Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cn1nc(-c2cccnc2)cc1N
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2cccnc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
Acetic anhydride (431 μL, 4.4 mmol) was added dropwise to a solution of methyl 2-[5-amino-3-(3-pyridyl)pyrazol-1-yl]acetate (510 mg, 2.2 mmol) in pyridine (1.7 mL) at 0° C. under an atmosphere of nitrogen. Upon complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the solid was washed with diethyl ether to provide the title compound as a white solid (430 mg).
Reaction SMILES: [F:1][C:2]([F:35])([C:31]([F:34])([F:33])[F:32])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[O:8][C:9]([F:22])([F:21])[CH2:10][O:11][CH2:12][C@@H:13]([F:20])[CH2:14][O:15][CH2:16][CH2:17][CH2:18]Cl.FC(F)(C(F)(F)F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COC[C@@H](F)CO.BrCCCCl.[CH2:72]([C:79]1[CH:80]=[N:81][C:82]([C:85]2[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=2)=[N:83][CH:84]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]>C(#N)C.CN(C)C=O>[CH2:72]([C:79]1[CH:84]=[N:83][C:82]([C:85]2[CH:86]=[CH:87][C:88]([O:91][CH2:18][CH2:17][CH2:16][O:15][CH2:14][C@H:13]([F:20])[CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:24])([F:23])[C:6]([F:26])([F:25])[O:5][C:4]([F:28])([F:27])[C:3]([F:30])([F:29])[C:2]([F:35])([F:1])[C:31]([F:34])([F:33])[F:32])([F:22])[F:21])=[CH:89][CH:90]=2)=[N:81][CH:80]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]
Reactant: F[C@@H](COCCCCl)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: ClCCCBr
Agent: OC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCc1cnc(-c2ccc(OCCCOC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The starting material, 3-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)propyl chloride, was prepared by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropanol (20 g, 39.4 mmol) and 1-bromo-3-chloropropane (18.6 g, 118 mmol). The resulting compound (2.0 g, 3.4 mmol) was then combined with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (0.9 g, 3.4 mmol) in acetonitrile/dimethyl formamide (1:1, 20 mL) using essentially the procedure of Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 30:1 toluene/ethyl acetate, followed by Kugelrohr distillation (180-90° C. at 0.01 torr; yield 0.96 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:36][C:6]1[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:29])[N:11]2[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of (S)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.063 mmol), β-alanine (672 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 535.39 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7](NS(CC)(=O)=O)[C:6]=2[CH:18]=1.[H-].[Na+].C(I)CCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc2c1OCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (2.6 mmol) of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 ml of DMF was added dropwise under nitrogen to a suspension of 0.1 g (2.7 mmol) of 80 percent sodium hydride in 8 ml of DMF. After stirring at RT for 30 min, 0.68 g (3.7 mmol) of butyl iodide was added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. After washing the organic phase with dil. hydrochloric acid in water, and drying over magnesium sulfate, it was concentrated in vacuo. 0.9 g of 5-N-butyl-N-ethylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 83-87° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:18]12CC(C=C1)C=[CH:19]2>O1CCOCC1>[I:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:19]=[CH:18][N:3]=[N:2]3)[O:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
(5R)-5-(Azidomethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (10.0 g, 29.1 mmol) was dissolved in 1,4-dioxane (100 ml). Bicyclo[2.2.1]hepta-2,5-diene (9.4 ml, 87.2 mmol) was added and the mixture heated to 100° C. for 24 h. The solution was cooled and purified by silica flash chromatography with 1-10% methanol in dichloromethane as eluent giving 7.2 g of the desired product.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][C:30]1([NH2:34])[CH2:33][O:32][CH2:31]1>>[CH3:29][C:30]1([NH:34][C:15]([C:14]2[CH:18]=[CH:19][N:20]=[CH:21][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:11])=[O:16])[CH2:33][O:32][CH2:31]1
Reactant: CC1(N)COC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Product: CC1(NC(=O)c2ccncc2NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)COC1

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 3-methyloxetan-3-amine, providing the title compound was obtained as yellow solid (44%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.ClC(Cl)(Cl)C[O:23][C:24](=O)[NH:25][C:26]1[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([C:29]1[CH:30]=[C:26]([NH:25][C:24]([NH:19][CH2:18][C:17]2[C:12]([O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:23])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cn1ncc2cc(Oc3ncccc3CN)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cccnc2Oc2ccc3c(cnn3C)c2)cc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
C-[2-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-methylamine (4n) (0.017 g, 0.067 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (5n) (0.035 g, 0.087 mmol) were placed in a 10 mL reactor vial and dissolved in DMF (5 mL). DIEA (0.058 mL, 0.334 mmol) was added to the reaction mixture and the system heated to 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography using Sep-pak 10 g (35 cc) silica cartridge (50% EtOAc/Hexanes) to furnish the desired product (6n) (0.034 g, 100% yield). 1H NMR (400 mHz, DMSO) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=4.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 2H), 6.26 (s, 1H), 4.37 (d, J=6.3 Hz, 2H), 4.06 (s, 3H), 2.36 (s, 3H), 1.25 (s, 9H); MS (ESI+) m/z 510 (M+H) detected.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CN(SSc1ccccc1)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1OCSC1=NOC(=O)N(C)SSc1ccccc1

