Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([C:4]([CH3:7])([CH3:6])[CH3:5])Cl.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:2]([CH3:8])([CH3:1])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Reaction time: 72 h

Procedure:
To 33 g. of dimethyl-tert-butylchlorosilane in 100 ml. of dimethylformamide is added 27 g. of 6-chlorohexan-1-ol and 340 g. of imidazole. The reaction mixture is allowed to stand at room temperature for 3 days to yield 6-chlorohexyloxy-dimethyl-tert-butylsilane, which is worked up by pouring into water, extracting with ether, washing with water, drying over calcium sulfate, removing the solvent by evaporation and purifying by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].[CH2:14]1[O:16][CH2:15]1>>[OH:16][CH2:15][CH2:14][S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: C1CO1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1

Procedure:
A process for the preparation of the sulphone of the formula ##STR3## wherein 2-chloro-5-nitrobenzenesulphochloride is reacted with sodium sulphite to give 2-chloro-5-nitrobenzenesulphinic acid, the benzenesulphinic acid product is then reacted with ethylene oxide to give 2-chloro-5-nitrophenyl hydroxyethyl sulphone and the latter is then treated with hydrogen in the presence of hydrogenation catalysts to form the sulphone.
Reaction SMILES: CC([N:5]([C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:13])[CH2:11][CH2:10]1)C(=O)[O-])(C)C.[ClH:20].CCOC(C)=O.CCCCCC.II>C(OCC)(=O)C.C(O)(C)C>[ClH:20].[NH2:5][C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:13])[CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(=O)[O-])C1(C(=O)Nn2cccc2)CC1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: NC1(C(=O)Nn2cccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[1-[(1H-pyrrol-1-ylamino)carbonyl]cyclopropyl]carbamate (3.18 g) in ethyl acetate/isopropanol (70 ml) was added excess ethereal HCl. After stirring for 48 hours at room temperature, the reaction appeared complete by thin layer chromatography (TLC) (silica gel, 30% EtOAc/hexane, I2 stain). The solid product was filtered under nitrogen and recrystallized from ether/ethanol to afford 1.20 g of the product as a solid, m.p. 238°-240° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH:15]1([C:18]2[CH:19]=[C:20]([CH3:30])[C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:19]=[C:20]([CH3:30])[C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:10]([C:9]4[CH:8]=[CH:7][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=4)=[O:12])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)[CH2:17][CH2:16]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(=O)NCc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 40.7 %

Procedure:
Using 4-(acetylaminomethyl)benzoic acid (116 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (96 mg) was obtained.
Reaction SMILES: [N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[Cl-].[Cl-].[NH3+:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][NH+:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:34])[F:35])=[CH:27][N:26]=3)[CH3:24])=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-c2cnn3ncccc23)cc1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](NC(=O)Cc1ccc(-c2cnn3ncccc23)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 0.69 g (2.74 mmol) (4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)acetic acid in 10.0 ml CH2Cl2 was added 0.96 g (3.28 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.48 g (3.56 mmol) of HOAt, 0.68 g (3.56 mmol) of EDC, and 1.43 mL (8.21 mmol) of DIEA. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient 0-100% EtOAc in hexanes) afforded 0.85 g (68%) of 2-(4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 8.40 (m, 2-H); 8.28 (s, 1H); 8.27 (d, J=2.93 Hz, 1H); 7.61 (dd, J=1.83, 6.41 Hz, 2H); 7.43 (m, 3H); 7.31 (d, J=8.61 Hz, 1H); 7.22 (dd, J=4.58, 9.07 Hz, 1H); 5.04 (quintet, J=6.86 Hz, 1H); 4.62 (q, J=8.43 Hz, 2H); 3.61 (s, 2H); 1.46 (d, J=7.05 Hz, 31-1). HRMS (ES) [M+1]+calcd for C23H21F3N5O2: 456.1647, Found: 456.1652. FLEPR alpha1I IP=5.0 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)[CH:5]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Yield: 65.2 %

Procedure:
To a mixture of 2.81 g of ethyl 4-nitro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 26 in 50 ml of ethanol-tetrahydrofuran (1:1) was added 0.5 g of palladium-carbon. Catalytic reduction was performed at room temperature under normal pressure until absorption of hydrogen was discontinued. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with isopropyl alcohol to obtain 1.72 g of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: C([O:5][C:6](=[O:29])[C:7]([CH2:24][S:25]C(=O)C)([CH3:23])[CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15]C(OC(C)(C)C)=O)=[CH:13][CH:14]=1)(C)(C)C>Cl>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:7]([CH2:24][SH:25])([CH3:23])[C:6]([OH:29])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(=O)SCC(C)(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(CS)(Cc1ccc(N)nc1)C(=O)O

