Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C.[O-][V](=O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: O=[V](=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 8 h
Yield: 385.3 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (10.0 g) was dissolved in ethanol (75 ml), to which was added a solution of sodium metavanadate (15 mg) in 35% aqueous solution of hydrogen peroxide (3.07 g), and allowed to react by stirring at 20°-25° for about 8 hours. After completion of the reaction an aqueous solution of sodium thiosulfate (1 g/5 ml) was added to the reaction mixture, which was stirred vigorously for about 10 minutes. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (1:1). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 50 ml), heated (65°-70° C.) and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization, and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (9.0 g). (yield: 90.5%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.C(OCC)C>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]([OH:27])[CH2:1][CH3:2])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 10° C., 1.1 ml (1.1 mmol) of a 1 M solution of ethylmagnesium bromide in THF were added dropwise to 300 mg (0.99 mmol) of 1-benzyl-3-(5-formyl-2-furyl)indazole in 20 ml of diethyl ether. After 1 h at 10° C., the mixture was poured into ice-water and extracted with ethyl acetate, dried and concentrated. The crude product was purified by silica gel chromatography using dichloromethane/methanol (95:5). This gave 200 mg (61%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>C1(C)C=CC=CC=1>[S:24]1[CH2:23][CH2:22][CH2:21][S:25][CH:1]1[C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1
Reactant: SCCCS
Reactant: Cn1cncc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cncc1C1SCCCS1
Yield: 63.9 %

Procedure:
8.3 g (75.4 mmol) of 5-formyl-1-methylimidazole are dissolved in 120 ml of toluene, and 17.1 g (89.9 mmol) of 4-toluenesulfonic acid monohydrate are added. After addition of 8.12 g (75.0 mmol) of 1,3-propanedithiol, the suspension obtained in this way is boiled under reflux with a water trap. It is subsequently washed with 4N sodium hydroxide solution, and the organic phase is dried over sodium sulfate and concentrated in vacuo until crystallization starts. After storage in a refrigerator overnight, 9.6 g (47.9 mmol, 64%) of 5-(1,3-dithian-2-yl)-1-methylimidazole are obtained as a white solid of melting point 111.5°-112.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 2,5-dimethoxyaniline and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and isolated as a green-yellow solid (46 mg, 64%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.79 (dd, J=1.8, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.80 (bs, 1H), 7.70 (s, 1H), 7.07 (s, 1H), 6.91 (d, J=9.3 Hz, 1H), 6.72 (dd, J=3.0, 9.0 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(N)C3)c(Cl)c21
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 72 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6][CH:5]=2.[H-].[Na+].[C:22](=O)([O:26]C1C=CC=CC=1)[O:23][CH2:24][CH3:25].O>CN(C)C=O.C(O)(=O)C>[C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:8]=2)[NH:3][C:2]=1[NH:1][C:22](=[O:26])[O:23][CH2:24][CH3:25])#[N:12]
Reactant: CCOC(=O)Oc1ccccc1
Reactant: N#Cc1c(N)[nH]c2ccc(Sc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1[nH]c2ccc(Sc3ccccc3)cc2c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of 2-amino-3-cyano-5-(phenylthio)indole (1.5 g., 5.7mM.) in dimethyl formamide (20 ml.) was added sodium hydride (0.27 g., 50% w/w dispersion in mineral oil, 5.7mM.) followed by ethyl phenyl carbonate (0.94 g., 5.7mM.). The mixture was stirred overnight and allowed to warm to room temperature. T.l.c. indicated the reaction was complete. The reaction mixture was poured into rapidly stirred water and neutralised with acetic acid. The cream-coloured precipitate was filtered off and dried to give the crude product (1.62 g.) m.p. 181°-2° C. Recrystallisation from ethanol gave colourless crystals of ethyl 3-cyano-5-(phenylthio)indol-2-ylcarbamate, m.p. 190.5°-191.5° C. (0.82 g., 43%). ##STR2##
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8](N)=[O:9]>O.OS(O)(=O)=O>[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8]([OH:2])=[O:9]
Reactant: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A solution of NaNO2 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in conc. H2SO4 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 18 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting mixture was extracted with Et2O (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, 1H).
