Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:47])[C:12]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[CH:13][N:14]2[CH2:23][CH2:24][NH:25][C:26]([C@@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:29][OH:30])=[O:27]>C(O)C>[ClH:7].[NH2:31][C@@H:28]([CH2:29][OH:30])[C:26]([NH:25][CH2:24][CH2:23][N:14]1[C:15]2[C:10](=[C:9]([F:8])[CH:18]=[CH:17][C:16]=2[O:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:47])[C:12]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[CH:13]1)=[O:27]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCNC(=O)[C@@H](N)CO)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
A 4N hydrogen chloride ethyl acetate solution (5 ml) was added to an ethanol solution (5 ml) of tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate (330 mg, 0.6 mmol) and stirred at room temperature for 14 hours. The resulting mixture was concentrated under reduced pressure. Water was added to the residue, which was then washed with ethyl acetate. A 2N aqueous sodium hydroxide solution (6 ml) was added to the water layer to adjust its pH to 11, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=20:1→15:1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol (3 ml) and ethyl acetate (3 ml), and a 4N hydrogen chloride ethylacetate solution (0.1 ml) was then added thereto. The mixture was stirred and concentrated to dryness under reduced pressure, and recrystallized from ethyl acetate, giving a white powder of (S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionamide hydrochloride (145 mg, yield: 50%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])C.CO.[OH-].[Na+].Cl>O>[CH2:13]([CH:5]([CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[C:4]([OH:20])=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 299 mg of 2-benzyl-3-dimethylaminosulphonyl-propionic acid ethyl ester, 1 ml of methanol, 2 ml of water and 0.42 ml of 1H NaOH is stirred for 16 hours at room temperature, then neutralise with 0.42 ml of 1N HCl and extracted with ethyl acetate. The organic extracts are washed with water, dried, concentrated by evaporation and purified by chromatography on silica gel with eluant I. Rf (J)=0.48.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([C:13]([Cl:16])([Cl:15])[Cl:14])[C:10](F)=[S:11].[CH3:17][N:18]1[CH:22]=[C:21]([OH:23])[CH:20]=[N:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[C:21]([O:23][C:10](=[S:11])[N:9]([CH3:8])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH:20]=[N:19]1
Reactant: CN(C(F)=S)C(Cl)(Cl)Cl
Reactant: Cn1cc(O)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=S)Oc1cnn(C)c1)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 86.6 %

Procedure:
5.1 g (0.05 mol) of triethylamine were added dropwise to a mixture of 11.3 g (0.05 mol) of N-methyl-N-trichloromethylthio-carbamoyl fluoride, 4.9 g (0.05 mol) of 1-methyl-4-hydroxypyrazole and 150 ml of toluene. After 4 hours, the mixture was extracted twice with 25 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation under a high vacuum. 12.5 g (82% of theory) of N-methyl-N-trichloromethylthiocarbamic acid O-(1-methyl-pyrazol-4-yl) ester were thus obtained in the form of a yellow oil with a refractive index nD23 of 1.5492.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20]([OH:22])=O)[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.Cl.Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([N:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[C@@H:40]([CH3:45])[CH2:39]2)[CH3:37])[CH2:31][CH2:30]1>>[OH:44][C@H:41]1[CH2:42][CH2:43][N:38]([C@@H:36]([CH3:37])[CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:22])[CH2:34][CH2:33]2)[CH2:39][C@@H:40]1[CH3:45]
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 106 (see example 55) and amine 56.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:58])[C:16](=[O:57])[C:17]([CH3:56])=[C:18]2[C:23]=1[C:22](=[O:24])[N:21](CC1C=CC(OC)=CC=1)[C:20](=[O:34])[N:19]2[C:35]1[CH:36]=[C:37]([CH:53]=[CH:54][CH:55]=1)[C:38]([N:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1)=[O:39].CO>C1(OC)C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:58])[C:16](=[O:57])[C:17]([CH3:56])=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][C:20](=[O:34])[N:19]2[C:35]1[CH:55]=[CH:54][CH:53]=[C:37]([C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])[CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)[nH]c(=O)n(-c3cccc(C(=O)N4CCNCC4)c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.2 %

