Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].N1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:16]([C:5]1([CH2:4][CH2:3][CH:2]=[CH2:1])[CH2:13][C:11](=[O:12])[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10]1)[CH2:17][CH:18]=[CH2:19]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: C=CCCC1(CCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Yield: 208.4 %

Procedure:
A mixture of 719 mg (5.21 mmol) of the title product of Example 63, 970 mg (5.00 mmol) of 2,4-dihydroxy-3-propylacetophenone, 360 mg (5.00 mmol) of pyrrolidine, and 5.5 ml of toluene containing 2.0 g of 3A molecular sieves was stirred at reflux for six hours, then kept overnight at room temperature. The solution was then decanted from the sieves, and the sieves were washed with methylene chloride. The solvent was then removed under reduced pressure. Chromatography of the residue over silica gel, using 14:5:1 methylene chloride:hexane:ethylacetate as eluent, gave the title compound (439 mg) as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15]>CN(C)C=O>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(Br)ccnc1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N=[N+]=[N-])ccnc1C#N

Procedure:
To 1 g (0.0155 moles) of sodium azide in 25 mL of dimethylformamide at 0° C., there is added gently 3 g (0.0141 moles) of 4-bromo-2-cyano-3-methoxypyridine from Example b), dissolved in 40 mL of dimethylformamide.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[S:30]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCC2=S)CC1
Yield: 128.7 %

Procedure:
A solution of tert-butyl 2-oxo-1,4′-bipiperidin-1′-carboxylate (2.8 g) and Lawesson's reagent (2.0 g) in toluene (30 mL) was refluxed for one hour. Toluene was distilled off under reduced pressure, and the residue was diluted with dichloromethane, and washed with an aqueous 1N sodium hydroxide solution and saturated saline solution. This dichloromethane solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/2) to obtain the title compound (1.9 g, 64%) as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>CCOCC.CCCCCC>[CH3:13][O:12][C:3]1[C:2]([CH:21]=[O:22])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: CN(C)C=O
Reactant: COc1ncc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ncc(C(F)(F)F)cc1C=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.18 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 50 ml of ether was cooled to -100° C. and blanketed with nitrogen. A solution containing 0.024 mole of butyl lithium in hexane (15.0 ml of 1.6 M) was added slowly with stirring keeping the temperature below about -95° C. and the mixture was allowed to react for another 15 min. Dimethylformamide (7.5 ml, 0.097 mol) was added to the mixture at below -95° C. and stirring continued for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and 1N hydrochloric acid. The mixture that formed was extracted with ether and the extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled in a Kugelrohr apparatus to obtain 3.6 g (86 percent of theory) of the title compound as an oil which solidified to a white crystalline solid. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(Br)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 419 [M+1]+.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>N1C=CC=CC=1.C(Cl)Cl>[CH3:2][NH:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methylamine hydrochloride (1.4 g) in pyridine (5 ml) was added 4-acetamidobenzenesulfonyl chloride (2.3 g), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (50 ml), washed with water, 1N hydrochloric acid, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(acetamido)benzenesulfonamide (1.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:19][CH2:18][CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCC1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (6.5 g, 29.5 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (4.25 g, 36.9 mmol) and potassium carbonate (16.33 g, 118 mmol) in N,N-dimethylformamide (130 mL) was heated at 80° C. for 1 hour. After cooling, the mixture was diluted with 400 mL ethyl acetate. The mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1.[CH3:16][C:17]([CH3:19])=O>>[C:17](=[N:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1)([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: NCC1CCSc2[nH]c3ccccc3c21
Product: CC(C)=NCC1CCSc2[nH]c3ccccc3c21
Temperature: 50 °C

