-3-trifluoromethyl-1H-pyrazole of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[Li]CCCC.[C:22](=[O:24])=[O:23].[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1.C1COCC1>[C:7]([C:6]1[CH:9]=[C:2]([CH:3]=[CH:4][C:5]=1[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[C:22]([OH:24])=[O:23])#[N:8]
Reactant: CC(Oc1ccc(Br)cc1C#N)C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Oc1ccc(C(=O)O)cc1C#N)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 5-bromo-2-(2,2,2-trifluoro-1-methylethoxy)benzonitrile in a mixed solvent of toluene/THF (4:1) was added a solution of n-BuLi in n-hexane at −78° C. With passing a CO2 gas therethrough, the solution was stirred for 0.5 hour. To the reaction solution was added a 1M aqueous NaOH solution to complete the reaction, and followed by extraction with diethyl ether. The organic layer was acidified by adding 1M HCl, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography (chloroform:CH3OH=97:3 to 90:10) to obtain 3-cyano-4-(2,2,2-trifluoro-1-methylethoxy)benzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=O)=O.OS(O)(=O)=O.O.C(Cl)Cl>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[SH:11]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC)c(S)c1
Reaction time: 8 h

Procedure:
16 g of 2,5-dimethoxybenzene-sulphonyl chloride are dissolved in 100 ml of THF, while stirring, and a mixture of 20 ml of concentrated H2SO4 and 60 ml of water is then added, followed by 25 g of zinc dust, added in portions at 50°-55° and stirring is continued overnight at 20°. The THF is then stripped off and the mixture is worked up with water and methylene chloride to give 2,5-dimethoxythiophenol, b.p. 106°-108°/0.3 mm.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH3:2][C:1]1[O:3][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C)n1
Temperature: 85 °C
Yield: 44.4 %

Procedure:
To a solution of acetamide (4.0 g) in tetrahydrofuran (300 ml) was added sodium hydrogen carbonate (28.4 g), followed by addition of 80% ethyl bromopyruvate (21.5 g) at 0° C. The mixture was heated at 85° C. overnight, the temperature was returned to room temperature, the insolubles were filtered using Celite and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (150 ml), and to the solution was added dropwise trifluoroacetic anhydride at 0° C. After concentrated under reduced pressure, to the mixture was added ethyl acetate, and the mixture was washed with saturated sodium hydrogen carbonate solution twice and further with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, followed by distillation under reduced pressure to give ethyl 2-methyloxazole-4-carboxylate (4.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O:19]C)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].NCC(O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Oc1ccc(Cl)cc1
Agent: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 48 °C
Reaction time: 120 h
Yield: 76.1 %

Procedure:
27.8 g (216 mmol) of 4-chlorophenol and 47 g (205 mmol) of methyl 2-bromophenylacetate were suspended in 790 mL of dioxane. The mixture was heated to 48° C. and 141 g of cesium carbonate, 4.5 g of glycine and 8.6 g of cuprous chloride were added. The resulting suspension was heated to reflux and stirred at this temperature for 5 days. After cooling down to room temperature, the solid was removed by filtration, washed with 100 mL of dioxane, and discarded. The mother liquors were combined and concentrated under vacuum. 100 mL of ethyl acetate were added to the residue, and the pH was adjusted to 1 with HCl 2 M. The organic phase was extracted, washed with brine and dried. The solvent was removed under vacuum. 100 mL of water were added to the residue, and the pH was adjusted to 1 with HCl 2 M. The resulting suspension was stirred and filtered, to obtain 41 g of 2-(4-chlorophenoxy)phenylacetic acid (compound XIVb) as a brown solid. Yield: 76.1%.