Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=O.O=P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2nnc(-c3cccs3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To 250 mL round bottom flask was added 2.0 g (11.7 mmol, 1 eq) of 4-chlorobenzhydrazide (1) in 100 mL of amelene stabilized chloroform, followed by addition of 4 mL (29.25 mmol, 2.5 eq) of TEA. Then, 1.4 mL (12.87 mmol, 1.1 eq) of 2-thiophenecarbonyl chloride (2) was added drop-wise and the mixture was stirred at ambient temperature for 1 h. Reaction progress was monitored by LCMS on a twelve minute gradient. The formed white precipitate was filtered, washed with chloroform and then dried on the high vacuum for two hours. The resulting material was confirmed to be the desired diacylhydrazide and was used in the next step without further purification. The crude diacyl-hydrazide was dissolved in 60 mL of POCl3 under heating. The resulting mixture was then heated under reflux in oil bath (100-110° C.) for 5-7 h. The reaction progress was monitored by LCMS on a twelve minute gradient. Once the cyclization reaction was completed as determined by LCMS, POCl3 was carefully evaporated in vacuum and the reaction was then neutralized with a 1 N solution of ammonium hydroxide. The product was extracted with ethyl acetate (300 mL) from saturated solution of NaHCO3 (200 mL), washed with a brine (2×200 mL), then dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by flash column chromatography (hexane→12% ethyl acetate/hexane), and then recrystallized from mixture of hexane/ethyl acetate (5:1) to give 1.3 g of the desired compound 2-(4-Chloro-phenyl)-5-thiophen-2-yl-[1,3,4]oxadiazole (42%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Li+]>O1CCCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:48]([O:50][C:51](=[O:72])[C@H:52]([O:54][C:55]1[CH:60]=[C:59](Cl)[N:58]=[C:57]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:56]=1)[CH3:53])[CH3:49]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:48]([O:50][C:51](=[O:72])[C@H:52]([O:54][C:55]1[CH:60]=[C:59]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[N:58]=[C:57]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:56]=1)[CH3:53])[CH3:49]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)C2CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of cyclopropanesulfonamide (prepared according to patent WO 2003/099274, 0.14 g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.30 g
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([CH3:36])[CH:26]=1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][C:8]([NH:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([CH3:36])[CH:26]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)ccc1C(=O)N(C)C
Reactant: CSc1nc2cccc(Br)c2o1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nc3cccc(Br)c3o2)ccc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.49 g (2.01 mmol) 7-bromo-2-methylsulfanyl-benzooxazole in 30 ml dichloromethane, 3-chloroperbenzoic acid (0.494 g, 2.01 mmol) is added. This mixture is stirred for 1 h at room temperature. Then, 0.325 g (1.82 mmol) 4-amino-2,N,N-trimethyl-benzamide is added and the reaction mixture is heated to 40° C. with stirring continued for 20 h. The reaction mixture is concentrated in vacuo and the residue is purified by chromatography (silicagel, hexane:EtOAc=1:1=>1:4) to afford the title compound as an off-white crystalline solid.