Procedure:
4-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 5.0 g (0.0375 m) of 5-methyl-4-oximino-1,3-oxathiolane, 8.15 g (0.0375 m) of N-methyl-N-(phenylthiosulfenyl) carbamoyl fluoride and 3.79 g (0.0375 m) of triethylamine in 100 ml of dioxane. The crude residual oil was purified using silica gel column to yield 3.5 g of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27].O>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([CH2:12][OH:13])[C:3]([O:14][CH3:15])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1CO
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
A solution of (3-amino-5-tert-butyl-2-methoxyphenyl)methanol (1.72 g, 8.23 mmol) and N,N-diisopropylethylamine (2.15 mL, 12.3 mmol) in THF (27.4 mL) was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (1.24 mL, 9.01 mmol) was added, followed by stirring the mixture for 10 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=75/25-50/50) to obtain 2.23 g of the captioned compound (71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19](C(O)=O)=[CH:18][O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C([N:27](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]([NH2:27])=[CH:18][O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(-c3nocc3C(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(-c3nocc3N)cc2)cc1
Temperature: 52.5 °C

Procedure:
A solution of 3-[4-(4-methoxy-benzyloxy)-phenyl]-isoxazole-4-carboxylic acid (1.0 g, 3.07 mmol) and triethylamine (0.5 mL, 3.4 mmol) in DMF (30 mL) was cooled to 0° C. Diphenylphosphorylazide (0.8 mL, 3.86 mmol) was added and the reaction mixture was warmed to 45-60° C. for 2 h. Water (15 mL) was then added and the reaction temperature increased to 90° C. for 28 h. The reaction mixture was cooled and 3-[4-(4-methoxy-benzyloxy)-phenyl]-isoxazol-4-ylamine was isolated by chromatography (5-40% ethyl acetate in hexane) as a white solid. m.p. 92-98° C. HRMS+1=297.123
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Br:8])[CH2:5][CH2:6][Br:7].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:3](=[O:2])[CH:4]([Br:8])[CH2:5][CH2:6][Br:7]
Reactant: CN
Reactant: COC(=O)C(Br)CCBr
Product: CNC(=O)C(Br)CCBr

Procedure:
reacting the methyl-2,4-dibromobutyrate with methylamine in an aqueous medium to form N-methyl-2,4-dibromobutyramide;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(OCC)(=O)C>[CH3:15][CH2:14][O:13][P:9]([O:10][CH2:11][CH3:12])([CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N+:1]([O-:25])=[CH:6][CH:5]=1)=[O:16]
Reactant: CCOP(=O)(CCc1ccncc1)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCc1cc[n+]([O-])cc1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
Diethyl 2-(4-pyridyl)ethylphosphonate (10.3 g, 42 mmol) and 3-chloroperbenzoic acid (77%, 12.3 g, 54 mmol) were dissolved in ethyl acetate (200 ml), and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethanol-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (9.9 g, 99%).
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][C@@H:6]1[C:19]([O:21]C)=[O:20].[OH-].[Na+]>O1CCOCC1>[OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][C@@H:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H]1CN(CCc2ccc(Cl)s2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCc4ccc(Cl)s4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 67.1 %

Procedure:
A solution of 0.460 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(5-chlorothien-2-yl)ethyl]piperidine-3-carboxylate in 5 cm3 of dioxane which had been added 0.51 cm3 of a 5N aqueous sodium hydroxide solution was stirred at a temperature in the region of 60° C. for 48 hours. After a further addition of 1 cm3 of 5N sodium hydroxide solution, the mixture was again heated at a temperature in the region of 70° C. for 72 hours. The reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. and then the residue obtained was purified by chromatography under a nitrogen pressure of 40 kPa on a column of silica gel (particle size 40-63 μm; diameter 3 cm; silica height 27 cm), elution was carried out with a dichloromethane/methanol/28% aqueous ammonia (14/4/0.6 by volume) mixture, and 15-cm3 fractions were collected. Fractions 7 to 16 were evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.30 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(5-chlorothien-2-yl)ethyl]piperidine-3-carboxylic acid was obtained in the form of a foam with a white color.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:19]([O:23][C:24](=[O:42])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([NH:40][NH2:41])=O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26])([CH3:22])([CH3:21])[CH3:20]>CO>[C:19]([O:23][C:24](=[O:42])[C:25]([CH3:27])([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]2[NH:40][N:41]=[C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=3)[N:8]=2)=[CH:31][CH:30]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:22]
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCCc2nc(-c3ccc(C(F)(F)F)cc3)n[nH]2)cc1
Yield: 43.6 %