Reaction SMILES: [OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C:10](=[CH2:22])[CH2:9]3.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C=O.[CH3:33]CCCCC.C(OCC)(=O)C>N(CCO)(CCO)CCO>[OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([CH2:33][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13](=[O:21])[CH2:14][CH2:15]1)[C:10](=[CH2:22])[CH2:9]3
Reactant: Sc1ccccc1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Reactant: CCCCCC
Agent: C=O
Solvent: CCOC(C)=O
Solvent: OCCN(CCO)CCO
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)CCC(=O)C(CSc3ccccc3)=C12

Procedure:
Analogously to Example 6(a), 200 mg of 17β-hydroxy-17α-methyl-6-methyleneandrost-4-en-3-one (Tetrahedron 20: 597, 1964) is reacted with thiophenol and formaldehyde in triethanolamine. After chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient, 190 mg of 17β-hydroxy-17α-methyl-6-methylene-4-(phenylthiomethyl)androst-4-en-3-one is obtained as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CO>CN(C)C=O.C(O)(=O)C>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:40][CH2:39]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(CNc3nc4ccccc4[nH]3)CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 1-methyl-1H-indole-2-carboaldehyde (0.26 mmol) and sodium triacetoxyborohydride (0.26 mmol) to a solution of (1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (20.0 mg, 0.09 mmol) in dimethylformamide-acetic acid (10:1) (1.0 ml), the mixture was stirred at room temperature overnight. Methanol (1.0 ml) was added to the reaction mixture to suspend the reaction, and after stirring for 1 hour, the solution was passed through SCX (Bond Elute SCX500MG: cationic ion-exchange resin, Varian). The SCX was washed with methanol and then with a mixed solution of chloroform/methanol (1/1), and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain (1H-benzimidazol-2-yl)-[1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-4-ylmethyl]-amine. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)(O)=[O:2].Cl.[NH2:47][C@H:48]([C:52]([NH2:54])=[O:53])[CH:49]([CH3:51])[CH3:50].C(P(C#N)(CC)=O)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:52]([C@@H:48]([NH:47][C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])[CH2:12]2)[S:7][CH:8]=1)=[O:2])[CH:49]([CH3:51])[CH3:50])(=[O:53])[NH2:54]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.6 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.48 mmol) (obtained as described in Reference Example 41(7)) and L-valinamide hydrochloride (272 mg, 1.78 mmol) obtained as described in Reference Example 47(2) in dimethylformamide (50 ml) were added diethylphosphoryl cyanide (275 μl, 1.78 mmol) and diisopropylethylamine (620 μl, 3.56 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→methylene chloride:ethyl acetate (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-carbamoyl-2-methylpropylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (934 mg, yield 82%).
