Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2](O)[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C([NH:21][NH2:22])(OC(C)(C)C)=O>CO>[O:1]=[C:2]([NH:21][NH2:22])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: NNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Five grams of gluconic acid were suspended in 15 ml of warm MeOH. After the complete dissolution 4 grams of monoBOC-hydrazine were added to the reaction vessel. The solution was refluxed for 36 h. After the addition of monoBOC-hydrazine the suspension disappeared. At the end, the reaction showed a white precipitate which contained most of the product. The solvent was removed under vacuum and the solid product was extracted in a mixture of NaOH sol. 0.1 N/chloroform. The organic phase was removed while the aqueous phase was passed through anionic exchanger resin and lyophilized. Finally, product was dissolved in cold MeOH and deprotected from the BOC-function by bubbling HCl gas into the solution over 30′. The purity of the protected and the deprotected product was checked by TLC, HPLC and the identity was confirmed by ESI-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:23]2[CH:24]=[C:25]([C:28]([OH:30])=[O:29])N[CH:27]=2)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.[N+]([C:40]1[CH:41]=C(C(O)=O)N[CH:44]=1)([O-])=O.CC1C=CC([N+]([O-])=O)=CC=1C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:23]2[CH:27]=[CH:44][C:40]([CH3:41])=[C:25]([CH:24]=2)[C:28]([OH:30])=[O:29])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1c[nH]c(C(=O)O)c1
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(C)c(C(=O)O)c1

Procedure:
Instead of the starting material compound of Example 262, that is, the 4-nitropyrrole-2-carboxylic acid, 2-methyl-5-nitrobenzoic acid was used for the similar procedure as in Example 262 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[CH:6]=[CH2:7])C=C.N1CCC1>C(Cl)Cl>[O:4]1[CH2:1][CH:7]=[CH:6][CH:5]1[CH:8]1[CH2:9][CH2:10][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:16][CH2:17]1
Reactant: C=CCOC(C=C)C1CCC2(CC1)OCCO2
Agent: C1CNC1
Solvent: ClCCl
Product: C1=CC(C2CCC3(CC2)OCCO3)OC1
Temperature: 40 °C

Procedure:
A solution of 8-(1-(allyloxy)allyl)-1,4-dioxaspiro[4.5]decane (347 mg, 1.46 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (62 mg, 0.07 mmol) in DCM was degassed and heated to 40° C. under argon for 4 hours. After extraction with saturated NaHCO3 solution, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[N:19]=[C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)[O:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2oc(N3CCN4CCC3CC4)nc2c1
Product: c1ccc(-c2cnc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Yield: 50 %

Procedure:
The title compound was prepared according to the procedure in Example 44 using phenylboronic acid and 4-(6-bromo-oxazolo[5,4-b]pyridin2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 23) in 50% yield as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.10 (d, 1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.44 (m, 2H), 7.39-7.36 (m, 1H), 4.58 (br s, 1H), 3.98 (t, 2H, J=5.8 Hz), 3.22-3.14 (m, 4H), 3.11-3.01 (m, 2H), 2.22-2.15 (m, 2H), 1.89-1.82 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH2:16]3)=[CH:12][C:11]=2[CH:19]=O)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([CH2:6][N:7]([CH2:8][CH3:9])[C:10]2[CH:18]=[C:17]3[C:13](=[CH:12][C:11]=2[CH2:19][NH:27][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:14][CH2:15][CH2:16]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC1CCCC1)c1cc2c(cc1C=O)CCC2
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC1CCCC1)c1cc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCC2
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution (20 ml) of 6-(N-cyclopentylmethyl-N-ethylamino)indane-5-carbaldehyde (1.09 g) and 3,5-bis(trifluoromethyl)benzylamine (1.26 g) in dichloromethane was added sodium triacetoxyborohydride (1.70 g) with stirring at room temperature. The reaction solution was stirred overnight. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1) to give the title compound (1.65 g, 83%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19](Cl)=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1.[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25]([OH:32])[CH:24]=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19]([O:32][C:25]3[CH:24]=[CH:23][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=3)=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Solvent: Cc1ccccc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Yield: 33 %