Procedure:
2-Acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester (4 mg, 9.4 μmol) was dissolved in conc. HCl under argon. The solution was heated to reflux for 1 h. Concentration under reduced pressure yielded the title compound as the hydrochloride salt (2.5 mg, 100%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][CH2:27][CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH:28]([O:44][C:47](=[O:49])[CH3:48])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:45][CH:46]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (2R and 2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol (6.08 g, 9.5 mmol) in a mixture of pyridine (15 ml) and acetic anhydride (15 ml) was stirred at 22° C. for 1 hour. The excess reagents were then evaporated in vacuo and the residue was filtered through a silica gel pad (elution toluene-ethyl acetate, 95:5) to give 6.48 g (100%) of the title material as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:34][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 8.73 g (0.088 mol) of cyclohexylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.7 g (73.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:8]#[N:7]
Reactant: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c(C#N)c(Cl)c2ccccc21
Yield: 82 %

Procedure:
A solution of Compound 2 (1.5 g, 5 mmol) in 20 mL phosphorus oxychloride was heated at 90° C. for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 903 mg (82%) of white solids. M.P. 235° C. 1H NMR (DMSO-d6): 3.66 (s, 3H), 7.50 (t, J=7.7 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.91 (t, J=8.7 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H). EIMS m/z 219 (M+1), 241 (M+23). Anal. (C17H7ClN2O) C, H, N.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccnc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 80B (0.065 g, 0.100 mmol) in a mixture of THF (0.3 mL), methanol (0.3 mL), and aqueous HCl (0.5 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 129.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 6-bromonicotinic acid (2 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (3.1 g) described in Preparation Example 53, the title compound (5 g) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1.[I-:12].[Cs+].II.N(OCCC(C)C)=O>COCCOC>[CH:1]1([C:4]2[CH:5]=[C:6]([I:12])[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1
Reactant: [I-]
Reactant: Nc1ccc(F)c(C2CC2)c1
Agent: CC(C)CCON=O
Agent: II
Agent: [Cs+]
Solvent: COCCOC
Product: Fc1ccc(I)cc1C1CC1
Temperature: 60 °C
Yield: 71.9 %

