Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.[CH3:74][S:75](Cl)(=[O:77])=[O:76]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][S:75]([CH3:74])(=[O:77])=[O:76])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOS(C)(=O)=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylene chloride (1.0 mL) was added triethylamine (23 μL) followed by methanesulfonyl chloride (7.2 μL) and the mixture stirred at room temperature. After 10 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic portion dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol) gave the title compound (74 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:25][C:26]([CH3:28])=O>C(O)(C(F)(F)F)=O>[CH3:25][C:26]1([CH3:28])[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[C:6](=[O:8])[O:7]1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2c(c1)OC(C)(C)OC2=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 27 %

Procedure:
To a stirred suspension of 4-methylsalicylic acid (50 g, Aldrich) in TFA (320 mL) under nitrogen was added TFAA (105 mL) followed by dry acetone (60 mL). The reaction mixture was heated to 65° C. for 5 hours. At this time was added another portion of acetone (50 mL) and heating was continued for 15 hours. The solvent was removed under reduced pressure and the residue was taken up with Et2O (250 mL). The organic layer was washed with a 10% aqueous solution of NaHCO3 (2×100 mL), brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by chromatography (Pet Ether/EtOAc 98/2) to give 17 g (27%) of the titled compound as a liquid. TLC-Pet. Ether/EtOAc (9/1): Rf=0.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][N:34]1[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]2[C:30]1=[O:40]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1c(Br)cncc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzylic alcohol 18 (300 mg, 1.13 mmol), triphenylphosphine (357 mg, 1.36 mmol) and phthalimide (200 mg, 1.36 mmol) in dry THF (10 mL) was added DIAD (0.26 mL, 1.36 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 24 hours after which solvents were evaporated under reduced pressure. The crude product mixture was purified by chromatography on silica gel to give the title compound 19 as a white (300 mg, 0.762 mmol, 67%). 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 2H), 7.88-7.83 (m, 2H), 7.78-7.75 (m, 2H), 5.13 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.1, 151.8, 142.7, 135.1, 132.4, 124.4, 43.3; MS (ESI) Calculated for C14H9N2O2Br2[M+H]+: 397.04. Found: 396.90.
Reaction SMILES: Br[CH:2]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:21][C:3]1([NH2:37])[NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH2:40]([C:56]1[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[NH2:37][C:3]1([CH:2]=[CH:24][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:22][CH:21]1[O:62][C:59]1[CH:58]=[CH:57][C:56]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:61][CH:60]=1)[NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCC1=CC(Br)C(N)(Nc2cccc3c2C(=O)c2ccccc2C3=O)C=C1
Reactant: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCc1ccc(OC2C=C(CCCCCCCCCCCC)C=CC2(N)Nc2cccc3c2C(=O)c2ccccc2C3=O)cc1

Procedure:
A mixture of 56 g of 2-bromo-1-amino-p-dodecyl-anilino-anthraquinone, 10 g of caustic soda powder and 700 g of p-n-hexadecylphenol was heated at 170°-175° C. for 4 hours. Then, 2000 g of a 5% aqueous solution of caustic soda were added thereto, and the resulting blue precipitate was recovered by filtration, washed sufficiently and dried to yield 1-amino-2-p-n-hexadecylphenoxy-4-dodecylanilinoanthroquinone. The reaction is expressed by the following formula: ##STR11##
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([CH:35]=1)[C:30](OCC)=[O:31]>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[CH2:19][N:18]([CH3:24])[CH2:17][CH:16]2[C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([CH:35]=1)[C:30]([NH:10][C:9]([NH2:11])=[NH:8])=[O:31]
Reactant: CCOC(=O)c1cc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)ccc1O
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(O)c(C(=O)NC(=N)N)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
2.52 g of potassium tert-butoxide was added to a solution of 2.39 g (25 mmol) of guanidine hydrochloride in 15 ml of abs. DMF and stirred at room temperature for 45 min. A solution of 950 mg (2.5 mmol) of ethyl 5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate (example 29, intermediate 3) in 10 ml of abs. DMF was added, and the mixture was stirred at room temperature for four hours. After no further increase in conversion was detectable, the precipitate was removed by filtration with suction and the solvent was removed in vacuo. The residue was taken up in 2 N HCl and extracted twice with dichloromethane. The aqueous phase was adjusted to a pH of about 10 with KOH, whereupon the desired acylguanidine separates out as a colorless precipitate. Filtration with suction and drying affords 793 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15](OCC)=O)=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].C=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:15])=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Agent: C=O
Product: Cc1[nH]c(C)c(CCC(=O)O)c1C