Procedure:
Aluminium chloride (1.57 g, 11.76 mmol) was added in small portions to a solution of crude tert-butyl 4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (1 g, 1.176 mmol) in Anisole (5 ml). The resulting reaction mixture was stirred at room temperature for 17 h, methanol (10 ml) was added dropwise and the resulting mixture was concentrated in vacuo. Aq. ammonia was added to the resulting residue and the reaction mixture was extracted several times with DCM. The combined organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography over neutral alumina to afford the titled compound (23) (0.113 g).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[CH3:19][OH:20]>>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: CO
Product: COCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (2.15 gm, 7.5 mmol) in methanol (60 mL) containing five drops of concentrated sulfonic acid was stirred at room temperature, monitoring reaction progress by TLC until complete (3 hours). The reaction mixture was poured into ice water and the crude product extracted into ethyl acetate which was dried (Na2SO4) and evaporated. The residue was dissolved in a minimum amount of acetonitrile and diluted with chloroform. Upon standing overnight product crystallized (1.8 gm). After several recrystallizations from acetonitrile/chloroform pure product was obtained (1.2 gm), m.p. 153°-155° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (3.83 g, 14.0 mmol) and commercially available 4-iodo-imidazole (4.07 g, 21.0 mmol) according to the general procedure IVa. Obtained as a brown solid (1.41 g, 24%). MS (ISP) 431.0 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>O.C(O)COCCO>[NH2:18][C:17]1[C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Nc1cc(C(=O)O)cc(OCc2ccccc2)c1Cc1ccccc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid (2.7 g), 98% aqueous hydrazine hydrate (4.5 ml), potassium hydroxide (1.5 g) in water (3.0 ml) and di-ethylene glycol (20 ml) is stirred at about 130° C. for 1 hour. The temperature is then slowly raised to 215° C. allowing volatile material to distil off. The stirring at 215° C. is continued for a further 2-3 hours until the nitrogen evolution has ceased. After cooling and dilution with water (30 ml), the resulting solution is acidified with conc. hydrochloric acid (3 ml). The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from 96% ethanol, 5-amino-4-benzyl-3-benzyloxybenzoic acid is obtained with a melting point of 207.5° -209.5° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]3[O:17][C:15](=[O:16])/[C:14](=[CH:27]/[C:26]4[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=4)/[N:13]=3)=[CH:18][CH:19]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(OC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 1 (1c) was conducted using N-[4-(2-cyclopropylethoxy)benzoyl]glycine (150 mg) prepared in Example 1 (1b) and 4-(trifluoromethoxy)benzaldehyde (90 μL) to give (4Z)-2-[4-(2-cyclopropylethoxy)phenyl]-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (176 mg). A reaction similar to that described in Example 1 (1d) was conducted using 80 mg of this given compound to give 74 mg of 4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide (white powder).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.C1C=C[NH+]=CC=1.[Br:31][Br-]Br.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Br:31][C:9]1[N:10]([CH:17]([CH3:19])[CH3:18])[C:11]2[C:16]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 3 °C
Reaction time: 1.25 h

Procedure:
20 g (78.95 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 200 ml of THF and 200 ml of chlorobenzene are introduced into a 1.5 liter sulfonating flask, equipped with an anchor stirrer, thermometer and nitrogen delivery line, and cooled to 3° C. with stirring. 26.58 g (78.95 mmol) of pyridinium bromide perbromide are then added and stirring is carried out for 1.25 hours at 3° C. 680 g of a 5% sodium hydrogen carbonate solution are then added dropwise in the course of 10 min. The phases are separated and the aqueous phase is extracted three times with 150 ml of chlorobenzene. The combined organic phases are washed twice with 340 ml of 5% sodium hydrogen carbonate solution and twice with 220 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The brown residue is dissolved in 125 ml of methylene chloride, 125 ml of 94% ethanol are added and the methylene chloride is distilled off at normal pressure. The solution is cooled slowly to room temperature and then to 3° C., and the precipitate is filtered off, washed three times with 10 ml of ice-cold 94% ethanol and dried overnight at RT/125 T. Beige crystals having a melting point of from 110 to 111.5° C. are obtained. Elemental analysis: Found 4.95% H; 61.23% C; 4.04% N; 22.9% Br; 5.67% F. Theory 4.55% H; 61.46% C; 4.22% N; 24.05% Br; 5.72% F.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].[Li]>O1CCCC1.NC1C=CC=CC=1.N>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Add 13β-n-propyl-3-methoxy-gona-1,3,5(10), 8-tetraen-17β-ol (3.1 g.) dissolved in a mixture of tetrahydrofuran (10 cc.) and freshly distilled aniline (60 cc.) to liquid ammonia (160 cc.) and add lithium metal (1.5 g.) in small pieces. Stir the reaction mixture for 3 hours, then quench with solid ammonium chloride (12.5 g.) and take up in water. Ether-extract the product and evaporate the washed and dried extracts to obtain a semisolid residue of crude 13β-n-propyl-3-methoxy-gona-1,3,5(10) -trien-17β-ol (3.1 g.); ultraviolet absorption peak at 279 mμ (ε1,800).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2.C[O-].[Na+]>CO.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2
Reactant: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](COC(C)=O)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 198.1 %