Reaction SMILES: [Na].[C:2]([OH:5])(=[S:4])[CH3:3].[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11]Cl>CO>[CH3:6][O:7][C:8](=[O:15])/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11][O:5][C:2](=[S:4])[CH3:3]
Reactant: CC(O)=S
Reactant: COC(=O)/C=C(\CCl)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C(\COC(C)=S)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
4.07 g (0.177 mol) of sodium is dissolved in 180 ml of methanol and cooled to 0° C. 13.47 g (0.171 mol) of thioacetic acid is instilled in this solution. Then this solution is mixed at 0° C. with a solution of 29.15 g (0.150 mol) of 3-methoxy-4-chloro-2E-butenoic acid methyl ester in 'ml of methanol. It is stirred again overnight at room temperature. The precipitated salt is filtered off, the solvent is evaporated on the rotary evaporator and mixed with a little methylene chloride for precipitation of the remaining salt. After filtering off, evaporation of the solvent and drying of the residue in a high vacuum, 36.53 g of a yellow-colored liquid with a content according to GC of 82.8 percent is obtained. This corresponds to 30.25 g of 100 percent product ≐98.7 percent yield. Further data concerning the compound is:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: Cc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(n1)NCCC2
Reaction time: 24 h
Yield: 82.5 %

Procedure:
The compound was prepared according to the procedure as described in WO 0033838. To a solution of 2-methyl-1,8-naphthyridine (2 g, 13.9 mmol) in ethanol (35 ml) was added 10% Pd/C, and the reaction mixture was stirred under H2 (10 psi) for 24 hours. Palladium was filtered out through celite and washed with excess ethanol. The filtrate was concentrated under vacuum to give 1.7 g (83%) pink solid. NMR (CD3OD) δ1.82-1.87 (m, 2H), 2.22 (s, 3H), 2.65-2.76 (m, 2H), 3.33-3.36 (m, 2H), 6.32 (d, 1H, J=7.25 Hz), 7.07 (d, 1H, J=7.38 Hz). Mass spectrometry: 149.15 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:35]5[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
The compound (200 mg, 0.43 mmol) obtained in Example 3-2), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), tricyclohexylphosphine (15 mg, 0.05 mmol), and tripotassium phosphate (160 mg, 0.73 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (50 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (140 mg, 64%) in a light yellow solid form.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cc(F)cc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 70.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24)(126 mg, 0.364 mmol) in sodium carbonate (96.3 mg, 0.909 mmol), Pd(PPh3)2Cl2 (10.63 mg, 0.015 mmol), toluene/ethanol/water (3/5/1 ml) to give 160 mg (72.7% yield) of titled compound. MS: m/z=753.1 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 70 °C
Yield: 77.6 %

Procedure:
To a solution of 16.3 g of the N-[3-[3-(piperidinomethyl)phenoxy]propyl]phthalimide in 150 ml of methanol was added 2.3 g of hydrazine monohydrate, and the mixture was heated at 70° C. for 4 hours. The mixture was cooled, then the solvent was distilled off, 30 ml of 6N hydrochloric acid was added to the residue, and the mixture was heated at 60° C. for 15 minutes. The resulting mixture was cooled, the insolubles were then filtered off, the solution was made alkaline with potassium hydroxide and subjected to extraction with a mixture of ethyl acetate and diethyl ether (1:1), and the organic layer was dried over magnesium sulfate and thereafter distilled to remove the solvent, giving 8.3 g of pale yellow oily 3-[3-(1-piperidinomethyl)phenoxy]propylamine (yield 78% ).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:12]([C@H:7]1[C:8]2[C:4](=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C#N)cccc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To (R)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-52 (0.700 g, 2.7 mmol) was added anhydrous DMF (10 mL) and the reaction mixture was stirred in a 0° C. ice bath under N2. Sodium hydride (0.541 g, 13.5 mmol) was added and the mixture was stirred at 0° C. for 2 h. After 2 h, (2-bromoethoxy)-tert-butyldimethylsilane (1.43 g, 5.9 mmol) was added and the reaction mixture was allowed to warm to room temperature for 1 h. The reaction was cooled to 0° C. and quenched with MeOH followed by saturated NaHCO3. The mixture was extracted with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to produce a brown oil. The crude product was purified by silica gel flash chromatography (20% EA/Hexanes) to afford 0.868 g (77%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate INT-59 as a yellow oil. LCMS-ESI (m/z) calculated for C23H36N2O3Si: 416.6; found 317.1 [M+H−Boc]+, tR=4.05 min. 1H NMR (400 MHz, (CD3)2SO) δ 7.50 (m, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 5.78 (m, 1H), 4.02 (m, 2H), 3.51 (m, 2H), 3.29 (m, 1H), 2.97 (m, 1H), 2.26 (m, 2H), 1.40 (s, 9H), 0.83 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[C:14]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]=3[O:19][CH3:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:40]=1.C(N(C(C)C)C(C)C)C>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[C:14]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:27]4)=[N:15][C:16]([N:48]4[CH2:49][CH2:50][N:45]([C:41]5[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=5)[CH2:46][CH2:47]4)=[N:17][C:18]=3[O:19][CH3:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: c1cncc(N2CCNCC2)c1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc(-c2ccc(F)cc2)cs1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(N2CCN(c3cccnc3)CC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc(-c2ccc(F)cc2)cs1

Procedure:
A solution of tert-butyl (3R)-3-([5-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-2-methanesulfonyl-6-methoxypyrimidin-4-yl]amino)piperidine-1-carboxylate (45.0 mg, 0.08 mmol, 1.00 equiv), 1-(pyridin-3-yl)piperazine (15.6 mg, 0.10 mmol, 1.20 equiv) and N-ethyl-N-isopropylpropan-2-amine (20.7 mg, 0.16 mmol, 2.00 equiv) in CH3CN (6.0 mL) was heated for 15 h at 100° C. in an oil bath. Concentration under reduced pressure gave 80.0 mg (crude) of the title compound, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 647.
