Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:19][CH3:20].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:19][CH3:20])=[C:2]([F:1])[CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][N:8]=1
Reactant: COc1cc2c(N3CCOCC3)c[nH]c(=O)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(N3CCOCC3)cnc(Cl)c2cc1F
Yield: 46.8 %

Procedure:
A solution of 7-fluoro-6-methoxy-4-morpholinoisoquinolin-1(2H)-one (0.25 g, 0.898 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.13 g, 46.8%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.98-7.95 (m, 2H), 7.56-7.54 (d, J=8 Hz, 1H), 7.45-7.40 (m, 2H), 4.08 (s, 3H), 3.89-3.86 (m, 4H), 3.11-3.09 (m, 4H); MS: MS m/z 297.07 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(C(C)=O)CC2)cc1
Yield: 102 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (7.7 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in dimethylformamide (50 ml) was stirred at 80° C. for 5 hr. The reaction mixture was poured into water (250 ml) and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil. The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (11.5 g) as a colorless transparent oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20].[Pb]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([OH:32])[CH:26]=1)[CH3:20]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: O=[Pb]
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(O)c2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Ethyl (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (18.95 g., 0.05 mole) dissolved in trifluoroacetic acid (100 ml.) is added portionwise at less than 10° C. to a stirred mixture of lead tetrakistrifluoroacetate (.055 mole) prepared by stirring lead oxide (37.5 g.), trifluoroacetic acid (85 ml.) and trifluoroaceticanhydride (75 g.) at 25° C. for 96 hrs. After stirring the reaction mixture at 25° C. for 6 hours it is poured into crushed ice-water (1 l.) to precipitate 19.7 g. of a mixture of esters which is hydrolyzed by heating at reflux with ethanol (400 ml.) -water (250 ml.) - 10N sodium hydroxide solution (40 ml.) for 3/4 hr. On addition to crushed ice-water (1 l.) -12N hydrochloric acid (50 ml.) a gummy product precipitates, is extracted with ether then concentrated to give 60% of [1-oxo-2-(3-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid and 20% of the 4-hydroxyphenyl derivative. Crystallization from acetic acid gives 2.6 g. of [1-oxo-2-(3-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid, m.p. 248° - 255° C.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].[P:5]([OH:8])([OH:7])[OH:6].Cl>>[NH2:4][C:1]([P:5]([OH:8])(=[O:6])[OH:7])([P:5]([OH:8])(=[O:7])[OH:6])[CH3:2]
Reactant: CC(N)=O
Reactant: OP(O)O
Agent: Cl
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Reaction time: 3 h

Procedure:
Into a mixture of 59 gm of acetamide and 82 gm of phosphorous acid, hydrogen chloride gas was introduced therein for a period of 3 hours. During this time the mixture was stirred and the temperature was maintained at 145° - 155° C. By further processing of the reaction mixture, analogously to Example 1, the 1-aminoethane-1,1 -diphosphonic acid was isolated and purified. The yield was 19.2 gm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[CH:17]([O:19][CH2:20][CH3:21])=[CH2:18].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C(=O)([O-])O.[Na+].OCCOC1C(OC)=CC(OC)=CC=1C=O>C(Cl)Cl>[CH2:17]([O:19][CH:20]([O:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])[CH3:21])[CH3:18]
Reactant: C=COCC
Reactant: COc1cc(C=O)cc(OC)c1OCCO
Agent: COc1cc(C=O)c(OCCO)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(C)OCCOc1c(OC)cc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-(2-hydroxyethoxy)-3,5-dimethoxybenzaldehyde (1.5 g, 6.6 mmol) in methylene chloride (22 mL, 0.3 M) was added ethyl vinyl ether (3.4 mL, 19.9 mmol). After addition of PPTS (168 mg, 0.66 mmol), the reaction mixture was stirred for 40 minutes at room temperature. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction fluid, which was then extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure to afford a residue containing an ethoxyethyl-protected 4-(2-hydroxyethoxy-3,5-dimethoxybenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:23]([O:27][C:28](=[O:40])[NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37](Br)[CH:38]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:40])[NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]3)[CH:38]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CC(C)(C)OC(=O)NCCOc1cncc(Br)c1
