Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([Cl:12])[CH:3]=1)=[O:22]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(Cl)(Cl)Cl
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 4-amino-2-chlorobenzotrifluoride (300 mg) and pyridine (243 mg) in dichloromethane (10 mL) was added a solution of trichloroacetyl chloride (279 mg) in dichloromethane (5 mL) dropwise. The solution was stirred for 2 hrs and then concentrated at reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexane to give the title compound as a white solid (360 mg, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH:29]3CCC[O:31][CH2:30]3)=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH2:30][OH:31])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nnc1C1CCCOC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Product: Cn1c(CCO)nnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A 25 mL scintillation vial was charged with {5-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-4-fluoro-phenyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-acetic acid ethyl ester (synthesized according to general procedure P, 95 mg, 0.186 mmol) in 2 mL of anhydrous MeOH. To this solution under a nitrogen atmosphere was added of lithium aluminum hydride (14 mg, 0.372 mmol) at room temperature. LCMS indicated completion of the reaction after 30 minutes and 1 mL of 20% H2SO4 was added. The solvent was subsequently removed in vacuo and the residue was extracted with DCM. The organic layer was then washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resultant residue was purified via automated silica gel chromatography to afford 4-tert-butyl-N-{4-chloro-5-fluoro-2-[5-(2-hydroxy-ethyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenyl}-benzenesulfonamide as a white powder: MS (ES) M+H expected 467.1, found 467.4.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33].Cl>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
A solution of y mol of 2,2,6,6-tetramethylpiperidine in 400 ml of anhydrous tetrahydrofuran is cooled under a stream of argon to to and there is added dropwise thereto at this temperature within 30 minutes 100·y/0.16 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 20.2 ml (0.13 mol) of 1,3-bis(trifluoromethyl)benzene are added dropwise thereto at to within 15 minutes, the wine-red solution obtained is stirred for a further×minutes at to and then at this temperature 20 ml (0.26 mol) of N,N-dimethylformamide are allowed to flow in rapidly from a dropping funnel. The internal temperature t rises by about 15° as a consequence of the exothermic reaction. The dark red solution obtained is then slowly added dropwise and while stirring and cooling to 500 ml of cold 3M hydrochloric acid (strongly exothermic). The emulsion obtained is diluted with 300 ml of hexane, the aqueous phase is separated, the organic phase is extracted with 500 ml of cold 3M hydrochloric acid, washed neutral twice with 250 ml of saturated sodium chloride solution each time, dried over sodium sulphate and the organic solvent is largely distilled off at 40° bath temperature/20 kPa. The residue is distilled over a column having a length of 20 cm, whereby firstly residual solvent is removed at 50° bath temperature/20 kPa and then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. During the increase in the internal temperature a forerun of about 1 g is removed and then the 2,4-bis(trifluoromethyl)benzaldehyde obtained distils over at 56°./1.4 kPa as a colourless liquid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](I)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:42]#[CH:43].C(N(CC)CC)C>O1CCCC1.C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:43]#[C:42][CH2:41][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 15B (1.69 g) in tetrahydrofuran (30 mL) was added bis(triphenylphosphine)palladium (II) dichloride (88 mg), CuI (4.8 mg), prop-2-ynylbenzene (584 mg) and triethylamine (1.5 mL). The mixture was stirred at room temperature for 3 hours, diluted with diethyl ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 10% ethyl acetate in hexanes, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][C:20]4([CH2:25][CH2:24][CH2:23][N:22]4[CH3:26])[CH2:19]3)=[CH:11][C:10]=2[O:27][CH3:28])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][C:20]4([CH2:25][CH2:24][CH2:23][N:22]4[CH3:26])[CH2:21]3)=[CH:11][C:10]=2[O:27][CH3:28])=[N:6][CH:7]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 33.9 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 46, 95 mg, 0.18 mmol), iron (61 mg, 1.09 mmol) and NH4Cl (7.32 mg, 0.14 mmol) was heated at reflux in ethanol (10.5 mL) and water (3.5 mL) for 2 h. The mixture was cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2. This solution was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2-6% 7N methanolic ammonia in CH2Cl2 gave the title compound (30 mg, 34%) as a brown gum; m/z: ES+ MH+ 491.5.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[Na+].C(=O)(O)[O-].[K+].[C:50]([O:53][CH2:54]Cl)(=[O:52])[CH3:51]>CC(C)=O>[C:50]([O:53][CH2:54][O:23][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:24])(=[O:52])[CH3:51]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-Hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (1g.) was warmed with tetra-butyl ammonium hydroxide (1.94g. Of 40% solution) and acetone (10 ml.) to effect solution. The solution was refluxed with sodium iodide (100 mg.). potassium bicarbonate (150 mg.) and chloromethyl acetate (0.6 ml.) for 2 hours. The mixture was evaporated to small volume, diluted with ethyl acetate, washed with water, dried (Na2SO4) and evaporated to a residue. Purification by preparative t.l.c. gave title compound (less polar band) (318 mg.) as white foam; [α]D + 52°.