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O.Cl>C1COCC1>[OH:2][CH2:1][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C=O)cc3)nc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CO)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-formyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide (194 mg, 0.5 mmol), in THF (40 ml) was added sodium borohydride (19 mg, 0.5 mmol) and the mixture stirred for 2 h at r.t. Water was added (30 ml) followed by 1N HCl (4 ml) and the mixture agitated. The aqueous phase was then extracted twice with EtOAc (30 ml), the combined organic phases were then washed with saturated NaCl solution, dried with Na2SO4 filtered and evaporated. The crude residue was suspended in ether and ultrasonnicated for 10 min., the solid precipitate was filterted off, washed with ether then dried under vacuum (0.05 mmHg, 50° C.) to afford the title compound as a light yellow solid (150 mg, 77% yield), MS: m/e=390.0 (M+).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCNCCCl
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
A stirred solution of bis (2-chloroethyl) amine hydrochloride (150 g, 0.84 mol), potassium carbonate (255 g, 1.9 mol) and benzyl bromide (110 ml, 0.92 mol) in DMF (1500 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool to ambient temperature, then the DMF removed in vacuo. The residue was taken into ethyl acetate (1000 ml), then washed with water (2×1000 ml). The organic phase was separated, dried (MgSO4) and evaporated. The crude residue was chromatographed in 20:1 petrol:ether, to give N-benzyl bis(2-chloroethyl)amine (36 g, 18%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].O=[CH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:8]([O:9][CH3:10])[C:6]=1[OH:7].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]>C(O)C>[CH3:10][O:9][C:8]1[C:6]2[O:7][C:15]([C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:17])=[CH:4][C:5]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: COc1cccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2cc(C(=O)c3ccncc3)oc12
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Sodium hydroxide (1.22 g) was added to a solution of o-vanillin (2.11 g) in ethanol (50 ml) at 55° C. under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes to give a yellow suspension. 4-(Bromoacetyl)pyridine hydrobomide (5 g) was then added portionwise and the solution heated at 55° C. for 12 h, then at 65-70° C. for a further 12 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between water (250 ml, containing sodium hydroxide (0.5 g)) and dichloromethane (2×200 ml). The combined organic phases were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated in vacuo onto silica gel. The compound was washed through a pad of silica with ethyl acetate, the ethyl acetate was removed in vacuo and the residue azeotroped with hexane. The resulting solid was washed with hexane and filtered to furnish the title compound (0.95 g) as a yellow solid. TLC Rf 0.53 (ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][N:15]1[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:14]1=[O:21]
Reactant: COc1ccc(CBr)cc1OC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1OC
Yield: 67 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(bromomethyl)-1,2-dimethoxybenzene. Yield 67%, white solid. 1H NMR (DMSO-d6, 400 MHz): .s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 4.49 (s, 2H), 5.20 (s, 2H) 6.92 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 7.83 (d, J=0.4 Hz, 1H), 8.20 (d, J=0.4 Hz, 1H). MS 454 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an 1050 of 0.08 μM.