Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:33]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 372) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; 1H NMR (300 MHz, DMSO d6) δ 2.80 (m, 4H), 3.29-3.42 (3H, obstructed by H2O), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C24H20ClN2O3S.0.25 H2O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:4]=[N:3]1.O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:23]=[O:24])=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:4]=[N:3]1
Reactant: Cn1ncc(N2CCCCC2)cc1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(N2CCCCC2)c(C=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-5-(piperidin-1-yl)pyridazin-3(2H)-one [F. Farina, M. V. Martin and A. Tito, An. Quim., 77, 188-195 (1981)] (1.35 g, 7 mmol) in dry DMF (23.3 ml) was cooled to 5° C., then a solution of POCl3 (1.44 ml, 15.4 mmol) in dry DMF (3.5 ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. Then, the temperature was raised to 70° C. and stirring was continued for 75 min. After cooling, the volatile components were removed under reduced pressure and the residue was treated with crushed ice (15 g). The mixture was adjusted to pH 7-8 with aqueous NaOH. Then it was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. Residual volatile material was removed at 10−2 mbar to leave an oily residue which slowly solidified on storage in a refrigerator.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1Br
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3-bromo-4-fluorobenzaldehyde and 20 ml of DMSO was added 0.49 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product extract with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.69 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 8.10-8.47 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tlc (Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:13]([O:15]CCCC)=[CH2:14].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(Br)c2ncccc2c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(F)cc2cccnc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 6-fluoro-8-bromo-quinoline (1.53 g, 6.8 mmol) in acetonitrile (35 mL) was added palladium(II) acetate (0.31 g, 1.36 mmol, 0.2 eq.), butyl vinyl ether (2.04 g, 20 mmol, 3.0 eq.), and 1,3-bis(diphenylphosphino)propane (0.70 g, 1.7 mmol, 0.25 eq) was added triethylamine (1.1 g, 11 mmol, 1.6 eq). The resulting mixture was heated to 90° C. for 17 hr and then evaporated under reduced pressure. The residue was dissolved in aqueous hydrochloric acid (2M, 15 mL) and stirred, at room temperature, for 1.5 hr. This mixture was then diluted with water (35 mL) and the pH adjusted with solid sodium hydrogen carbonate until neutral. The mixture was then extracted with ethyl acetate (100 mL); the organic phase was dried over magnesium sulphate. The resulting mixture was filtered and concentrated under reduced pressure to give a brown oil. This crude product was purified by chromatography on silica gel eluting with 10% ethyl acetate in pentane (by volume) to produce the title compound as a pale yellow solid (0.91 g, 71%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:7][CH:6]=1)[CH3:3].O.NN>CO>[NH2:15][CH2:14][CH2:13][S:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:10]=1
Reactant: CN(C)Cc1cccc(CSCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)Cc1cccc(CSCCN)n1

Procedure:
6-Dimethylaminomethyl-2-[(2-phthalimidoethyl) thiomethyl]pyridine (24.3 g, 0.068 mol) is dissolved in methanol (150 ml) and hydrazine hydrate (4.8 g, 0.087 mol) is added. The solution is refluxed for 11/2 hours and is concentrated in vacuo. The solid residue is dissolved in water (250 ml) 12N HCl (35 ml) is added and the mixture is cooled and filtered. The filtrate is washed with chloroform and concentrated in vacuo. The residue is basified with excess sodium bicarbonate and concentrated to dryness in vacuo. The solid residue is extracted with chloroform/methanol (50/50) (200 ml) and the extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gives 10.3 g of 2-[(2-aminoethyl)thiomethyl]-6-dimethylaminomethyl pyridine as a light amber oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.[OH-].[Li+].Cl>CO.O>[Cl:30][C:26]1[CH:25]=[C:24]([C@@H:22]([OH:23])[CH2:21][NH:20][CH2:19][CH2:18][NH:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of the (R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester (4.12 g) in methanol (60 mL) was added a solution of lithium hydroxide monohydrate (2.08 g) in water (20 mL). The mixture was stirred for 16 h, and 1 N hydrochloric acid was added until the mixture was neutral. The mixture was decanted and the residue was purified by flash silica chromatography eluting with 6:2:0.1 chloroform/methanol/ammonium hydroxide to afford a viscous oil. Trituration with ether and washing with water afforded the title compound as a white solid (2.22 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1Cl)[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-:3])=[O:2].[NH3:18]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:18])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-:3])=[O:2]
