Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1([CH2:24]CCC)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:34]1COCC1>>[CH3:24][C:3]1([CH3:34])[CH:6]([OH:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: CCCCC1(OC)C(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Temperature: 0 °C

Procedure:
To a solution of Example 14 (100 mg) in THF (1 mL) at 0° C., was added LAH (1M, THF, 920 μL). The mixture was stirred at 0° C. for min., quenched with H2O, and diluted with EtOAc. The organic phase was washed with HCl 1N, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (70:30)) to give the title compound as a white solid, m.p. 79°-81° C.
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:43]4[CH:48]=[N:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[N:45][CH:44]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.321 mmol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinyl]-1-piperazinecarboxylate (0.353 mmol) in 1,4-dioxane (3 ml) was added saturated NaHCO3(aq) (0.85 ml). After degassing with argon for 10 minutes, dichlorobis(triphenylphosphine)palladium(II) (0.0161 mmol) was added and the resulting mixture was heated at 95° C. overnight. Upon cooling, the reaction was concentrated and partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (quant.). ESMS [M+H]+: 722.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:14][CH2:15]3)=[O:9])[N:6]=2)=[O:23])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 644.3 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][C:15](OC(C)(C)C)=[O:16]>O1CCCC1.C(OCC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)CN(c1ccccn1)c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCN(c1ccccn1)c1ccccn1
Temperature: 25 °C

Procedure:
To a slurry of LAH (lithium aluminum hydride) (1.17 g, 30.8 mmol, 3.0 equiv) in THF (tetrahydrofuran) (45 ml) was added Tert-butyl 2-(di(pyridine-2-yl)amino)acetate (2.9 g, 10.2 mmol) at 0° C. under 1 atm argon (Ar). The reaction was slowly warmed to room temperature over 4 h. The reaction mixture was then diluted with diethyl ether and cooled to 0° C. The reaction was quenched via careful addition of water (4.0 ml) and then dried with magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (SiO2, hexane/ethyl acetate=1:1) to afford DPAE as a pale yellow oil. DPAE was obtained (Yield: 1.2 g (55%)), and confirmed by 1H NMR (DMSO-d6, 300 MHz): δ 8.27 (m, 2H), 7.62 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.93 (m, 2H), 4.92 (t, J=5.4 Hz, 1H), 4.16 (t, J=6.5 Hz, 2H), 3.58 (q, J=6.5 Hz, 2H). ESI-MS (cation): 216.1 m/z (M+H+) obsd, 215 m/z calcd.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].ClCCl.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(N)C(=O)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(Br)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl aminomalonate hydrochloride (1.83 g, 10 mmol) in dichloromethane (30 mL) triethylamine (3 mL, 22 mmol) will be added at 0° C. 4-bromobenzoyl chloride (2.19 g, 10 mmol) will be slowly added the resulting solution will be allowed to stand at room temperature overnight. Water will be added and the organic layer will be separated and dried over anhydrous MgSO4. The evaporation of solvent will result in Int P.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[C:9](O)[CH:10]=[CH:11][CH:12]=1.C1(C(=CC=CC=1)O)[OH:20]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[OH:20]
Reactant: Oc1ccccc1O
Reactant: Oc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Product: Oc1ccccc1Oc1cccc(C(F)(F)F)c1

Procedure:
Then, 1-chloro-4-(1,1,1,2,2-pentafluoroethylsulfonyl)benzene was prepared as follows: ##STR19## 64 g of 1-chloro-4-(1,1,1,2,2-pentafluoroethylthio)benzene and 250 mL of glacial acetic acid were placed into a flask and stirred to form a mixture. While stirring, 250 mL of a 30% H2O2 /water solution was added dropwise. After this addition, the mixture was stirred for four hours at reflux and allowed to cool to room temperature. GC analysis showed reaction was complete. The resulting solids ("first product solids") were filtered off and rinsed with water. The filtrate was poured into 500 ml of water, stirred, and extracted with 300 mL of methylene chloride to form an aqueous phase and a methylene chloride product phase. The methylene chloride product phase was separated, dried by passing it through sodium sulfate, and low boilers were distilled off. The resulting product phase was combined with the first product solids and distilled at 80°-85° C. and 1.0 mm Hg to produce a total of 62 g of white solids having a melting point of 37°-38° C. The white solids were confirmed by GC-MS analysis as 1-chloro-4-(1,1,1,2,2-pentafluoroethylsulfonyl)benzene. ##STR20## 2-(3-trifluoromethylphenoxy)phenol was prepared by a procedure identical to the one described above for preparing 3-(3-trifluoromethylphenoxy)phenol, with the exception that catechol (Aldrich Chemical Company) is used in place of resorcinol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=C(O)C=[C:6]([OH:9])[C:7]=1[CH3:8].[ClH:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2[C:3]3[C:2]([OH:1])=[C:7]([CH3:8])[C:6]([OH:9])=[CH:30][C:29]=3[O:28][C:26](=[O:27])[C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: Cc1c(O)cc(O)cc1O
Agent: Cl
Product: Cc1c(O)cc2oc(=O)c3c(c2c1O)CCN(Cc1ccccc1)C3
Yield: 24 %