Procedure:
A solution of 4-aminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.0 g) in acetone (10 ml) is kept at room temperature for 30 minutes and then heated at 50° C. for 5 minutes. The solution is cooled with ice. The colorless precipitate is collected by filtration to give 4-isopropylideneaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.07 g) melting at 173° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:14]1=2.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccc(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2cc(C#N)ccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-5-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (68 mg, 88.2 μmol) in CH2Cl2 (353 μl) was added TFA (88.2 μl). The reaction was stirred at rt for 2.5 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((2S,3S)-5-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide 2,2,2-trifluoroacetate (68.6 mg, 99%) as a white solid. MS m/z 670/672 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([C:11]3[S:12][C:13]4[C:18]([N:19]=3)=[CH:17][CH:16]=[C:15]([C:20]3([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:21][CH2:22]3)[N:14]=4)=[C:2]([F:1])[CH:3]=2)[CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (93 mg, 0.238 mmol) and cyclopropanamine (20 μl, 0.286 mmol). MS (ESI) m/z: Calculated: 429.1; Observed: 430.1 (M++1).
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1>C(Cl)Cl>[C:10]([Si:7]([O:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1C=CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Pyridine (4.74 g, 60 mmol) and tert-butyldimethylsilyl chloride (4.83 g, 32 mmol) were added to a solution of cyclohex-2-enol (1.96 g, 20 mmol) in DCM (40 mL). The reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dispersed in EtOAc and water. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica flash chromatography eluting with EtOAc and petroleum ether (5-10% EtOAc) to give the title compound as an oil (4.1 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 0.06-0.09 (m, 6 H), 0.92 (s, 9 H), 1.50-1.57 (m, 2 H), 1.74-1.89 (m, 2 H), 1.93-2.03 (m, 2 H), 4.21-4.23 (m, 1 H), 5.61-5.64 (m, 1 H), 5.72-5.76 (m, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][C:20]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C>[N:25]1([C:22]2[CH:23]=[CH:24][C:19]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[C:20]([N+:30]([O-:32])=[O:31])[CH:21]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: O=[N+]([O-])c1cc(-n2ccnc2)ccc1Cl
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-n2ccnc2)ccc1Sc1cccc2cnccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 360 mg (2.2 mmol), DMF 9 ml, potassium carbonate 600 mg (4.3 mmol) and 1-(4-chloro-3-nitrophenyl)-1H-imidazole 420 mg (2.0 mmol) was stirred at 100° C. for 2.5 hours, and 5-[4-(1H-1-imidazolyl)-2-nitrophenylsulfanyl)isoquinoline 680 mg (97.6%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:31](=[O:32])[CH2:30][C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 27.9, 28.1, 35.9, 42.7, 46.8, 51.8, 53.1, 56.3, 102.2, 102.5, 102.7, 105.1, 112.2, 112.3, 112.4, 112.5, 131.3, 137.9, 139.2, 161.8, 164.2, 164.3, 169.4, 169.9, 170.0; MS 451.2 m/z (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: ClCCCCn1ccc2ccccc21
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCCC(=O)Nc1ccc(C2CCN(CCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(4-chlorobutyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH2:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1
Yield: 74 %

Procedure:
The same procedure as employed in the preparation of Example 228 (step a) using 4-amino-N-dodecylbenzamide (Example 150, step b) and 4-(trifluoromethyl)benzaldehyde gave the title compound as colorless oil (74%). 1H NMR(DMSO-d6, 300 MHz) δ 7.68 (d, 2H, J=8.3 Hz), 7.47-7.60 (m, 4H), 6.53 (d, 2H, J=8.6 Hz), 4.41 (s, 2H), 3.31 (s, 2H), 3.14 (t, 2H, J=6.8 Hz), 1.35-1.51 (m, 2H), 1.11-1.32 (m, 18H), 0.83 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 7.00 min (HPLC purity: 91.2%).
Reaction SMILES: O=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.O.[NH2:14][NH2:15]>C(O)CCC>[NH:14]([CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1)[NH2:15]
Reactant: NN
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: O
Solvent: CCCCO
Product: NNC1NS(=O)(=O)c2ccccc21
Yield: 91.1 %

Procedure:
36.6 g (0.2 mol) of 3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide and 20 g of hydrazine hydrate in 200 ml of n-butanol are boiled under reflux for about 35 hours. The yellow solution is then evaporated down in vacuo, and the residue is stirred with 50 ml of acetic acid. The crystal slurry is filtered under suction, and the crude product which is obtained in this manner and has a melting point of 249° C. can be recrystallized from water. 36.3 g (91% of theory) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 263° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([S:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].ClC1C=CC=C(C(OO)=O)C=1.[OH2:30].[OH2:31].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:18][C:2]([F:1])([S:13]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:31])=[O:30])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: OCCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 93.1 %