Reactant: N
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1nccs1
Solvent: CCO
Product: Nc1ccc(C(=O)c2nccs2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 63 g. (0.24 mol) of 2-(3-nitro-4-chlorobenzoyl)thiazole in 3 liters of a saturated solution of ammonia in ethanol was autoclaved at 100° C. for 24 hrs. The mixture was concentrated in vacuo and the resulting residue dissolved in 1.5 liters of warm 5N hydrochloric acid. The solution was cooled to room temperature and neutralized with concentrated ammonium hydroxide to yield 2-(3-nitro-4-aminobenzoyl)thiazole as yellow-orange prisms, mp. 179°-181° C. (methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].O1CCCC1.Cl>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[C:13]([S:15]([N:29]([CH3:30])[CH3:28])(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COc1cc(-c2noc(C)n2)c(S(=O)(=O)Cl)cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(-c2noc(C)n2)c(S(=O)(=O)N(C)C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonylchloride, dimethyl-amine hydrochloride (203 mg) and tetrahydrofuran (20 mL) was added triethylamine (0.693 mL) under ice-bath cooling. After stirring at room temperature overnight, 2 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonamide.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH:5]1[OH:14])=[N+:2]=[N-:3].[H-].[Na+].[CH3:17]I>O1CCCC1>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:11])=[O:12])[CH2:6][CH:5]1[O:14][CH3:17])=[N+:2]=[N-:3]
Reactant: CI
Reactant: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(S(C)(=O)=O)CCC1N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
To the stirred solution of the azide (500 mg, 2.27 mmol, Example 304) in tetrahydrofuran (8 mL) at 0° C., sodium hydride (60% in oil dispersion, 180 mg, 4.54 mmol, Aldrich) was added slowly and the mixture was stirred for 30 minutes. Methyl iodide (184 uL, 2.95 mmol, Aldrich) was then added and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried with sodium sulfate. The solvent was removed and the residue was purified by chromatography (15% ethyl acetate/hexanes first and then 35%) to give a yellow oil. 280 mg, 53%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5]Br.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.O>C(#N)C>[CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: CON=C(CBr)c1ncc(Cl)cc1Cl
Reactant: NC1CC1
Solvent: O
Solvent: CC#N
Product: CON=C(CNC1CC1)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To 700 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-methyloxime prepared in the same manner as in Steps 1 to 3 in Synthetic Example 2 in 10 ml of acetonitrile, 402 mg of cyclopropylamine in 5 ml of acetonitrile was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (40 ml×2, the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 5:5) as the eluent to obtain 450 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.FC(F)(F)C(O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[OH:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1nc(O)cc(O)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (42 g, 0.257 mol) in trifluoroacetic acid (91 ml, 1.186 mol) was stirred at 23° C. and warmed until all solid had gone into solution. The reaction was stirred for five hours at 23° C. Next, fuming HNO3 (15 ml, 350 mmol) was added portion wise to the reaction mixture over 25 minutes at 0° C. The reaction was stirred for twenty hours at 23° C., and treated with H2O (at 23° C.) at 80% conversion (according LC-MS). The solid precipitate was captured via filteration giving 4,6-dihydroxy-2-methylthio-5-nitropyrimidine as a tan-colored solid. The crude solid was azeotroped with toluene to give 35 g of pale tan powdery solid. 1H-NMR: 300 MHz, (CD3OD, 300 MHz) d (ppm) 2.63 (s, 3H). LCMS-ESI+: calc'd for C5H4N3O4S: 202.0 (M−H−); Found: 202.0 (M−H−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[NH:14][C:13](=[O:15])[O:12][C:10](=O)[C:9]=12)([O-:3])=[O:2].[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1C(O)=O>CS(C)=O.C(O)C>[N+:1]([C:4]1[C:9]2[C:10](=[O:12])[N:16]3[CH2:23][CH2:22][CH2:21][C@H:17]3[C:13](=[O:15])[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Solvent: CCO
