Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:8]1([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[Mg]Cl
Reactant: O=C1CCCOc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CCCOc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 119.5 %

Procedure:
A solution [sic], maintained under an inert atmosphere, of 33.5 ml (0.1 mol) of 3M methylmagnesium chloride in solution in tetrahydrofuran is heated to 50° C. 11.3 g (0.069 mol) of 3,4-dihydro-2H-benzoxepin-5-one, dissolved in 150 ml of tetrahydrofuran, are added fairly quickly. This solution is brought to reflux for 4 hours and is then left stirring overnight at room temperature. The reaction mixture is subsequently gently hydrolysed with water under cold conditions. An ammonium chloride solution (120 g per litre) is then poured into the reaction mixture. The latter is extracted with ethyl acetate and then the organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. 14.7 g of a yellow oil are obtained, which oil is purified by crystallization from isoctane. 11.9 g of the title compound are thus obtained, the melting point of which is 92° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH:19]1[C:24]([NH2:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH:19]3[C:24]([NH2:26])=[O:25])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C1CSCCN1
Product: NC(=O)C1CSCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 3-thiomorpholinecarboxamide (CAN 103742-31-0, 68.9 mg, 472 μmol) as starting materials and isolated (119 mg, 77%) as white solid; LC-MS (UV peak area, ESI) 100%, 362.1540 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:22]([C:21]4[C:20]([N:27]5[N:31]=[CH:30][CH:29]=[N:28]5)=[N:19][C:18]([CH3:17])=[CH:26][CH:25]=4)=[O:23])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(C)nc4-n4nccn4)CC3C2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pale yellow solution of 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 23) (50 mg, 0.23 mmol) in 2 mL of DMF was added 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid (Intermediate 70) (51 mg, 0.25 mmol) followed by HATU (131 mg, 0.34 mmol) and DIPEA (0.118 mL, 0.69 mmol). The resulting solution was allowed to stir at room temp for 1 h and turned progressively more intense yellow as the reaction continued. The reaction was monitored via LCMS and quenched with H2O once starting materials we no longer observed. The resulting biphasic mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried with Na2SO4 and conc. into a pale yellow oil under reduced pressure. The yellow residue was purified via FCC using 5-50% 2M NH3/MeOH in DCM. Minor impurities remained so the material was further purified via HPLC 0-99% CH3N to give the desired product. MS (ESI) mass calcd. for C21H24N8O, 404.47; m/z found 405.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 7.80 (s, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.29-7.24 (m, 1H), 6.30 (s, 1H), 3.90-3.80 (m, 2H), 3.73-3.63 (m, 2H), 3.59 (dd, J=11.6, 5.3 Hz, 1H), 3.47 (dd, J=11.6, 3.7 Hz, 1H), 3.33 (s, 1H), 3.00 (ddd, J=38.4, 21.7, 7.2 Hz, 3H), 2.68 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=CC)[C:5]([O:7][CH3:8])=[O:6].I([O-])(=O)(=O)=[O:17].[Na+].C(O)(C)(C)C>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:15])[C:2]=1[OH:1])=[O:17]
Reactant: CC=Cc1ccc(C(=O)OC)c(C)c1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(C=O)c(O)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-hydroxy-2-methyl-4-(prop-1-en-1yl)benzoate (1.66 g, 8.05 mol) in dioxane/water (280 mL 2.5/1 ratio) was added sodium periodate (3.96 g, 18.51 mmol) and 2.5 wt % solution of osmium tetroxide in tert-butanol (3.3 ml, 2.66 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed a single peak with the expected product mass. After aqueous work up and extraction with EtOAc, the crude product was purified on ISCO system (40 g silica gel column, hexane/EtOAc gradient) to get 1.2 g (77% yield) of the aldehyde. 1H NMR (400 MHz, CDCl3) δ 11.39 (s, 1H), 9.93 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: FC(F)(F)C1N=C(NC2C=CC([C@@H](C)C(O)=O)=CC=2)SC=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:28][CH:27]=1)(=[S:24])[NH2:23].Br[CH2:39][C:40](=O)[C:41]([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:40]1[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([CH3:37])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[S:24][CH:39]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Agent: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Product: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(C)(C)C)cs2)cc1
Yield: 55 %

Procedure:
The acid was obtained following the same procedure described for (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid and starting from methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (2.0 g, 8.40 mmol) and 1-bromopinacolone (1.13 ml, 8.40 mmol). The following acid hydrolysis afforded the pure (2R)-2-{4-[(4-tert-butyl-1,3-thiazol-2-yl)amino]phenyl}propanoic acid (1.41 g, 4.62 mmol) as pale yellow oil (55%). 1H-NMR (CDCl3): δ 8.30 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.40 (s, 1H), 3.75 (q, 1H, J=7 Hz), 1.50 (d, 3H, J=7 Hz), 1.40, (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH2:18][CH:19]=[O:20])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: C=CCNCCC=O