Procedure:
Add 4-(trifluoromethyl)benzonitrile (0.51 g, 3.0 mol) and potassium tert-butoxide (0.023 g, 0.21 mmol) to a solution of 2-[4-(3-Hydrazinocarbonyl-propyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester (0.5 g, 1.5 mmol) in MeOH (5 mL). Stir the mixture at reflux overnight. Add an additional 0.2 equivalents of potassium tert-butoxide and stir the reaction for 24 h. Quench the crude with water, remove the MeOH in vacuo, and extract the aqueous layer with EtOAc. Separate the organic layer, dry with MgSO4, and concentrate in vacuo. Purify the crude by Biotage (Hexane/EtOAc 4:1) yielding 0.32 g (44%) of the title compound, example 10 as a pale yellow oil. MS Data (ES+) m/z 490.6 [M+H]
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH2:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[BH3-][C:18]#N.[Na+].C=O>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH:15][CH3:18])[C:6]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)c1cc(N)c(O)c(C(C)(C)C)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 14.8 %

Procedure:
A mixture of 2,4-di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol), NaBH3CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 mL) was stirred at reflux for 3 h. After removal of the solvent, the residue was purified by column chromatography (petroleum ether-EtOAc, 30:1) to give 2,4-di-tert-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 15%). 1H NMR (DMSO-d6) δ 8.67 (s, 1H), 6.84 (s, 1H), 5.99 (s, 1H), 4.36 (q, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 3H), 1.23 (s, 18H); ESI-MS 236.2 m/z (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[S:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:20]=[S:2]1(=[O:1])[C:6]2[CH:7]=[C:8]([NH:11][C:12]([N:34]3[CH2:33][CH2:32][N:31]([C:29]4[S:28][N:27]=[C:26]([C:22]5[S:21][CH:25]=[CH:24][CH:23]=5)[N:30]=4)[CH2:36][CH2:35]3)=[O:19])[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)N1CCN(c2nc(-c3cccs3)ns2)CC1

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1,1-dioxido-1-benzothien-6-yl)carbamate (257 mg, 0.720 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.792 mmol) and diisopropylethylamine (0.129 ml, 0.720 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and 69.6 mg (21.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:16](=[O:17])[NH:15][C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1.I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[Br:3][C:4]1[C:16](=[O:17])[N:15]([CH:19]([CH3:21])[CH3:20])[C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1
Reactant: CC(C)I
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Temperature: 46 °C
Yield: 59.4 %

Procedure:
To a suspension of NaH (120 mg, 5.00 mmol) in DMF (15 mL) was added 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (572 mg, 2 mmol). The mixture was heated to 46° C. The solution was cooled down slightly and 2-iodopropane (0.30 mL, 3.0 mmol) was added. The mixture was heated at 46° C. for 30 min and then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and concentrated. The crude product was purified by silica gel flash chromatography, using EtOAc/Hexane, to give the title compound (390 mg, 59%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([C:19]([F:22])([F:21])[F:20])([C:16](F)=[O:17])[C:13](F)=[O:14]>C(COC)OC>[CH3:11][C:12]1([C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:13]1=[O:14]
Reactant: NC(N)=O
Reactant: CC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a suspension of 1.50 g (0.025 mol) of urea in 30 ml of glyme and 4.0 g (0.050 mol) of pyridine was added dropwise with stirring a solution of 5.0 g (0.026 mol) of methyltrifluoromethylmalonyl fluoride in 20 ml of glyme. Urea dissolved during a mildly exothermic reaction and the homogeneous solution was allowed to stand overnight. The mixture was then refluxed briefly, solvent was removed under vacuum, and the residue was stirred with 25 ml of water. Filtration and rinsing with water gave 3.80 g of 5-methyl-5-trifluoromethylbarbituric acid, mp 205°-206.5°C. A second crop, mp 205°-207°C, 0.84 g, brought the yield to 88% (4.64 g). Recrystallization from water gave an analytical sample, mp 205°-206°C; ir (KBr): 3.07 and 3.17 (NH), 5.67 shoulder and 5.80 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 7.0 (very broad, 2 (partly exchanged into acetone-d6), NH) and 1.72 ppm (quartet, JHF = 0.7 Hz, 3, CH3); 19F at -70.8 ppm (quartet, JHF = 0.7 Hz, CF3).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>CN(C=O)C>[CH3:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3]
Reactant: Cc1cccc(OCCCCBr)c1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCCN2C(=O)c3ccccc3S2(=O)=O)c1
Yield: 55 %

Procedure:
The title compound was synthesized analogously to 83.8 (see experimental below), using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-3-methylbenzene (146 mg, 0.6 mmol) in DMF (anhydrous, 1 mL). The crude product obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.6 as a viscous liquid in 55% yield (95 mg).