Procedure:
3-(Perfluorobutylthio)propanol (8.60 g, 27.6 mmol) prepared in Synthetic Example 1 was dissolved in methylene chloride (80 ml), and m-chloroperbenzoic acid (m-CPBA) (52 g, 232 mmol) was added at room temperature in two portions with stirring, the reaction vessel being equipped with a calcium chloride tube. The mixture was stirred at room temperature for 7 days. The reaction mixture was injected into a mixture of sodium thiosulfate pentahydrate (130 g) and water (200 ml), and stirred for 1 hour. Methylene chloride (100 mL) was added and an organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a 5% aqueous sodium hydrogen carbonate and with a saturated saline solution, and then dried over sodium sulfate. A filtrate after filtration was concentrated at reduced pressure. A residue was subjected to a silica gel column chromatography (eluting solvent: hexane/ethyl acetate (2/1)), and fractions having Rf value of 0.32 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered, concentrated at reduced pressure and dried at vacuum to give crystalline 3-(perfluorobutylsulfonyl)propanol (8.79 g). Yield: 91.8%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:18]([N:24]([CH3:26])[CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][CH2:3][C:4]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1)[N:24]([CH3:26])[CH3:25])=[O:5]
Reactant: CN(C)C(CCCCO)C1(c2ccc(Cl)cc2)CCC1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COCC(=O)OCCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 24 h

Procedure:
Methoxyacetyl chloride was added dropwise to a solution of the product of Example 144 and triethylamine in ether and the mixture stirred for 24 hours and then poured into ice-cold aqueous sodium hydroxide solution. The mixture was extracted with ether and the extract washed, dried and evaporated to give an oil. which was purified by flash chromatography on a silica column using ether as eluant to give 5-[1-(4-chlorophenyl)cyclobutyl]-5-dimethylaminopentyl 2-methoxyacetate as an oil the boiling point of which was not determined.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([OH:11])[CH:3]=1.C(N1C=CN=C1)([N:14]1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[N:14][O:11][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc2cc(F)ccc12

Procedure:
A mixture of 4′-fluoro-2′-hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to just under reflux, treated with a solution of 1,1′-carbonyldiimidazole (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol) in tetrahydrofuran, refluxed for one hour, cooled, concentrated in vacuo, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as a yellow oil which is identified by 1H NMR spectral analysis.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]1[O:34][CH:9]1[C:10]1[N:14]=[CH:13][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]=1)[CH3:6].[ClH:37]>>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]([OH:34])[CH:9]([Cl:37])[C:10]1[N:14]=[CH:13][NH:12][N:11]=1)[CH3:6]
Reactant: CCC(CC)C1OC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cl
Agent: O=[PH](O)O
Product: CCC(CC)C(O)C(Cl)c1nc[nH]n1

Procedure:
Diethyl (2RS,3RS)-2,3-epoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.39 g, prepared as described in Example 52) was treated with hydrochloric acid, as described in Example 53 for the (RS,SR) isomer, to give diethyl (2RS, 3RS)-3-chloro-2-hydroxy-3(1,2,4-triazol-3-yl)propane phosphonate (0.21 g) as a colourless oil, probably as its hydrochloride. NMR(D2O): δ 1.15(6H,t), 2.15(2H,m), 4.00(4H,m), 4.45(1H,m), 5.17(1H,d), 8.75(1H,s). (No internal standard, solvent signal at δ 4.67).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=12.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:17]1[CH:16]=[C:15]([C:3]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][N:5]3[N:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 44.7 %

Procedure:
To a solution of the 3-bromo-2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (50 mg, 0.139 mmol) in DMF (5 ml) was added 4-methanesulfonylphenylboronic acid (37 mg, 1.3 eq), ground potassium phosphate (83 mg) and tetrakis(triphenylphosphine)palladium(0) (10 mg) and the mixture heated to 90° for 18 h under N2. The cooled mixture was poured into water (10 ml) and extracted into ethyl acetate (4×10 ml). The combined organic phases were washed sequentially with water, brine, 2N sodium hydroxide and brine, dried and concentrated in vacuo to give the title compound as an off-white solid (27 mg, 45%). MH+ 435