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.C(OC(=O)[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:32]=2)=[CH:26][N:25]=1)=S)C>CO>[C:41]([O:40][C:38](=[O:39])[NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:27]2[CH:28]=[CH:29][C:24]3[N:25]([N:6]=[C:21]([NH2:20])[N:23]=3)[CH:26]=2)[CH:32]=1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (4.34 g, 62.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (12.7 mL, 72.8 mmol) in methanol (70 mL)/ethanol (70 mL) was added ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]phenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (4.50 g, 10.4 mmol), and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (500 mL), and washed with water (200 mL) and saturated brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (2.98 g, 83%) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=O.O.[NH2:15][NH2:16].C(O)C(C)C>O>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:2])[NH:15][NH2:16])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: NN
Reactant: COC(=O)Nc1cc(F)cc(Cl)c1
Solvent: CC(C)CO
Solvent: O
Product: NNC(=O)Nc1cc(F)cc(Cl)c1
Temperature: 25 °C

Procedure:
N-methoxycarbonyl-3-chloro-5-fluoroaniline (51.8 gms, 254M) is added to a mixture of hydrazine hydrate (125 ml) and isobutyl alcohol (160 ml). The mixture is heated to 100° for 10 hours under nitrogen. The solution is cooled to room temperature, diluted with water and filtered. The solid is rinsed with water (2×) and dried under vacuum to give 4-(3-chloro-5-fluorophenyl)semicarbazide as a white solid.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:18]([CH2:21][CH3:22])CC)C.CN([CH:26]=[O:27])C>>[C:21]([C:22]1[CH:6]=[CH:7][C:2]([C:26]([NH:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[O:27])=[CH:3][CH:4]=1)#[N:18]
Reactant: CC(C)(C(=O)O)C(N)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Agent: Cl
Product: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
β-Phenyl-α,α-dimethyl-β-alanine hydrochloride (1.88 g, 8.19 mmol) was dissolved in DMF (100 ml). To the resulting solution, triethylamine (Et3N) (3.5 ml, 25.11 mmol) and 4-cyanobenzoyl-N-hydroxysuccinimide ester (4-cyanobenzoyl-OSu) (2.2 g, 9.01 mmol) were added under cooling with ice and the mixture was stirred at room temperature overnight. The solvent was distilled off and the residue was dissolved in a 5% aqueous ammonia and washed with ether. The aqueous layer was adjusted to pH 3 with citric acid under cooling with ice and extracted with ethyl acetate. The collected ethyl acetate layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. The solvent was distilled off and a crystal of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine was obtained upon recrystallization from an ether-hexane mixed solution (2.54 g, 96.2%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:14]1=[C:13]2[CH3:24].BrBr>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]1[CH2:19][CH2:20][CH:21]([Br:1])[C:22](=[O:23])[C:14]1=[C:13]2[CH3:24]
Reactant: Cc1c2n(c3ccc(Br)cc13)CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: ClCCl
Product: Cc1c2n(c3ccc(Br)cc13)CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aged N-bromosuccinimide (4.89 g, 27.5 mmol) was added in small portions (over 15 min) to a solution of 2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 8, 5.0 g) in methylene chloride (100 mL) and stirring at room temperature was continued for 30 min. This crude mixture was then protected against light, and a solution of bromine (2 mL) in methylene chloride (200 mL) was added very slowly from a dropping funnel. The reaction mixture was washed successively with cold water, 5% sodium bicarbonate, and water again. After drying (MgSO4) and filtration, the solvent was evaporated, and the title compound was crystallized from chloroform, mp 156° C.; yield 6.6 g; Anal. Calcd for C13H11Br2NO: C, 43.72% H, 3.10% N, 3.92% and Found: C, 43.35% H, 3.00% N, 3.99%.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:4][CH2:3]1.[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](O)=[O:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([C:44]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH:14]([F:15])[F:16])=[C:7]([O:6][CH2:5][CH:2]5[CH2:3][CH2:4]5)[CH:8]=4)=[N:21]3)[CH2:23][CH2:24]2)=[O:45])[CH:47]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)N1CCC(N2N=C(c3ccc(OC(F)F)c(OCC4CC4)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B3) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:26].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15][I:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 39.9 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-methanesulfonyloxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (2.38 g) in dimethylformamide (24 ml) was added sodium iodide (4.77 g), and the mixture was stirred at 70° C. for 7 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:32]([C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])(=[O:34])=[O:33])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 110 mg, 0.35 mmol) and 2,4-dichlorobenzenesulfonyl chloride (171 mg, 0.7 mmol) in THF (6.0 mL) was added N,N-diisopropylethylamine (183 μL, 1.05 mmol). The resulting light yellow solution was allowed to warm to room temperature during 2 hours and then it was stirred for 15 hours at room temperature under nitrogen. The reaction mixture was diluted with water and brine solution and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over MgSO4. Filtration and concentration gave the crude product which was purified by flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate in hexanes) to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (119 mg, 65%) as an off-white solid. MS cald. for C20H25FNO4S [(M+H)+] 524, obsd. 523.8.