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O.[CH3:17][C:18]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[N:19]=1>CO>[NH2:25][C:20]1[N:21]=[C:22]([NH2:24])[N:23]=[C:18]([CH:17]=[CH:9][C:1]2[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=2)[N:19]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1nc(N)nc(N)n1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc(N)nc(C=Cc2ccc(C=O)cc2)n1
Temperature: 80 °C
Yield: 41 %

Procedure:
To 107.2 g (800 mmol) of benzene-1,4-dicarboxaldehyde suspended in 450 mL methanol was added with stirring 294.0 g of 31% aqueous sulfuric acid (50 mL of concentrated sulfuric acid was added slowly to 200 mL of water while stirring). The solid dissolved and a yellow solution was obtained. The solution was heated to 80° C. with an oil bath, and 25.0 g (200 mmol) 6-methyl-[1,3,5]triazine-2,4-diamine powder was added. The solution was stirred at 80° C. for 8 h then cooled to room temperature. Next, 1.2 g of yellow byproduct (1,4-bis[4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]]-benzene) was removed by filtration, and the filtrate was treated with 2000 mL water. The resulting solid was collected by filtration and washed with saturated aqueous NaHCO3 and water until neutral. The excess benzene-1,4-dicarboxaldehyde was removed by sonicating and washing with acetone three times. Yield: 20.0 g of light yellow product. Yield=41%. 1HNMR (500 MHz, DMSO): δ9.992 (s, 1H), 7.894 (d, J=8.0 Hz, 2H), 7.847 (d, J=7.5 Hz, 2H), 7.806 (d, J=15.5 Hz, 1H), 6.928 (d, J=15.5 Hz, 1H), 6.806 (br, 4H). 13CNMR (500 MHz, DMSO): δ 193.914, 193.417, 170.671, 167.847, 141.836, 136.833, 131.461, 130.688, 128.883.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.ON1C=CC=CC1=S.ClC(Cl)CCCCCN=C=N.C([SnH](CCCC)CCCC)CCC>CN(C)C1C=CN=CC=1.C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCC
Reaction time: 6 h
Yield: 94.8 %

Procedure:
286 mg (1 mmol) of stearic acid (7) are mixed with 151 mg (1.2 mmol) of N-hydroxypyridine-2-thione, 183 mg (1.5 mmol) of p-dimethylaminopyridine (DMAP) and 310 mg (1.5 mmol) of dichlorohexylcarbodiimide (DCC). The mixture in 20 ml of benzene is stirred under an atmosphere of nitrogen and the solution obtained is brought to reflux so as to distil 10 ml of benzene. After 45 minutes under reflux, 10.8 ml (3 mmol) of tri-n-butylstannane and 10 mg of azobis(isobutyronitrile) (AIBN) in 10 ml of benzene are added dropwise during 15 minutes. Heating under reflux is continued for 6 hours, 10 ml of carbon tetra-chloride are then added, and refluxing is continued for one hour before evaporating the mixture to dryness. The residue is treated with iodine (20% in 10 ml CH2Cl2) and potassium fluoride (10% in 10 ml H2O), and the two phases are then vigorously stirred for 10 minutes. The polymeric tin residues are filtered under vacuum on Celite and washed with 5 ml of dichloromethane. The organic phase is removed and the aqueous layer is extracted twice with dichloromethane (2×10 ml). The combined organic phases are washed with sodium thiosulfate (10%, 10 ml) and 10 ml of water, dried over sodium sulfate, filtered and evaporated to dryness. The crude product purified by filtration on silica gel (100% pentane) gives 228 mg of n-heptadecane (8).