Procedure:
2,4-Dimethyl-3-carbethoxy ethyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-carboxyethyl-pyrrole. ##STR110##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:16]3[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:13][C@@H:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](=[O:24])[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)=[C:16]3[CH:15]=2)[CH2:10]1)(=[O:54])=[O:53]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](OS(C)(=O)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-33) (150 mg, 0.26 mmol) in DCM (anhyd, 2 mL) at 0° C. was added triethylamine (0.070 mL, 0.5 mmol) followed by dropwise addition of methanesulfonyl chloride (28 μL, 0.36 mmol). After stirring 2 hours at room temperature the reaction mixture was concentrated under reduced pressure. The resulting solid was taken up in EtOAc and washed twice with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (3R,5R)-1-(3-(bis(4-methoxybenzyl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-5-(3-fluorophenyl)pyrrolidin-3-yl methanesulfonate (I-34), which was used without further purification. MS m/z 659.2 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][O:21]C)[N:14]=2)=[CH:9][CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:24][C:2]([F:1])([F:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][OH:21])[N:14]=2)=[CH:11][CH:12]=1
Reactant: COCCn1nc(-c2ccc(OCCCC(F)(F)F)cc2)oc1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1oc(-c2ccc(OCCCC(F)(F)F)cc2)nn1CCO
Yield: 29.8 %

Procedure:
To a solution of 0.70 g of 5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-methoxyethyl-1,3,4-oxadiazol-2(3H)-one in 10 ml of dichloromethane are added dropwise 1.2 g of boron tribromide. The mixture is left to react overnight and is then treated with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated. The crude product obtained is purified on a column of silica with a 1/1 mixture of ethyl acetate and heptane. 200 mg of product are obtained.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][CH2:15][CH2:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: BrCCCBr
Reactant: Oc1cccc2c1CCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: BrCCCOc1cccc2c1CCCC2
Yield: 66.5 %

Procedure:
The title compound was prepared according to the procedure of Example 7 using 5,6,7,8-tetrahydronaphthalene-1-ol (10 g, 0.067 mol) in methylene chloride (100 ml), sodium hydroxide (5.5 g, 0.134 mol) in water (100 ml), 1,3-dibromopropane (47 g, 0.23 mol) and tetra-n-butylammonium bisulfate (23 g, 0.067 mol). Chromatography of the crude product on silica gel using 1% ethyl acetate/hexane as eluent gave 12 g (60%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:34])C=C.O>C(#N)C.CCCCCC>[Br:34][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: C=CCBr
Reactant: OCCCc1ccc(F)c(Oc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCC
Solvent: CC#N
Solvent: O
Product: Fc1ccc(CCCBr)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To 5.30 g (0.0215 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propanol in 18 mL of dry acetonitrile wa added first 3.5 g (0.022 mole) of 1,1'-carbonyldiimidazole and then 13.0 g (0.107 mole) of allyl bromide. After stirring at room temperature for 1.5 hours the reaction mixture was heated at gentle reflux for two hours. The reaction mixture was poured into water, and this mixture was extracted twice with diethyl ether. The combined extracts were washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, an aqueous solution of sodium thiosulfate, water, and a saturated aqueous solution of sodium chloride. The organic solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving an oil as a residue. The residue was dissolved in approximately 50 mL of hexane and the solution was filtered through a pad of silica gel. Evaporation of the solvent from the filtrate yielded 4.4 g of 1-bromo-3-(4-fluoro-3-phenoxyphenyl)propane as a colorless oil.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]2[C:63]([O:80][CH3:81])=[CH:64][C:65]3[C:71](=[O:72])[N:70]4[CH:73]=[C:74](/[CH:76]=[CH:77]/[CH3:78])[CH2:75][C@H:69]4[CH:68]=[N:67][C:66]=3[CH:79]=2)=[CH:55][C:12]2[N:13]=[CH:14][C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25][C:26](=[O:54])[C@@H:27]([NH:29][C:30](=[O:53])[C@@H:31]([NH:35]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)[CH:32]([CH3:34])[CH3:33])[CH3:28])=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C.C(Cl)Cl>[NH2:35][C@@H:31]([CH:32]([CH3:34])[CH3:33])[C:30]([NH:29][C@@H:27]([CH3:28])[C:26]([NH:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[CH:14]=[N:13][C:12]3[CH:55]=[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]4[C:63]([O:80][CH3:81])=[CH:64][C:65]5[C:71](=[O:72])[N:70]6[CH:73]=[C:74](/[CH:76]=[CH:77]/[CH3:78])[CH2:75][C@H:69]6[CH:68]=[N:67][C:66]=5[CH:79]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1)=[O:54])=[O:53]
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Piperidine (0.04 mL, 4.1 mmol, 13.7 eq.) was added to a stirring mixture of Fmoc amine 19c (0.030 g, 0.0295 mmol, 1 eq.) in anhydrous DMF (0.5 mL) and the mixture was stirred at ambient temperature. After 20 minutes, LCMS showed reaction was completed so the reaction mixture was diluted with DCM (75 mL) and washed with water (3×75 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Co-evaporation with n-hexanes afforded the product as a brown oil, and the material was not subjected to further purification (0.023 g, assumed 100%). LC/MS (1.868 min (ES+)), m/z: 794.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1
Reactant: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2ccc(F)cc2)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.82-7.88 (m, 2H), 7.06-7.12 (m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 5.2 (s, 2H), 3.68-3.84 (m, 4H), 3.06-3.18 (m, 4H), 2.4 (s, 3H). 13C NMR (400 MHz, CDCl3): 164.8, 158, 147, 135, 127.4, 127, 119, 112.4, 112.2, 110, 108.8, 52.8, 52, 51.8, 45.4, 42.2, 18.6.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: O=C1CCCC1
Reactant: CC[C@@H](N)c1nnco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](NC1CCCC1)c1nnco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
(1R)-1-(1,3,4-oxadiazol-2-yl)propan-1-amine (610 mg, 4.798 mmol) in THF (6.972 mL) was treated with cyclopentanone (407.6 mg, 428.6 μL, 4.846 mmol) then acetic acid (288.1 mg, 272.8 μL, 4.798 mmol). The reaction was stirred at ambient temperature for 20 minutes then treated with sodium triacetoxyborohydride (1.485 g, 7.005 mmol). The reaction was stirred at ambient temperature for 5 hours then basified with aqueous NaHCO3. The mixture was extracted with DCM (×10), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/petrol) to give the sub-title compound as a colourless solid (694 mg, 74%); 1H NMR (400.0 MHz, CDCl3) d 0.81 (3H, t), 1.10-1.87 (10H, m), 2.85 (1H, m), 3.95 (1H, t), 8.33 (1H, s); MS ES (+) 196.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([S:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1.NN>CCO>[NH2:3][CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([S:22][C:23](=[O:27])[N:24]([CH3:25])[CH3:26])[CH:16]=[CH:15][C:14]=2[CH2:13]1
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CCC(N1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: CCO
Product: CN(C)C(=O)Sc1ccc2c(c1)CCC(N)C2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 103.7 %