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) has been coupled to [2-(5-bromo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a yellow waxy solid. MS: 416.4 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[N:17]([CH:19]=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]1([C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[CH:9]=[C:8]([C:19]#[N:17])[CH:7]=[CH:12]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: N#Cc1ccc2cc(-c3ccccc3)ccc2c1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 121B (300 mg, 1 mmol), palladium (II) acetate (22 mg, 0.1 mmol) and 1-1′-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 minutes, treated with Cs2CO3 (813 mg, 2.5 mmol) and phenylboronic acid (228 mg, 1.5 mmol), stirred for 20 minutes at 80° C., cooled, treated with pH 7 buffer (10 mL), and extracted with diethyl ether. The ether extracts were dried (MgSO4), concentrated, filtered, and purified on silica gel with 10% ethyl acetate/hexane to provide 140 mg of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:35](=[NH:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:48]=[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(C(=Nc2cccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)c2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (3.00 g, 5.8 mmol) in toluene (60 mL) was added benzophenone imine (3.15 g, 17.4 mmol), tris(dibenzylideneacetone)dipalladium (0.26 g, 0.3 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.54 g, 0.15 mmol) and sodium tert-butoxide (1.67 g, 17.4 mmol). The reaction was heated at reflux for 5 hours, then allowed to cool to room temperature. Water and ethyl acetate were added to the reaction mixture. The phases were separated and the organic phase was washed with brine and dried (magnesium sulfate). Filtration and concentration of the filtrate followed by purification with flash chromatography (4:6 ethyl acetate:hexanes) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine (2.61 g, 73%) as a yellow solid. 1H NMR (CDCl3): δ 7.89 (d, 1H), 7.80–7.75 (m, 3H), 7.48 (m, 1H), 7.41 (m, 2H), 7.27 (m, 5H), 7.23–7.12 (m, 4H), 7.04 (s, 1H), 6.80 (d, 1H), 6.03–5.97 (m, 3H), 4.39 (m, 1H), 4.00 (m, 1H), 2.15–2.05 (m, 4H), 1.83–1.56 (m, 12H); MS m/z 618 (M+1).
Reaction SMILES: [C:1]1([OH:8])(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O.ClCCl>[OH:8][C@H:1]1[CH2:2][CH2:3][C@H:4]([C:12]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=3)[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:5][CH2:6]1
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Reactant: OC1(O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cc3ncccc3c([C@H]3CC[C@H](O)CC3)n2)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (1.7 mmol) cyclohexanediol was placed in 1.5 ml dimethylacetamide and 47 mg (1.17 mmol) sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg (0.31 mmol) 6.1 was added and the mixture was stirred for 2 h at 70° C. The reaction mixture was diluted with dichloromethane and extracted 1× with water. The organic phase was dried with MgSO4 and evaporated down. The residue was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH3:10].CCN(CC)CC>CC#N.CCOC(C)=O.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.[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:21])=[CH:14][CH:15]=2)[N:3]=1
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cccc(N)n2)cc1

Procedure:
2-Amino-6-bromopyridine (0.38 g, 2.4 mmol), alkyne 29-2 (0.35 g, 2.0 mmol), Et3N (1.0 mL, 7.2 mmol), (Ph3P)2PdCl2 (76 mg, 0.11 mmol), an CuI (26 mg, 0.14 mmol) were combined in 5 mL CH3CN, sealed in a glass pressure tube and heated to 100° for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), concentrated, and purified by flash chromatography (silica, 5% acetone/hexane), to give 29-3 as a tan solid.