Procedure:
Reaction of chloro-oxo-acetic acid 2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl ester prepared as Example 11 reacted in toluene at the reflux with p-nitrophenol gave after purification oxalic acid (4-nitro-phenyl) ester (2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl) ester (33% yield). Analysis C,63.5; H,3.3; N,3.5; C22H13NO8 requires C,63.0; H,3.1; N,3.3%. Mass Spectrometry shows a molecular ion at 419.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([C:10]([CH3:12])=O)[CH:7]([CH3:9])[CH3:8].N1CCCC1>CO.CCOCC.O>[CH3:12][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: CC(=O)CC(C)C
Reactant: C1=CCC=C1
Solvent: CO
Solvent: C1CCNC1
Solvent: O
Product: CC(CC(C)C)=C1C=CC=C1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a solution of 10.00 g (151.3 mmol) of cyclopentadiene in 30 ml of methanol, 18.9 ml (151.1 mmol) of methyl isobutyl ketone and 12.8 ml (153.3 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (83-88° C./10 mmHg) to obtain 15.80 g (106.58 mmol) of a yellow liquid (yield: 71%). The analyzed values are given below.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:9][CH:10]([C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]>C(OC(=O)C)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:9][CH:10]([C:12]1[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=1)[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 500 milliliter, neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 50 milliliters of ethylacetate was added and 8.0 grams of 5-[1-(3,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) was added. The resulting solution was stirred for 17 hours with formation of an emulsion, and then purged with nitrogen until no COCl2 was detected. The solution was filtered, and topped at 70° C. in a roto-vac to form 9.0 grams of a viscous yellow oil of 5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O1CCCC1>[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:37][CH:36]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NCc1ccc(OCCN(C)C)cc1

Procedure:
To a cooled suspension of 14.3 g of 2-methoxy-5-sulfamoylbenzoic acid in 60 ml of tetrahydrofuran were successively added dropwise 6.25 g of triethylamine and 7.45 g of pivaloyl chloride with stirring. The mixture was stirred at the same temperature for 1 hour and then a solution of 10.0 g of 4-[2-(dimethylamino)ethoxy]-benzylamine in 40 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate to give a precipitate, which was washed with water and ethyl acetate, of 16.6 g of colorless crystals. Recrystallization of the crystals from ethanol gave the title compound as colorless needles, m.p. 154°-155° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][N:14]=2)[N:11]=1)=[O:4].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([N:12]=[CH:13][N:14]=4)[N:11]=3)=[O:4])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)Nc1ccc2ncnn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
2-Bromo-N-([1,2,4]triazolo[1,5-b]pyridazin-6-yl)acetamide (636 mg) and 1-(diphenylmethyl)piperazine (627 mg) were dissolved in acetonitrile (20 ml), followed by addition of potassium carbonate (411 mg). The mixture was stirred at room temperature for 2 hours, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals were collected by filtration and recrystallized from methanol to yield the title compound (525 mg).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(Oc2ccc(N3CCN(c4ccncc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of 4-phenoxybenzaldehyde (198 mg) in dichloromethane (20 ml), N-(4-pyridyl)piperazine (163 mg) and acetic acid (240 mg) were added. The mixture was stirred at ambient temperature for 30 mins, and then sodium triacetoxyborohydride (318 mg) was added in one portion. Stirring was continued at ambient temperature overnight. The reaction mixture was poured into 1M hydrochloric acid (50 ml) and washed With ethyl acetate (50 ml). The aqueous layer was made basic with 2M sodium hydroxide solution and extracted with dichloromethane (2×25 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to give a white solid which was purified by chromatography on silica gel (Mega Bond Elut column) using an increasing concentration of methanol in dichloromethane (up to 4% methanol) as eluant to give 1-(4-pyridyl)-4-(4-phenoxy-phenyl)piperazine (168 mg) as a solid: microanalysis, found: C,76.5; H,6.6; N,11.9%; C22H23N3O requires: C,76.5; H,6.7; N,12.2%; NMR: 3.2-3.45(m,8H); 3.5(s,2H); 6.8(d,2H); 6.9-7.05(m,4H); 7.1-7.2(m,1H); 7.25-7.45(m,4H); 8.1(d,2H); MS: m/z 345 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31][CH3:32])=[O:30])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31][CH3:32])=[O:30])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CN(CCc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1CN(CCc1ccc(Cl)cc1)C1CCNCC1