Solvent: CS(C)=O
Product: O=C1Nc2cccc([N+](=O)[O-])c2C(=O)N2CCC[C@@H]12

Procedure:
10.6 g (50.9 mmol) of 6-nitroisatoic acid anhydride and 6.1 g (50.9 mmol) of L-proline in 70 ml of dimethyl sulphoxide are heated to 90° for 45 minutes, the mixture is subsequently evaporated in a high vacuum and the residue obtained is heated to 140° for 4 hours. The crystalline crude product is taken up in 100 ml of boiling ethanol, left to stand in the cold overnight, the material obtained is filtered off under suction while back-washing with cold ethanol and dried to constant weight. There is obtained (S)-1,2,3,11a-tetrahydro-6-nitro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which has a decomposition point of 235°-237°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:42]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)c1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (52.5 mg, 0.0879 mmol), 3-isopropylbenzeneboronic acid (17.3 mg, 0.106 mmol), DME (370 μL), EtOH (120 μL), and 1M aqueous Na2CO3 (264 μL, 0.264 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (10.2 mg, 8.8×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for two hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (15% EtOAc/hexanes). LCMS=590.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.72 (s, 1H), 7.68 (s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.15 (bs, 1H), 7.11 (bd, J=7.5 Hz, 1H), 5.46 (d, J=8.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.21 (d, J=15.8 Hz, 1H), 3.69 (m, 1H), 2.96 (m, 1H), 1.26-1.28 (m, 6H), 0.38 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([CH3:23])[C:19]([CH3:24])=[N:18][C:17]=2[C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:25]([C:16]3[C:17]4[N:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:22]=4[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[CH:14][CH:15]=3)=[O:27])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nc(C)c(C)nc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nc(C)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylic acid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.15 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:33]1([CH2:32][S:29]([C:26]2[CH:27]=[CH:28][C:20]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:21]([CH:25]=2)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1N1CCOCC1
Yield: 27 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-cyclopropylmethanesulfonyl-benzoic acid and morpholine and obtained in 27% yield. MS (m/e): 324.2 (MH−, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.CCN(CC)CC.[CH3:41][C:42](OC(C)=O)=[O:43]>CN(C1C=CN=CC=1)C.C1COCC1>[C:42]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:43])[CH3:41]
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol), and Et3N (0.1 g, 1.05 mmol) in 50 ml of THF, was added Ac2O (0.204 g, 2 mmol). The reaction mixture was stirred at room temperature overnight. The yellow solid precipitated was filtered and redissolved in 50% ethanol in water (50 mL). The clear solution was then adjusted to pH1, and the solid formed was filtered and washed with water to give 0.31 g (62%) the title compound as a red solid, mp 218–220° C. 1H-NMR (300 MHz, DMSO-d6) δ 12.26 (br, 1H), 11.15 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=8 Hz, 2H), 8.04–8.09 (m, 3H), 7.83 (d, J=15 Hz, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02–7.07 (m, 1H), 6.93–6.97(m, 2H), 6.82 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.94 (s, 3H). HRMS (EI) Calcd for C27H24N2O6S: 504.1335 ([M]+); Found: 504.1365.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:28][O:29][C:30]1[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37](C2C=CC=CC=2)[C:38](=O)[O-:39])[N:31]=1>O1CCOCC1>[CH:1]1([O:6][C:7]2[C:12]([S:13]([NH:16][C:38]([NH:37][C:32]3[N:31]=[C:30]([O:29][CH3:28])[N:35]=[C:34]([CH3:36])[N:33]=3)=[O:39])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1OC1CCCC1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OC2CCCC2)n1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a mixture of 4.84 g of 2-cyclopentyloxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of absolute dioxan are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate at 20° to 25° C. The mixture is stirred for 1/2 hour, the precipitate is isolated and the filtrate is concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the crystals so obtained are isolated, washed with ether and water and dried, affording 7.79 g of N-(2-cyclopentyloxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6methyl-1,3,5-triazin-2-yl)urea with a melting point of 170°-172° C.