Reaction SMILES: Cl.Cl[C:3](=[C:8](Cl)[C:9]([F:12])([F:11])[F:10])[C:4]([F:7])([F:6])[F:5]>>[F:5][C:4]([F:7])([F:6])/[CH:3]=[CH:8]\[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Agent: Cl
Product: FC(F)(F)/C=C\C(F)(F)F

Procedure:
Additional products of the reaction may include partially hydrodechlorinated intermediates; saturated hydrogenated compounds; various partially chlorinated intermediates or saturated compounds; and hydrogen chloride (HCl). For example, wherein the chlorofluoroalkene is 2,3-dichloro-1,1,1,4,4,4-hexafluoro-2-butene (CFC-1316mxx, E- and/or Z-isomers), the compounds formed in addition to E- and/or Z-1,1,1,4,4,4-hexafluoro-2-butene (E- and/or Z-HFC-1336mzz) may include, 1,1,1,4,4,4-hexafluorobutane (HFC-356mff), pentafluorobutane (HFC-1345, different isomers), 2-chloro-1,1,1,1,4,4,4-hexafluorobutane (HFC-346mdf), E and/or Z-2-chloro-1,1,1,4,4,4-hexafluoro-2-butene (E- and/or Z-HCFC-1326mxz), and 1,1,1,4,4,4-hexafluoro-2-butyne (HFB).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:26])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:5][C:6]1[C:11]([N:12]([CH2:3][O:2][CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)(=[O:14])=[O:15])=[CH:10][C:9]([Cl:26])=[CH:8][N:7]=1
Reactant: COCCl
Reactant: O=S(=O)(Nc1cc(Cl)cnc1Br)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
Methoxymethyl chloride (720 mg, 8.94 mmol) was added dropwise to a mixture of N-(2-bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (2.51 g, 6.04 mmol) and potassium carbonate (5.1 g) in THF (60 mL) at room temperature. After 5 h, the potassium salts removed by vacuum filtration, and the filtrate was concentrated under reduced pressure. The residual light yellow solid was chromatographed on silica gel using ethyl acetate-hexane to provide N-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as white crystals. MS m/z 461.2 (M+H).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19](CO)=[C:20]([CH:29]([CH3:31])[CH3:30])[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][C:20]([CH:29]([CH3:31])[CH3:30])([CH:2]=[O:3])[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1CO
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C1(C=O)CC(c2ccc(F)cc2)=C(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.92 g of oxalyl chloride in 50 ml of methylene chloride at -78° was added dropwise a solution of 2.22 g of dimethylsulfoxide in 25 ml methylene chloride. After stirring at -78° for 10 minutes, a solution of 4.0 g of the title methanol product of Step 1, above, in 30 ml of methylene chloride was added dropwise. The mixture was stirred at -78° for 1 hour. Then 2.5 g of triethylamine was added. The mixture was allowed to warm to R.T., then was poured into water. The organic phase was separated and the solvent was removed under reduced pressure. The residue was dissolved in MTBE and washed with water. The organic solution was dried, and the solvent was removed under reduced pressure to give 3.8 g or the title product of this step. A sample of which was triturated with pentane to give refined product. M.P. 116°-120°.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8](=[CH2:28])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])=[O:5])C.C[N+]1([O-])CC[O:33]CC1.[O-]S([O-])=O.[Na+].[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[OH:33][CH2:28][C:8]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])[O:5][C:4](=[O:3])[CH2:6][CH2:7]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(CCC(=O)OCC)CCC(=O)OCCCCCCCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCOC(=O)CCC1(CO)CCC(=O)O1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