Procedure:
tert-Butyl 4-((4-chlorophenethyl)(2-(methoxycarbonyl)benzyl)amino)piperidine-1-carboxylate obtained in Step 1 was subjected to the deprotection reaction as described in Procedure 2 (4 N HCl in AcOEt).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:9]([NH:17][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNC(C)(C)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
100 g (1 mol) of ethyl acrylate was added to 135.2 g (1 mol) of α,α-dimethylbenzylamine, and the mixture was stirred at 100° C. for 18 hours. The reaction product was subjected to distillation to obtain 180.7 g (yield: 77.8%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])=[CH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:5]=[C:6](F)[CH:7]=1.BrC1SC(C(N2CC(=O)NC2)=O)=CC=1C1C=CC=C(Cl)C=1.[F:50][C:51]([F:63])([F:62])[O:52]C1C=C(B(O)O)C=CC=1>>[Cl:28][C:24]1[CH:23]=[C:22]([C:10]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:13][C:9]=2[C:4]2[CH:3]=[CH:2][CH:7]=[C:6]([O:52][C:51]([F:63])([F:62])[F:50])[CH:5]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3cc(F)cc(Cl)c3)s2)CN1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)s2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3cccc(OC(F)(F)F)c3)s2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 5 starting with 70.0 mg (0.15 mmol) of the compound from Example 16A and 45.1 mg (0.22 mmol) of 3-(trifluoromethoxy)phenylboronic acid. 26.7 mg (39% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:7][CH2:8][N:9]([C:35](=[O:37])[CH3:36])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid ethyl ester (0.7 g, 1.44 mmol) in CH2Cl2 (10 mL) and TEA (0.4 mL, 2.89 mmol) at 0° C. was added acetyl chloride (0.113 mL, 1.59 mmol). The reaction was allowed to warm to 25° C. over 19 h. The reaction was then taken up in CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and water (5 mL). The organics were washed with saturated aqueous sodium chloride (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate-hexanes, to provide 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid ethyl ester as a white solid (0.4 g, 53%). MS: 526 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C:25]1[CH:26]=[C:27]([SH:32])[CH:28]=[CH:29][C:30]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][C:25]1[CH:26]=[C:27]([S:32][C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: Cc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(C)c(C)c3)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a solution of the compound of Example 32A (40 mg, 0.12 mmole) in 2.5 mL of dimethylformamide was added 3,4-dimethylthiophenol (17 mg, 0.12 mmole), followed by potassium carbonate powder (20 mg, 0.14 mmole). The mixture was heated at 100° C. for 20 h. The solvent was removed using N2 gas flow. Water (5 mL) was then added to the residue, the resulting precipitate was collected through filtration, washed with cold water, and air dried to give the title compound (42 mg, 81%) as light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 3.45 (br, m, 2H), 3.63 (br, m, 6H), 6.79 (s, 1H), 6.82 (d, J=19 Hz, 1H), 7.18 (d, J=19 Hz, 1H), 7.24 (dd, J=4, 19 Hz, 1H), 7.27 (s, 1H), 7.34 (d, J=21 Hz, 1H), 7.56 (d, J=39 Hz, 1H), 8.32 (d, J=4 Hz, 1H). MS (APCI) (M+H)+ at m/z 440. FAB High Resolution MS calculated m/z for C23H26N3O4S (M+H)+: 440.1644. Observed m/z: 440.1646.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.[Pd]>[F:38][C:35]([F:36])([F:37])[C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH:30]=[CH:29][C:28]=1[C:31]([F:32])([F:34])[F:33]
Reactant: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)c(C(F)(F)F)c2)cc1O
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-[(E)-2-[3,4-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 73, 227 mg, 0.428 mmol) in THF (4279 μl) was added palladium on carbon (45.5 mg, 0.043 mmol) and the reaction vessel evacuated and purged with nitrogen (×3). The reaction was stirred under a hydrogen atmosphere for 4 hours and the resulting mixture was filtered through a short pad of diatomacious earth and concentrated in vacuo. The residue was purified by chromatography (C18 silica cartridge eluting with 0-50% acetonitrile in water with basic modifier). The appropriate fractions were combined and concentrated to remove the organics and the aqueous fractions were acidified with hydrochloric acid (2 N) and extracted with ethyl acetate (×2), dried (MgSO4) and concentrated in vacuo to yield 6-{2-[3,4-bis(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a cream solid (39 mg, 26%)
Reaction SMILES: O[Li].O.[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (0.379 g, 9.03 mmol) was added to a stirred solution of phenylmethyl 5-methyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 8; 1.0 g, 3.01 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 500 mg.
Reaction SMILES: [C:1]1([C:7](=[O:11])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:12].[OH-].[Na+].O=O>>[C:7]([NH2:12])(=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)C(=O)c1ccccc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 8.6 %

Procedure:
A solution of 15.4 g (0.1 mole) of 97% phenylglyoxylic acid, 150 g (3 moles) of 34% pure ammonia solution, 1.75 g (0.007 mole) of pentahydrated cupric sulfate and 6 g (0.15 mole) of sodium hydroxide in pellets are heated for 1 hour at 100° C. in an oxygen atmosphere, under agitation, and with a total pressure of 8 bars. Thereafter, after cooling to the ambient temperature, the reaction medium is filtered, thereby isolating 1.05 g (0.0086 mole) of benzamide, M.p.=128°-129° C. The alkaline filtrate is thereafter submitted to repeated extractions with ether.