Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]OC(=O)CC1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 95.0 mg, 0.34 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 90.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.62) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.54 g), which was subsequently deprotected.
Reaction SMILES: C[Al](C)C.[NH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:27][O:28][C:29]=2[CH3:30])=[CH:21][CH:22]=1)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[O:9]1[CH2:10][CH2:11][CH:6]([NH:5][C:15]([C:17]2[N:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[C:26]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[N:27][O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:8]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of 4-aminotetrahydropyran (121 mg, 1.2 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (102 mg, 0.3 mmol) in dioxane (3 mL) was added. The resulting mixture was heated at 85-95° C. for 5 h, cooled to room temperature, poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (62 mg, 52%) which was obtained as a white solid after recrystallisation from ethylacetate:heptane. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:34]1[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid dimethyl ester (250 mg, 0.65 mmol, see step (a) Example 19) and 4-trifluoromethylphenylboronic acid. Yield 230 mg (67%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:33]#[N:34].[Na+]>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:33]#[N:34])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Product: CCOc1cc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)ccc1CC#N

Procedure:
Prepared analogously to Example 29 from 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzyl chloride with sodium cyanide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]>C1COCC1.C(OCC)(=O)C.[Ni]>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccccn1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccccn1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(2-pyridyl)benzamide (4 g, 14.4 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney nickel (0.5 g). The mixture was placed under an atmosphere of hydrogen (4.1 bar) overnight. The mixture was then filtered and the filtrate was flushed through a pad of silica gel, eluting with ethyl acetate, and then concentrated in vacuo. The crude solid was suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 2.4 g (67%) of a faint green solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24]#[CH:25])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([C:16]1[CH:25]=[C:24]([CH:23]([O:26][CH2:27][CH3:28])[O:22][CH2:20][CH3:21])[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(OCC)OCC
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(OCC)c1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 52.4 %

Procedure:
A mixture of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (1.2 g, 4.5 mmol), 3,3-diethoxy-propyne (1.5 g, 11.4 mmol), CH2Cl2 (40 ml) and TEA (6 drops) was stirred until homogeneous, then Clorox bleach (20 ml) was added. After stirring vigorously for 12 h the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4; filtered; and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40(small) chromatography eluting with 10% EtOAc in hexanes gave 920 mg of the title compound as a colorless oil. MS [M+1]+391.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce].[NH4+].[CH2:7]([C:11]1[NH:12][C:13]([CH2:17][OH:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]>O.C(OCC)(=O)C>[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(I)c(CO)[nH]1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(I)c(C=O)[nH]1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of ammonium cerium nitrate (125 g; 228 mmol) in water (320 ml) was added to a solution of Example 28 (42 g crude; 95 mmol) in ethyl acetate (90 ml) and the mixture was stirred overnight. The aqueous phase was extracted three times with ethyl acetate, then rendered alkaline with NaHCO3 and extracted again with ethyl acetate. The combined organic phases were washed with 5% strength NaHCO3 solution and saturated sodium chloride solution, dried and concentrated. Silica gel chromatography of the residue (hexane/ethyl acetate step gradient) gave 19.2 g of a yellow solid [72% of theory; m.p. 80°-5° C.; Rf : 0.54 (methylene chloride: methanol=10:1)].
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:4][C:3]1([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)[CH3:5].B(Br)(Br)Br>C(Cl)CCl>[F:1][C:2]1([F:14])[CH2:4][C:3]1([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5]
Reactant: COc1ccc(C2(C)CC2(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: CC1(c2ccc(O)cc2)CC1(F)F

Procedure:
p-(2,2-Difluoro-1-methylcyclopropyl)phenol was prepared from 9.9 g. of p-(2,2-difluoro-1-methylcyclopropyl)anisole and 20 g. of boron tribromide in 200 ml. of ethylene dichloride according to the procedure described above in Example 1, part (c), affording 9 g. of pinkish oil which solidified upon standing.