Procedure:
Prepared by the procedure of Example 1 from 3,5-dihydroxy-4-methylphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. The crude product was converted to the hydrochloride salt. Yield 24%; mp 293°-299° C.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3].[BH4-].[K+].C(O)(=O)C>CO>[OH:22][C@H:16]1[CH2:15][CH2:14][C@H:13]2[C@H:12]3[C@H:21]([CH2:20][CH2:19][C@:17]12[CH3:18])[C@:4]1([CH2:1][C:2]#[CH:3])[C:9](=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1)[CH2:10][CH2:11]3
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
A solution of 312 mg of 10-(2-propynyl)estr-4-ene-3,17-dione in 10 ml of absolute methanol is treated with 15 mg of potassium borohydride at 0° C. for 1 hour. Acetic acid (0.05 ml) is added and the solvent is evaporated. The residue is dissolved in ether, the ether solution is washed with 1 N hydrochloric acid and with brine and dried, and the solvent is evaporated. The residue is recrystallized from methanol to give 17β-hydroxy-10-(2-propynyl)estr-4-en-3-one. This compound has the following structural formula ##STR9##
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:24][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([CH:39]=[CH:38][CH:37]=1)[CH2:24][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:40])(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)phenylsulfonamido)methyl)benzylcarbamate (0.4 g, 0.65 mmol) in CH2Cl2 (10 mL) was added TFA (1.49 mL, 19.4 mmol). The resulting mixture was stirred at rt for 16 h. The mixture was concentrated, and the residue was partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was washed with brine twice, dried over MgSO4, and concentrated in vacuo to give a light yellow solid (0.32 g, 86%). 1H NMR (DMF-d7): δ 7.52 (m, 2H), 7.50 (m, 4H), 7.48 (m, 2H), 7.2-7.0 (m, 2H), 4.75 (s, 2H), 4.51 (s, 2H), 4.25 (m, 2H); MS (ESI): (M+H)+=519.11.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12]([CH2:15][OH:16])=[N:13][S:14][C:10]=2[CH:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>O>[Cl:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12]([C:15]([OH:20])=[O:16])=[N:13][S:14][C:10]=2[CH:9]=1
Reactant: OCc1nsc2cc(Cl)ccc12
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1nsc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 15 %

Procedure:
Potassium permanganate (1.69 mmol) was added in several batches a solution of (6-chlorobenzo[d]isothiazol-3-yl)methanol (2.50 mmol) in water (3 mL). Potassium carbonate (2.90 mmol) was added and the reaction mixture was maintained for 30 min at 25° C. The insoluble materials were removed by filtration and the aqueous layer was extracted with ethyl acetate (3×10 mL). The pH of the aqueous layer was adjusted to 3-4 by the addition of 1 N hydrochloric acid and the reaction mixture was maintained for 10 min. The solids were collected by filtration to provide 6-chlorobenzo[d]isothiazole-3-carboxylic acid in 15% yield as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=1)[N:8]=[CH:7]2)([O-:3])=[O:2].[CH3:23]COC(C)=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:22]=[CH:21][C:17]3[O:18][CH2:19][CH2:23][O:20][C:16]=3[CH:15]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Reactant: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCCO4)ncc2c1
Yield: 70 %