Solvent: c1ccccc1
Product: C=CCN(CCC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-allylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
A solution of 335 mg (1.17 mmol) 5-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester in 10.0 ml ethanol was treated at room temperature (r. t.) with 44 mg (1.17 mmol) of sodium borohydride. The mixture stirred two days at 50° C. Then it was poured on ice and extracted tree times with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/methanol 5:1) gave 195 mg (64%) of [5-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:29][O:28]2)=[CH:23][N:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:29][CH:27]([C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)[OH:28])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C2CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C)nc2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) in DMF (10 mL) was added sodium hydride (96 mg, 2.6 mmol). After stirring for 5 min, a solution of 2-methyl-5-oxiranyl-pyridine (175 mg, 1.3 mmol) in DMF (1 mL) was added dropwise into the reaction mixture, which was stirred at RT for 5 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-(6-methyl-pyridin-3-yl)-ethanol. The product was further purified by chiral HPLC separation to give enantiomers 198a and 198b. Enantiomers 198c and 198d are also obtained by this method. 1H NMR, (CDCl3, freebase) δ (ppm): 8.45 (s, 1H), 7.6 (dd, 1H), 7.22 (m, 2H), 7.1 (t, 1H), 7.05 (t, 1H), 5.08 (q, 1H), 4.8 (dt, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 3.1 (d, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6 (m, 2H), 2.5 (s, 3H), 2.41 (s, 3H), 2.1 (m, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Br:1][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2ccccc2n1-c1cccc(F)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A solution of N-bromosuccinimide (0.24 g, 1.3 mmol) in DMF (1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (0.41 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (0.34 g, 68%). LCMS calculated for C21H22BrFN2O2Na(M+Na)+: m/z=455.1. Found: 455.0.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[S-:13][C:14]#[N:15].[NH4+].[Br-].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C>[NH2:15][C:14]1[S:13][C:9]2[CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CC#N
Product: Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a mixture of 4-trifluoromethoxyaniline (2.07 mmol) and ammonium thiocyanate (2 mmol) in acetonitrile, is added benzyltrimethylammonium tribromide, at room temperature. The reaction is left to proceed while stirring at room temperature for 24 hours; it is then neutralised with NaHCO3 and extracted with CH2Cl2. The combined organic extracts are washed with H2O, dried over Na2SO4, filtered and then evaporated under vacuum. The crude product is purified by chromatography through silica, eluting with petroleum ether/AcOEt (1:1), and a solid obtained that is recrystallised from hexane/ethyl ether to give 2-amino-6-(trifluoromethoxy)-benzothiazole as pale yellow flakes, with a yield of 80%.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:5]=1[N+:11]([O-:13])=[O:12]>CO>[F:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH:2][CH3:1]
Reactant: CN
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: CO
Product: CNc1cccc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A methanol solution of 40% methyl amine (12.2 mL, 119 mmol) was added dropwise to a methanol solution (39.5 mL) of 2,6-difluoronitrobenzene (7.90 g, 49.7 mmol) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours, and then stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. The resulting crystals were dried at 50° C., thereby obtaining 7.84 g of a red, powdery target compound (yield: 93%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>ClCCl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCCCBr
Reactant: C1=COCCC1
Solvent: ClCCl
Product: BrCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
3,4-Dihydro-2H-pyran (8.0 g, 95.36 mmol) was added to a 0° C. solution of 4-bromobutan-1-ol (12.0 g, 79.47 mmol) in dichloromethane (150 mL) followed by p-toulenesulphonic acid (20 mg). After 1 h, the reaction was carefully quenched with sat. aq. NaHCO3 solution (5 mL), washed with water (100 mL), brine (70 mL), and concentrated in vacuo. The residue was purified by SiO2 column chromatography using 2% EtOAc/hexanes as eluent to give 2-(4-bromobutoxy)tetrahydro-2H-pyran (16.57 g, 88%) as colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.50; 1H NMR (CDCl3, 300 MHz) δ 4.58 (t, J=2.5 Hz, 1H), 3.90-3.72 (m, 2H), 3.38-3.50 (m, 4H), 1.92-2.04 (m, 2H), 1.65-1.80 (m, 4H), 1.60-1.50 (m, 4H). Lit. ref: G. L. Kad; I. Kaur; M. Bhandari; J. Singh; J. Kaur Organic Process Research & Development 2003: 7, 339.