Reaction SMILES: Br[CH2:2][C:3]([OH:10])([CH2:7][O:8][CH3:9])[CH2:4][O:5][CH3:6].[OH-].[Na+]>O>[CH3:6][O:5][CH2:4][C:3]1([CH2:7][O:8][CH3:9])[CH2:2][O:10]1
Reactant: COCC(O)(CBr)COC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC1(COC)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To 1-bromo-2-hydroxy-3-methoxy-2-(methoxymethyl)propane (30 g) was added sodium hydroxide (5.6 g) in water (50 cm3). The mixture was stirred at room temperature for 1 h and then extracted with diethyl ether. The extracts were dried (Na2SO4) and the solvent removed under reduced pressure (40° C. at 15 mmHg) to give the oxirane (13 g, 70%) as a colourless liquid. No further purification of this material was needed.
Reaction SMILES: C([NH:4][C@H:5]([PH:19]([OH:21])=[O:20])[C:6]([CH2:15][CH:16]([CH3:18])[CH3:17])(C(O)=O)[C:7]([O:9]CC)=[O:8])(=O)C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:4][C@H:5]([PH:19]([OH:21])=[O:20])[CH:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)O)[C@H](NC(C)=O)[PH](=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)O)[C@H](N)[PH](=O)O

Procedure:
A mixture of 13.47 g of ethyl hydrogen 2-[(R)-(acetamido)(hydroxyphosphinyl)methyl]-2(RS)-isobutylmalonate and 8.42 g of triethylamine in 420 ml of dry toluene was heated under reflux for 2 hours. After cooling, the solvent was removed by evaporation and the residue was dissolved in a mixture of 96 ml of water and 144 ml of concentrated hydrochloric acid and the solution was heated under reflux for 4 hours under a nitrogen atmosphere. The solution was evaporated to dryness and the 2-[(R)-(amino)(hydroxyphosphinyl)methyl]-4-methylvaleric acid obtained was dissolved in 225 ml of aqueous saturated sodium hydrogen carbonate solution and 45 ml of tetrahydrofuran. 30 g of solid sodium hydrogen carbonate and 45 ml of benzyl chloroformate were added and the mixture was stirred at room temperature for 48 hours in a nitrogen atmosphere. The solution was extracted twice with diethyl ether and the aqueous solution was acidified by the careful addition of hydrochloric acid and then extracted five times with dichloromethane containing 10% methanol. The extracts were dried over magnesium sulfate and evaporated to give a colorless gum which was crystallized from ethyl acetate. There were obtained 7.0 g of 2(R or S)-[(R)-benzyl-oxyformamido)(hydroxyphosphinyl)methyl]-4-methylvaleric acid as a single diasteroisomer in the form of a white solid; MS: 344 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](I)[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[CH2:29]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:30]
Reactant: CCI
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (160 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. Ethyl iodide (155 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH(aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). The compound was known to inhibit the hT2R14 with IC50 of 20 μM. Yield 35%. MS M+H calculated 350.11. Found 350.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=O)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:20])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(=O)Cc1ccc2occc2c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 1 gm (5.7 mMol) 1-(benzofur-5-yl)-2-propanone, 8.9 gm (115 mMol) ammonium acetate, and 2.8 gm powdered 3A molecular sieves in 60 mL methanol was stirred at room temperature for 1 hour. To this mixture were then added 5.8 mL (5.8 mMol) sodium cyanoborohydride (1.0 M in tetrahydrofuran) and the mixture was stirred for an additional 5 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then filtered over a pad of celite and the pad was rinsed with 200 mL methanol and 200 mL dichloromethane. The combined filtrates were concentrated under reduced pressure and the resultant residue was partitioned between 200 mL dichloromethane and 20 mL water. The mixture was washed with two 25 mL portions of 5 N sodium hydroxide. The combined aqueous extracts were extracted with three 100 mL portions of dichloromethane. All of the organic phases were combined, washed with 25 mL 0.1 N sodium hydroxide followed by 25 mL water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 6% methanol to dichloromethane containing 9% methanol and 9% concentrated ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.498 gm (49%) of 1-(benzofur-5-yl)-2-aminopropane.