Reaction SMILES: Br[C:2]1[CH:50]=[CH:49][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:17](=[O:40])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=4[C:35]([F:38])([F:37])[F:36])=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:57][C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1.C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:41][C:42]([OH:44])=[O:43])[C:17](=[O:40])[C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:39])[CH2:26][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=5[C:35]([F:37])([F:38])[F:36])=[CH:22][CH:23]=4)=[CH:13][CH:14]=3)=[O:7])=[CH:49][CH:50]=2)=[CH:60][CH:59]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(OC(=O)c4ccc(Br)cc4)cc3)cc2)c(C(F)(F)F)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(-c5ccc(Cl)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 31 %

Procedure:
Prepared using General Procedures 16 then 8: To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-bromobenzoate INT-10 (50 mg, 0.07 mmol) in a microwave vessel were added Na2CO3 (15 mg, 0.15 mmol), 4-chlorobenzene boronic acid (17 mg, 0.07 mmol), acetonitrile (1 mL) and water (0.1 mL). The suspension was degassed with N2 then treated with PdCl2(dppf) (2.6 mg, 3.64 μmol) and degassed further. The reaction mixture was heated in the microwave at 100° C. for 30 min with stirring. The reaction mixture was diluted with DCM (10 mL) and passed through a phase separator cartridge. The organic layer was isolated and concentrated to 3 mL then TFA (2 mL) was added. After stirring for 2 h at room temperature, the solvent was concentrated and the product was purified by preparative HPLC to provide 17 mg (31%) of 2-(N-(4-((4′-chloro-[1,1′-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid 282. LCMS-ESI (m/z) calculated for C39H30ClF3N2O7: 731; found 732 [M+H]+, tR=8.89 min (Method 9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.COC(=O)C1C=C([S:44](=[O:49])(=[O:48])[N:45]([CH3:47])[CH3:46])C(C(C)(C)C)=CC=1OCC.C[Al](C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[CH:23][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[C:25]([S:44]([N:45]([CH3:47])[CH3:46])(=[O:49])=[O:48])[CH:26]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C(=O)OC
Agent: C[Al](C)C
Product: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 4-tert-butyl-5-dimethylsulfamoyl-2-ethoxy-benzoic acid methyl ester (prepared in an analogous manner as described in example 43) in the presence of trimethylaluminum to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethyl-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cn1cnc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cn(C)cn3)cc12
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (10.0 mg, 0.0229 mmol), 4-iodo-1-methyl-1H-imidazole (7.17 mg, 0.0344 mmol), potassium carbonate (9.53 mg, 0.0689 mmol) in DME (2.0 mL) and H2O (0.40 mL) was added (1,1′-bis-(diphenylphosphino)ferrocene) palladium dichloride (0.84 mg, 0.0011 mmol) under nitrogen atmosphere. The resulting mixture was refluxed at 100° C. for 90 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 2% MeOH in DCM) to give desired product. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 3.75 (s, 3 H), 5.30 (q, J=6.8 Hz, 1 H), 7.12-7.18 (m, 1 H), 7.22 (d, J=1.5 Hz, 1 H), 7.33 (d, J=1.3 Hz, 1 H), 7.39 (br. s., 1 H), 7.62 (s, 1 H), 7.67 (d, J=2.0 Hz, 1 H), 8.48 (d, J=2.0 Hz, 1H). MS (ES+): m/z 389.05 [MH+]. HPLC: tR=2.54 min (ZQ3, polar—5 min).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>CN(C=O)C>[CH2:37]([N:38]([CH3:33])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH2:36][CH2:35][CH3:34]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-methylbutylamine (581 μL, 4.9 mmol) are added. The reaction stirred at room temperature 2 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][O:6][N:7]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][O:6][N:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1nonc1-c1cccnc1
Reactant: CCCCCCO
Agent: [Na]
Product: CCCCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 ml) was added 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (180 mg, 1 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11].Cl.O.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[CH:7]=[C:6]([N:8]=[N+:27]=[N-:28])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1NC(=O)Nc1ccc(N)cc1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1NC(=O)Nc1ccc(N=[N+]=[N-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N′-(2-methoxyphenyl)urea (300 mg, 1.17 mmol) was added to HCl/H2O (1.17 mL/2.34 mL), cooled to 0° C. Sodium nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+.
Reaction SMILES: Cl.N1CCC1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC(=O)CC2)(=O)=O)C=C(OC)N=1.[F:35][C:36]1[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:37]=1[CH2:38][S:39][C:40]1[N:45]=[C:44]([NH:46][S:47]([N:50]2[CH2:55][CH2:54][CH:53]([N:56]3[CH2:61][CH2:60]OC[CH2:57]3)[CH2:52][CH2:51]2)(=[O:49])=[O:48])[CH:43]=[C:42]([O:62][CH3:63])[N:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[N:56]1([CH:53]2[CH2:52][CH2:51][N:50]([S:47]([NH:46][C:44]3[CH:43]=[C:42]([O:62][CH3:63])[N:41]=[C:40]([S:39][CH2:38][C:37]4[CH:64]=[CH:65][CH:66]=[C:67]([F:68])[C:36]=4[F:35])[N:45]=3)(=[O:48])=[O:49])[CH2:55][CH2:54]2)[CH2:61][CH2:60][CH2:57]1
Reactant: COc1cc(NS(=O)(=O)N2CCC(N3CCOCC3)CC2)nc(SCc2cccc(F)c2F)n1
Agent: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride (0.11 g) was added to a solution of acetic acid (0.025 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step (0.10 g) in DCM (4 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were concentrated then methanol (1 mL) was added and the resulting suspension filtered. The solid was washed with water, methanol and ethyl acetate to afford the title compound as a white powder. Yield: 47 mg