Procedure:
This compound was synthesized in 70% yield, according to the procedure described in example 1 for the synthesis of 6-nitro-2-(1,3-benzodioxole-5-yl)-quinazoline. C16H11N3O4, MW: 309.28. mp. 263-265° C.; TLC (tol/AcOEt 7/3) Rf=0.80.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:13].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:12]([S:13][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCS
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCSCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Dodecylthiol (5 g) was dissolved in 50 ml of dry N,N-dimethylformamide and 1 g of 60% sodium hydride was added thereto under ice-cooling. The mixture was stirred at room temperature for 1 hour. Further, a solution of 3.45 g of 3-bromopropanol in 10 ml of dry N,N-dimethylformamide was dropwise added thereto under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice, extracted with ether and washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The ether layer was dehydrated and concentrated. The resultant mixture was purified by silica gel column chromatography using hexane-ethyl acetate (10:1→3:1) as an eluent to give 6.071 g of 3-dodecylthiopropanol as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[CH3:7])[CH:3]([OH:5])O.N1C=CC=CC=1.[F:17][C:18]([F:31])([F:30])[S:19]([O:22]S(C(F)(F)F)(=O)=O)(=[O:21])=[O:20]>ClCCl>[F:8][C:6]([F:9])([C:2]([F:10])([F:1])[CH2:3][O:5][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:21])=[O:20])[CH2:7][O:22][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:20])=[O:21]
Reactant: CC(F)(F)C(F)(F)C(O)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2,2,3,3-tetrafluorobutanediol (15 g, 93 mmol) and pyridine (19 mL, 230 mmol) in dichloromethane (250 mL), was added dropwise trifluoromethanesulfonic anhydride (34 mL, 200 mmol). After the addition, the mixture was stirred at 0° C. for one hour, followed by stirring at room temperature for one additional hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to near dryness, leaving a dichloromethane-containing oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1C=CC=CC=1.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:15][C:14]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:13]=2[Cl:12])[C:9](=[O:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(Cl)cc1Cl)c1ccc(Br)cc1
Yield: 98.2 %

Procedure:
A mixture of 15.9 g of 1-(4-bromophenyl)acetone, 13 g of 2,4-dichlorobenzaldehyde and 0.5 g of piperidine in 300 ml of benzene is heated under reflux for 18 hours, removing the water that forms by means of a Dean Stark. 0.3 g of piperidine is added, and it is refluxed for a further 24 hours. The reaction mixture is concentrated under vacuum, obtaining 27 g of the expected compound in the form of oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:19]=[C:18]([C:17]([O:21][CH3:22])=[O:20])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (7.3 g, 0.03 mol) and methyl prop-2-ynoate (3.1 mL, 0.04 mol) in dichloromethane (150 mL) at 0° C. under nitrogen was added dropwise a solution of trifluoroacetic acid (0.12 mL, 0.002 mol) in dichloromethane (1 mL). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 2 h, then the solvent was evaporated. The residue was purified by FCC, eluting with 0-20% ethyl acetate in heptane, to afford the title compound (2.37 g, 29%) as a yellow oil. δH (250 MHz, CDCl3) 7.35-7.15 (5H, m), 6.70 (1H, s), 3.79 (3H, s), 3.75-3.60 (6H, m).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=1>[Li]CCCC.[Zn+2].[Br-].[Br-]>[Br:22][C:23]1[N:24]=[C:25]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccc(Br)n1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.4) (0.900 g, 2.15 mmol), n-BuLi/ZnBr2 and commercially available 2,6-dibromopyridine (0.510 g, 2.15 mmol) according to Tetrahedron Letters 1996, 37(15), 2537 and the general procedure IVc protocol b. Obtained as a yellow oil (0.658 g, 60%, 88% purity). MS (ISP) 447.8 [(M+H)+] and 450.0 [(M+2+H)+].
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl>[O:18]1[C:2]2([CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2(CO2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C9H15NO3: 185.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[O:19][C:18]([C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10][C:11]=4[CH:17]=3)=[N:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cc1
Reaction time: 0.33 h

Procedure:
To a 20 mL microwave vial was added 0.500 g (1.09 mmol) of 4-Chloro -benzoic acid N′-[2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide, 13 mL of THF, and 0.5187 g (2.18 mmol) of Burgess Reagent. The suspension was placed in the microwave at 150° C. for 20 min. The crude solution was concentrated and the residue was purified by silica gel column chromatography (ACN/DCM, 1:9 to 6:4) to give of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.67 (m, 1 H) 7.68-7.74 (m, 4.5 H) 7.78-7.81 (m, 0.6 H) 7.94 (d, J=8.46 Hz, 0.5 H) 8.02-8.10 (m, 1 H) 8.17-8.22 (m, 2 H) 8.33 (d, J=1.01 Hz, 0.4 H) 8.49-8.52 (m, 0.6 H) 13.36 (d, J=10.36 Hz, 1 H). MS (m/z) 442.9 M (+1), tR=1.49, Meth 10
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[O:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1
Reactant: COC(=O)c1cccc(Sc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: COC(=O)c1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 52.7 %

Procedure:
In a procedure analogous to Example 8, reaction of methyl 3-(2-chloropyrimidin-4-ylthio)benzoate (310 mg, 1.84 mmol) and 4-morpholinoaniline (394 mg, 2.21 mmol) furnished the product (410 mg, 87%).