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: Cc1cccc(Oc2ccc(Cl)cc2C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3-methylphenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.18 (1H, d, J=2.6 Hz), 8.00–7.86 (3H, m), 7.40–7.20 (4H, m), 7.07–6.98 (1H, m), 6.98–6.74 (3H, m), 5.38–5.20 (1H, m), 3.88 (3H, s), 2.33 (3H, s), 1.48 (3H, d, J=6.9 Hz); MS (ESI) m/z 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:34])=[O:33])=[C:29]([CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:28]=[C:27]([CH3:42])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:34])(=[O:9])=[O:33])=[C:29]([CH2:35][C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[CH:28]=[C:27]([CH3:42])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(CC(=O)OC(C)C)c(S(C)=O)c2c1c1ccccc1n2Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)C)c(S(C)(=O)=O)c2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
44 mg (0.25 mmol) of m-chloroperbenzoic acid was added to 6 ml of a solution of 100 mg (0.23 mmol) of isopropyl (9-benzyl-1-methylsulfinyl-4-methylcarbazol-2-yl)acetate, as obtained in Example 215 below, in methylene chloride at room temperature, and the mixture was stirred for 30 minutes. After this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, the aqueous layer was extracted with methylene chloride, the extract was dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 50% v/v solution of ethyl acetate in hexane) to yield 90 mg (87%) of the title compound as an amorphous solid.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)[CH:19]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Clc1cc(-c2ccccc2OCc2ccccc2)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-methanesulfonyl-phenylamine hydrochloride (4.98 g, 24 mmol) and 4-chloro-6-(2-benzyloxyphenyl)-pyrimidine (6.88 g, 23.2 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control). The reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The resulting precipitate was filtered out, washed with water (2×200 mL), dried and purified by column chromatography on silica (eluent chloroform-ethanol 20:1) to yield [6-(2-benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonyl-phenyl)-amine as colorless solid.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][NH:6][C:7]1[S:8][C:9]([SH:12])=[N:10][N:11]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:5][NH:6][C:7]1[S:8][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][N:11]=1
Reactant: CNc1nnc(S)s1
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of sodium ethoxide in ethanol (prepared by adding 13.5 g of anhydrous sodium methoxide to 300 ml of absolute ethanol) was added 31 g of 2-methylamino-5-mercapto-1,3,4-thiadiazole. After stirring for 15 min. at room temperature, 36 g of benzyl bromide was added to the homogeneous solution and the reaction heated to reflux for 4 hrs. At the end of the reflux period, most of the ethanol was removed at reduced pressure, water was added and the reaction extracted with ethyl acetate, which was washed with water and saturated NaCl, then dried over Na2SO4. Removal of the solvent gave a viscous oil which was crystallized from a mixture of ether and petroleum ether to give 29.7 g of 2-methylamino-5-benzylthio-1,3,4-thiadiazole, MP 87-891/4C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+].O1CCOCC1>O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[N:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
A microwave vial (80 mL) was charged with 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.496 g, 6.49 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (2.000 g, 5.90 mmol), potassium acetate (1.777 g, 18.10 mmol), Am-Phos (0.403 g, 0.649 mmol), dioxane (20 mL) and water (3.00 mL, 167 mmol). The vial was heated in a CEM Voyager Microwave (Large-Scale Unit) for 25 minutes at 120° C. while 100 Watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The reaction mixture was diluted with water (15 mL) and extracted with Chloroform (3×50 mL). The organic extracts were combined and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was adsorbed onto a plug of silica gel and purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (220 g) with a gradient of 10% to 100% ethyl acetate/hexanes over 45 min to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (3.000 g, 4.66 mmol, 79% yield) as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 8.50 (dd, J=9.39, 2.35 Hz, 1H); 8.28 (d, J=1.37 Hz, 1H); 7.25 (d, J=8.61 Hz, 4H); 6.89 (dd, J=11.15, 8.61 Hz, 4H); 6.70-6.81 (m, 1H); 4.77 (d, J=4.69 Hz, 4H); 3.65-3.82 (m, 6H); 3.58 (s, 2H); 3.24-3.37 (m, 4H); 2.47 (s, 3H); 2.28-2.38 (m, 4H); 1.33-1.50 (m, 9H). m/z (ESI, +ve ion) 644.2 (M+H)+.