Procedure:
To a solution of 3-cyclopropyl-4-fluorophenylamine (210 mg, 1.39 mmol) in DME (1.5 ml) was added caesium iodide (360 mg, 1.39 mmol), cuprous iodide (82 mg, 0.43 mmol), iodine (176 mg, 0.70 mmol) and isoamyl nitrite (1.11 ml, 8.34 mmol). The reaction mixture was heated to 60° C. for 2 h. The reaction mixture was cooled to RT and partitioned between pentane and sat. NH4Cl solution. The organic layer was separated, washed with 5% sodium thiosulfite and brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to yield the desired 2-cyclopropyl-1-fluoro-4-iodobenzene (262 mg, 72%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): 7.40 (m, 1H), 7.17 (m, 1H), 6.76 (m, 1H), 2.02 (m, 1H), 1.03-0.96 (m, 2H), 0.74-0.68 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([C:30]([F:33])([F:32])[F:31])=[N:22]2)=[CH:17][CH:16]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[CH:20][CH:19]=2)[N:22]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A mixture of cyclohexanecarboxylic acid (0.10 g, 0.8 mmol) and EDC (0.077 g, 0.4 mmol) in CH2Cl2 (1.5 mL) was stirred for 15 minutes. 1(4′-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.059 g, 0.2 mmol) was added followed by dimethylaminopyridine (0.01 g, 0.1 mmol). After 3 hours the mixture was diluted with CH2Cl2 (50 mL), washed with 10% NaHCO3 (2×50 mL), brine (3×25mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave the above-named compound as a solid that crystallized from benzene (0.075 g, 92%): mp 178-180° C.; 1H NMR (CDCl3) δ 1.35 (3H, m), 1.66 (2H, m), 1.75 (1H, m), 1.85 (2H, m), 2.0 (2H, m), 2.3 (1H, m), 7.08 (1H, s), 7.45 (1H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CN(C=O)C>[N:15]1([C:5]2[S:4][C:3]([NH2:2])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(-n2ccnc2)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-amino-5-bromothiazole hydrobromide (0.5 g, 1.92 mmol), DMF (6 mL), potassium carbonate (1.0 g, 7.2 mmol), and imidazole (132 mg, 1.94 mmol) was stirred at room temperature for 6 h. The mixture was filtered and the filtrate evaporated to dryness in vacuo. The crude product was purified on a silica gel column (eluent: gradient from 100% methylene chloride to 100% isopropanol) to give 5-imidazol-1-yl-thiazol-2-ylamine. Yield: 0.16 g (50
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([O:14][Si](C(C)(C)C)(C)C)[CH2:11][CH:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CN(Cc2ccccc2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CC(O)CN(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a stirred solution of compound 1E (2.33 g, 5.36 mmol) in 13 mL of THF at room temperature under argon was added (in one portion) 6.7 mL or 1M tetrabuylammonium fluoride (in THF, 6.7 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed once with saturated sodium bicarbonate solution. The organic extract was dried over MgSO4, filtered and evaporated under reduced pressure. The resulting white solid was dried in vacuo to give the title compound (1.74 g, 100% material balance) and used in the next reaction without additional purification. MS [M+H]+: found 321.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (556 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.75 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (290 mg, 23%) as a yellow oil.
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:9]1[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=1.[C:17]1([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.O.CO.CO>[CH:15]([C:13]1[N:14]=[C:9]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1-c1cccc(C=O)n1)c1ccccc1
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of water (160 mL) and methanol (40 mL) was combined with sodium carbonate (3.80 g, 35.9 mmol), and the mixture was sparged with nitrogen for 30 min. In a separate flask were combined, under nitrogen, 6-bromo-2-pyridinecarboxaldehyde (2.67 g, 14.4 mmol), tert-butyl phenyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.87 g, 14.4 mmol), tetrakis(triphenylphosphinio)palladium (0.829 g, 0.718 mmol), and toluene (150 mL). The water-methanol solution was added via cannula to the toluene solution, and the biphasic mixture was heated to 80° C. overnight. At this time 1H NMR spectroscopic analysis of an aliquot indicated that the reaction was complete. The clear yellow organic layer was separated, dried with brine, then over magnesium sulfate. The crude product was purified by chromatography on silica using 1:1 hexanes:dichloromethane elutant and increasing the strength by addition of up to 10% EtOAc. The product was isolated as a sticky oil (4.7 g, 840%). 1H NMR (CD2Cl2, 500 MHz): 10.0 (s, 1H), 7.83-7.92 (m, 2H), 7.56 (d, 1H), 7.50 (d, 1H), 7.44 (m, 1H), 7.36 (m, 2H), 7.17 (t, 2H), 7.01 (t, 1H), 7.0 (br d, 2H), 5.11 (s, 2H), 1.34 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:15][C:14]1[N:17]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[N:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncc2ccc([N+](=O)[O-])cc2n1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
2-Fluoro-4-nitrobenzaldehyde (1.00 g, 5.92 mmol) and acetamidine hydrochloride (0.783 g, 8.28 mmol) were added to a suspension of activated 4 Å MS (1.2 g) in acetonitrile (60 mL). K2CO3 (1.14 g, 8.28 mmol) was then added and the reaction was heated to reflux for 4 h. The reaction was then cooled to 25° C. and filtered through celite rinsing with CH2Cl2. The crude product was purified by flash chromatography on silica eluting with 0-10% acetone in CH2Cl2 to give 0.386 g of compound 25A as a yellow solid.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:11]1[CH2:18][O:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]1>ClCCl>[OH:4][CH2:3][CH2:2][N+:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:18][CH2:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15]
Reactant: O=S1(=O)CCCCO1
Reactant: OCCN(CCO)CCO
Solvent: ClCCl
Product: O=S(=O)([O-])CCCC[N+](CCO)(CCO)CCO
Temperature: 0 °C
Yield: 88.4 %

Procedure:
1.49 grams of triethanolamine was added to a 100 mL round bottom flask equipped with a stir bar. 40 mL of dichloromethane was added to the flask and the mixture stirred thoroughly. The solution was cooled to near 0° C. using an ice water bath. 1.36 grams of 1,4-butanesultone was dissolved in 8 mL of dichloromethane and the butanesultone solution added dropwise to the stirred triethanolamine solution. Following complete addition the ice water bath was removed and the solution allowed to warm to room temperature. The mixture was stirred for 16 hours during which a flocculent precipitate formed. The solid was filtered using a medium porosity glass fritted funnel. The white solid was washed using 30 mL of ethyl ether and the solid dried in a dessicator over Drierite® to give 2.52 grams of a white solid. The structure was confirmed by positive mode electrospray mass spectometry (M+Na)=308.3 m/z and 1H NMR.