Procedure:
A 3-neck flask, equipped with a reflux condensor and mechanical stirrer, is charged with EtOH (115 mL) and dimethylthiocarbamic acid S-[6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl] ester (8.7 g; 23.5 mmol). Hydrazine (6.6 mL; 2.11 mol) is added in 1-portion at RT and the reaction was refluxed with mechanical stirring for 40 min. The reaction is cooled to RT and the gelatinous, white solid is filtered and washed thoroughly with ether. The ether washes are combined, evaporated under reduced pressure and the crude residue was further triturated with ether, filtered and the ether evaporated under reduced pressure to afford 6.1 g (100%) of dimethylthiocarbamic acid S-[6-amino-5,6,7,8-tetrahydronaphthalen-2-yl) ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16][N:17]([CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:18][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(NCC1(c2ccc(I)cc2)CCNCC1)c1ccc(F)c(Cl)c1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)c1ccc(F)c(Cl)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3-chloro-4-fluoro-N-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-benzenesulfonamide (0.0321 g, 0.04 mmol) in ClCH2CH2Cl (0.5 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.005 mL, 0.048 mmol, 1.2 eq) and HOAc (0.05 mL, 1%v/v). The mixture was stirred for 0.5 h. Na(OAc)3BH (0.015 g, 0.06 mmol, 1.5 eq) was added and the mixture stirred for 16 h, diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, then dried under high vacuum to give 3-chloro-N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-4-fluorobenzenesulfonamide (0.047 g, 0.04 mmol, 95%). MS (ESI): 563.1/565.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5](CC)=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([O-:9])=[O:8])([O-])=O.[CH2:25](O)[CH3:26]>C(O)(=O)C>[CH2:15]([C:14]1[NH:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:25][CH3:26])=[O:8])[CH:10]=[CH:11][C:12]=2[N:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCc1c(C(=O)[O-])ccc(NC(=O)Cc2ccccc2)c1[N+](=O)[O-]
Reactant: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1

Procedure:
A mixture of 3-nitro-4-phenylacetylamino-ethylbenzoate (3.60 g), ethanol (47 ml), acetic acid (23 ml) and reduced iron (6.4 g) is refluxed for four hours. Solids are separated through filtration and the filtrate is concentrated. Ethanol (50 ml) and 35% hydrochloric acid (5 g) are added to the residue and the solution is refluxed for 40 hours. The solution is neutralized with sodium bicarbonate and chloroform extraction is performed. The organic layer is concentrated under reduced pressure and then purified using silica gel column chromatography. Thus, 2-benzyl-5-ethoxycarbonylbenzimidazole (2.30 g) is obtained. 1H-NMR (CDCl3, δ): 1.39 (3H, t, J=7.1 Hz), 4.26 (2H, s), 4.37 (2H, q, J=7.1 Hz), 7.22-7.36 (5H, m), 7.50 (1H, d, J=8.6 Hz), 7.94 (1H, dd, J=1.5 and 8.6 Hz), 8.23 (1H, d, J=1.3 Hz).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>>[C:1]([N:19]1[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(C)N1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCN(C(C)C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-isopropylpiperazine as starting raw materials, to produce an intended compound.