A stirred solution of olefin 3.18 (0.115 g, 0.29 mmol) in t-BuOH (3 mL) and water (1 mL) at 0° C., containing N-methyl morpholine N-oxide (0.069 g, 0.59 mmol), was treated with 2.5% OsO4 solution (0.16 mL). The reaction mixture was brought to room temperature slowly and stirred for 12 h; Na2SO3 (200 mg) was added and, after stirring for a few more minutes, it was concentrated under suction. The residue was extracted with EtOAc (3×10 mL) and the combined extract was washed with water (1×10 mL) and dried (Na2SO4). The residue obtained after evaporation of the solvent was purified by flash column chromatography over silica gel using hexane:EtOAc (3:2) as eluant to give 3.2 (0.070 g ,63%) as white solid; m.p. 61° C. (EtOAc/hexane); IR (KBr) 3380 (OH) and 1728 (C=O) cm-1 ; 1H NMR (CDCl3) δ 0.85 (distorted t, 3H, CH3 (CH2)13), 1.10-1.40 (m, 22H, CH3 (CH2)11CH2CH2OCO), 1.60 (m, 2 H, CH3 (CH2)11CH2CH2OCO), 1.86-2.12 (m, 4 H, H-4, CH2CH2COOC14H29), 2.25-2.78 (multiplets, 4 H, H-3, CH2CH2COOC14H29), 2.90 (t, J=6.5 Hz, 1 H, OH), 3.50 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 3.65 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 4.05 (t, J=6.7 Hz, 2 H, CH3 (CH2)11CH2CH2OCO); 13C NMR (CDCl3) δ 14.09, 22.65, 25.85, 28.05, 28.33, 28.51, 29.15, 29.21, 29.32, 29.48, 29.55, 29.61, 30.97, 31.88, 65.16, 66.41, 87.54, 173.28, 177.03; FAB MS m/z (relative intensity) 385 (38, MH+), 171 (100, MH-C14H29OH). Anal. Calcd for C22H40O5 : C, 68.7; H, 10.49. Found: C, 68.63; H, 10.44.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[BrH:13].C([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.O>[Br:13][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH:1]1[OH:7]
Reactant: Br
Reactant: CCOC(=O)C1CCC2OC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Br)C(O)C1
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate (17.8 g) in CH2Cl2 (350 mL) was added 40% HBr solution (120 mL). The biphasic mixture was stirred vigorously for 25 min, then was neutralized with aqueous NaHCO3 solution. The organic layer was collected and dried over MgSO4, then was concentrated in vacuo. The residue was diluted with toluene (120 mL), and para-toluene sulfonic acid (120 mg, 0.6 mmol) was added. The mixture was heated at 128° C. with azeotropic removal of water over 3.5 hours, then was concentrated in vacuo to afford 21 g of a brown residue, which was used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([C:21]3[S:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([C:21]3[S:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:13]=2)=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A 100-mL round bottomed flask was charged with 2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzoic acid (impure, obtained from several reactions on 1.3 mmol scale), THF (20 ml). To the mixture was added BH3 (1N in THF, 7.5 ml). The resulting mixture was stirred at rt overnight. Then treated with 2N HCl aq. (10 ml) followed by sodium bicarbonate to pH=7. The mixture was extracted with ethyl acetate (3×10 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using 0.5% of methanol in dichloromethane to give the title compound (198 mg, 35% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:30][C:31]#[N:32]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCOC(C)=O>[NH2:32][CH2:31][CH2:30][N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1
Reactant: CC#N
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: NCCN1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
N-[1-(2-Aminoethyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (114) was prepared as follows. A mixture of compound 19 (0.5 g, 1.4 mmol), compound 113 (160 mg, 1.3 mmol, Aldrich), K2CO3 (1.0 g, 7.2 mmol), KI (10 mg) and benzyltriethylammonium chloride (20 mg, 0.07 mmol, ACROS) in 4 mL of CH3CN was shaken at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with water (4 mL) and brine (4 mL), concentrated and purified by column (Silica gel, EtOAc/MeOH/NH4OH 100/10/1) to give the title compound 114 as a free base, which was converted to its HCl-salt by treating with 1N HCl and dried (HCl-salt, white solid, yield 30%): 1H NMR (400 MHz, CD3OD, HCl-salt): δ 8.22 (d, 1H, 7.9 Hz), 8.18 (s, 1H), 8.04 (d, 1H, 7.9 Hz), 7.88 (dd, 1H, 7.8 & 7.9 Hz), 4.24-4.31 (m, 1H), 3.69-4.73 (m, 2H), 3.44-3.47 (m, 4H), 3.2-3.26 (m, 2H), 2.45-2.59 (m, 2H), 2.08-2.11 (m, 1H), 1.88-1.92 (m, 2H), 0.95-0.98 (m, 2H), 0.85-0.88 (m, 2H); LC: 100%; MS: m/z=510 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:20]1[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=1)[CH3:15]
Reactant: Cn1cccc1C=O
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: Cn1cccc1CNC(C)(C)COc1ccc2ccccc2c1Cl
Yield: 39 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and methyl-1H-pyrrole-2-carbaldehyde in 39% yield as a red oil.