Reaction SMILES: [CH2:1]([C@@:8]1([OH:32])[C@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][OH:22])[O:10][C@H:9]1[N:23]1[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35](O)=[O:36].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C1CCCCC1>[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35]([O:22][CH2:21][C@H:11]1[O:10][C@@H:9]([N:23]2[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:32])[C@@H:12]1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:36]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@]2(O)Cc2ccccc2)cc1Br
Reactant: CCCCCCCCCCCCCCCCC(S)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCC(S)C(=O)OC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@@](O)(Cc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10 mmol of 2',3'-O-dibenzyl-5-bromouridine and 20 mmol of 2-mercaptostearic acid were added to 400 ml of dimethylformamide containing 40 ml of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred for 3 hours. The resulting reaction mixture was then concentrted at 0.2 atm. at a temperature of 60° C. 200 ml of cyclohexane was added to the residue, and the mixture was heated at a temperature of 80° C for 2 hours while refluxing. The reaction mixture was filtered to recover the residue, and the residue was washed three times with cyclohexane. The resulting residue was then added to 100 ml of dimethylformamide followed by heating at a temperature of 80° C to dissolve the residue. The solution was allowed to cool to room temperature and 100 ml of water was added to the solution. The white precipitate formed was collected by filtration and air-dried to obtain 5.6 mmol (56% yield) of 5'-O-(2-mercaptostearoyl)-2',3' -O-dibenzyl-5-bromouridine as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].[N:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:38]=3)[N:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([N:29]3[CH2:30][CH2:31][N:26]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]([F:45])([F:43])[F:44])[CH:38]=5)[N:33]=4)[CH2:27][CH2:28]3)=[O:20])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:23])([F:24])[F:25])([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added 2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline (93.1 mg, 0.33 mmol, 1.2 eq), EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), Et3N (84 mg, 0.83 mmol, 3 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml), extracted with of dichloromethane (3×30 ml) and the organic layers were combined and dried over anhydrous sodium sulfate. The organic solution was filtered and then concentrated under vacuum. The crude material was purified by Pre-TLC using 4% methanol in dichloromethane to elute. Concentration of the product-containing fractions afforded 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one as a yellow solid (77 mg, 45%). (ES, m/z): [M+H]+ 626.40. 1H NMR (300 MHz, CD3OD): δ 8.13 (d, J=9.0 Hz, 1H), 8.02-8.05 (t, J=4.5 Hz, 2H), 7.42-7.79 (m, 2H), 7.29 (d, J=9.3 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.78-6.81 (dd, J=2.4, 9.2 Hz, 1H), 4.34 (s, 2H), 3.88-3.94 (m, 4H), 3.72-3.78 (m, 4H), 3.45-3.50 (m, 2H), 2.10-2.20 (m, 4H), 1.34-1.54 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.CO>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:20](=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (22.3 mL, 0.160 mmol) was added with stirring to a solution of 3-amino-4-chloroquinoline, see Surrey et al., Journal of the American Chemical Society, 73, pp. 2413-2416 (1951), (13.2 g, 74.0 mmol) in anhydrous dichloromethane (100 mL). A solution of butyryl chloride (13 mL, 125 mmol) in dichloromethane (50 mL) was then added dropwise, and the reaction mixture was stirred at ambient temperature overnight. Methanol (25 mL) was added, and the reaction mixture was stirred for one hour at ambient temperature. Saturated aqueous sodium bicarbonate (50 mL) was added, and the resulting mixture was stirred at ambient temperature for 30 minutes and then allowed to stand. The aqueous layer was separated and extracted with dichloromethane (75 mL), and the combined organic fractions were then washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product (22.8 g) was recrystallized from a mixture of toluene (45 mL) and hexane (15 mL) to provide 9.2 of N-(4-chloroquinolin-3-yl)butanamide as brown needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH-].[Na+]>C(O)C.[Zn]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: Nc1ccc(N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
2-Amino-5-nitrobenzotrifluoride (51.6 g, 0.25 mole), manufactured by Marshallton Research Laboratories, Inc., was dissolved in 95% aqueous ethanol (100 ml) and 25% aqueous sodium hydroxide solution (20 ml) and was heated to gentle reflux. Zinc dust (65 g, 1.00 g atom) was added slowly (50 minutes) at a rate to maintain reflux without external heating. After one hour, the mixture was filtered hot and the filter cake was extracted with two 75 ml portions of hot ethanol. The filtrate, combined with the washings, was concentrated under vacuum producing dark crystals (42 g, 95% yield). These were recrystallized from methanol/methylene chloride.
Reaction SMILES: [OH:1][NH2:2].[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][C@@H:20]([O:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:19][C@@H:18]3[C:31](OC)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO>>[OH:1][NH:2][C:31]([C@H:18]1[CH2:19][C@H:20]([O:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:22][C@@H:17]1[C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11]1)=[O:16])=[O:32]
Reactant: COC(=O)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: CO
Product: O=C(NO)[C@H]1C[C@H](OCc2cccnc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 M of hydroxyamine solution (0.7 ml) was added to a solution of methyl(1S,2S,5R)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-ylmethoxy)cyclohexanecarboxylate (0.075 mmol, 0.000075 mol) made above in methanol (0.5 mL, 0.01 mol). It was stirred at rt for 2 hrs then purified by Prep-HPLC. LCMS: (M+H)+=439.3.