Procedure:
2,5,6-Trichloro-3-propionyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.44, 90 mg, 0.21 mmol) was dissolved in dry MeOH (15 mL) to which was added sodium methoxide (14 mg, 0.26 mmol). The solution was stirred at room temperature for 40 min, and the solvent was then removed under vacuum. The residue was suspended in brine (50 mL) and water (5 mL), and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in 10% MeOH/CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from boiling EtOAc to yield 170 mg (81%) of 4.47 as a white crystalline solid: mp 239-240 C; Rf0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.44 (s, 1H), 6.06 (d, 1H), 5.44-5.41 (m, 2H, D2O exch.), 5.29 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.17 (s, 1H), 3.74 (m, 2H), 3.04 (dd, 2H), 1.12 (t, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 195.17, 132.45, 132.41, 126.13, 125.91, 125.84, 122.09, 115.39, 112.60, 88.90, 86.36, 71.58, 69.54, 60.97, 35.05, 7.98. HRMS (EI) m/z calcd. for C16H16Cl3NO5 407.0094, found 407.0089. Anal calcd for C16H16Cl3NO5: C, 47.02; H, 3.95; N, 3.43. Found: C, 46.85; H, 3.96; N, 3.47.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10].[H-].[Na+].[NH:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)(O)[O-]>CN(C=O)C.O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:4]([I:10])[CH:5]=1
Reactant: Fc1ccc(CBr)c(I)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1I)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(bromomethyl)-4-fluoro-2-iodobenzene (Example 3, step 1) (5 g, 15.9 mmol) in dry DMF (50 mL) under argon was cooled to 2° C. and treated with NaH (60% dispersion in oil, 0.4 g, 17.5 mmol) and stirred for 5 minutes to give a fine slurry. A solution of di-tert-butyl iminodicarboxylate (Aldrich, 3.8 g, 17.5 mmol) in 20 ml dry DMF was added dropwise, keeping the temperature between 2 and 7° C. After stirring for 1 hr at 0° C., the solution was allowed to warm to room temperature and stirred overnight. The reaction was poured into bicarbonate solution and water was added until all the solids dissolved. The solution wag extracted with ether and the combined organic layers were dried over Na2SO4, filtered and evaporated and the crude product was purified on 120 g silica gel ISCO cartridge eluting first with a gradient of 0-5% EtOAc/Hexanes followed by a gradient of 5-10% EtOAc/Hexanes to give the product as a clear oil that solidified to a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:40]([NH:39][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[S:41])[CH:19]([CH3:21])[CH3:20])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=S)NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (250 mg, 0.75 mmol) in DCM (2 mL) was added DIEA (175 μL, 1 mmol) followed by the dropwise addition of benzoylisothiocyanate (106 μL, 0.78 mmol). The reaction was stirred for 2 h at rt., acidified with 1 N aqueous HCl solution to pH 3 and then extracted with Et2O (3×10 mL). The extracts were combined, washed sequentially with sat. aqueous NaHCO3 solution (1×10 mL) and sat. aqueous NaCl solution (1×10 mL), dried (MgSO4), and the solvent removed to give (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamothioyl)benzamide (m/z, 458, M+1) as an oil (300 mg) in greater than 90% HPLC purity.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:12][C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)=[N:12][C:11]([C:24]([F:25])([F:26])[F:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Temperature: 120 °C
Yield: 77.6 %

Procedure:
A mixture of 1-(4-methoxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (10 g, 25.2 mmol), 48% aqueous HBr (70 ml) and acetic acid (70 ml) was heated at 120° C. for 55 h. Then HBr 48% (20 ml) and AcOH (20 ml) were added and the mixture was heated again at 120° C. for 2 h. After cooling the solution was poured into water (2 l), the precipitate was filtered, washed several times with water and dried. Recrystallization from ethanol yielded a white solid (7.5 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(Br)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 588.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:12][CH2:11][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: c1ccc2c(c1)CCCc1ccccc1N2
Reactant: ClCCOCCOC1CCCCO1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCCc1ccccc1N2CCOCCOC1CCCCO1
Temperature: 25 °C

Procedure:
To a solution of 5,6,7,12-tetrahydrodibenz[b,g]azocine (2.5 g, 12 mmol, prepared in a similar way as described in Chem. Pharm. Bull. 1978, 26, 942-950) and 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (3.0 g, 14 mmol) in toluene (50 ml) was added a suspension of sodium amide (1.50 g, 19 mmol, 50% wt suspension in toluene). The reaction mixture was heated at reflux temperature for 10 h. The mixture was allowed to cool to room temperature and water (52.5 ml) was carefully added. The phases were separated and the aqueous phase was extracted with toluene (50 ml). The combined organic phases were washed with water (2×5 ml), brine (15 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (150 g) using a mixture of ethyl acetate and n-heptane (1:4) as eluent. Collecting the proper fractions afforded 3.0 g of crude 12-(2-(2 -((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5,6,7,12-tetrahydrodibenz[b,g]azocine. TLC: rf=0.11 (SiO2 ; ethyl acetate/n-heptane=1:4).