Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:25])[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (6.65 g) in toluene (50 mL) was added to a solution of o-tolylmagnesium chloride in THF (1M, 30.9) at 0° C. After the addition was complete, the solution was heated to 85° C. for 1.5 hours, and stirring was continued at rt overnight. The mixture was heated for additional 2 hours to 85° C., cooled and poured onto ice. 1M HCl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Et2O/n-heptane 1:3) to yield the title compound (6.45 g, 73%) as a light yellow oil, MS (ESI−): m/z=370.0444 ([M−H]−, 1Br).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 40 °C

Procedure:
A mixture of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.9 mmol), 2,4,5-trichloropyrimidine (5.67 g, 30.9 mmol, 1 equiv.) and Na2CO3 (3.60 g, 34.0 mmol, 1.1 equiv.) in EtOH (100 mL) was heated at 40° C. for 24 h. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layer was washed with water (3×), saturated aqueous NaCl (1×) and dried over Na2SO4. The resulting EtOAc solution was concentrated in vacuo, providing the product 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; SMS m/z 244.0 (M+H+).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>O>[CH2:1]([N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:26](=[O:27])[CH2:25][Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CCCCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Butyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.5 grams), benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (6 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-butyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:46][CH2:47]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O:25][CH2:47][Cl:46])=[O:24])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid (5.88 g, 15.5 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (10.1 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (100 mL) and then chloroiodomethane (11.3 mL, 155 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1-4% MeOH in CH2Cl2), to give 3.95 g of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:19]=[N+]=[N-].[Na+]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1[NH2:19]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si](C)(C)c1ccc(F)c(C(=O)O)c1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C[Si](C)(C)c1ccc(F)c(N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2.12 g (10 mmol) of 2-fluoro-5-trimethylsilyl-benzoic acid and 1.78 g (15 mmol) of thionyl chloride is heated 2 hours at 60° C. Then gases and excess of thionyl chloride are removed under reduced pressure. To the crude material dissolved in 10 ml of acetone is added dropwise 6.5 g (10 mmol) of sodium azide in 10 ml of water and the mixture is stirred one hour at 0° C. Acetone is removed under reduced pressure and the acyl azide was extracted with ethyl acetate. The organic phase is dried over MgSO4 and ethyl acetate is removed under reduced pressure. To the acyl azide 20 ml of benzene is added and the reaction mixture is stirred 30 minutes at reflux. Then the solution is cooled to 0° C., 10 ml of concentrated hydrochloric acid is added and the mixture is heated 30 minutes at reflux. Benzene and water are removed under reduced pressure and the hydrochloride salt is recrystallized from isopropanol. To the salt dissolved in 10 ml of water is added 10 ml of 1N sodium hydroxide and the aqueous mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO4 and concentrated to obtain pure 2-fluoro-5-trimethylsilyl-aniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH:15]1([C:18]2[CH:19]=[C:20]([NH2:23])[NH:21][N:22]=2)[CH2:17][CH2:16]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[NH:21][N:22]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[CH:19]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1ncc(-c2ccccc2)c(Cl)n1
Solvent: CCO
Product: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Yield: 60 %

Procedure:
To 2,4-Dichloro-5-phenyl-pyrimidine (187 mg, 0.83 mmol) and trethylamine (255 μL, 1.83 mmol) in ethanol (25 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (142 mg, 1.16 mmol) and the solution was heated to 80 C for 14 h. The solvent was removed in vacuum, and the title compound was obtained by flash chromatography (0–2% methanol in dichloromethane) to give: 150 mg (60% yield). HPLC tr=6.68 min (87%), LCMS m/e 312.1 (M+H), 310.0 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1cccc(-c2cc(S(N)(=O)=O)cc(C=O)c2OC)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-methoxybenzene boronic acid, gave 5-formyl-3′,6-dimethoxy-biphenyl-3-sulfonic acid amide.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[CH:8]1([C:11]([C:6]2[CH:5]=[C:4]([CH3:7])[S:3][C:2]=2[CH3:1])=[O:12])[CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C)s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)C2CC2)c(C)s1
Temperature: 25 °C

Procedure:
2,5 Dimethylthiophene (50 g, 0.446 mole) and cyclopropylcarbonyl chloride (54.36 g, 0.52 mole) were dissolved in dichloromethane (500 ml) and cooled in an ice bath. Tin(IV) chloride (122.44 g, 0.470 mole) in dichloromethane (150 ml) was added slowly over 1 hour with stirring to form a deep red solution. The mixture was warmed to room temperature and stirred for a further hour. The mixture was then poured into cold water (750 ml) and stirred rapidly for 30 min. The dichloromethane layer was washed with cold water and dried over magnesium sulfate. The dichloromethane solvent was removed to give the ketone, 2,5-dimethyl-3-thienyl cyclopropyl ketone, as a brown oil (73.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[O:9]1CCC[CH2:10]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:9][CH2:10][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cc[nH]c1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccn(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
840 mg of 3-nitro-1H-pyrole, 15 ml of tetrahydrofuran and 15 ml of formaldehyde 36% in water were mixed. 0.5 ml of tetrabutylammonium hydroxide 10% in water was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-nitro-1H-pyrole.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC.[Cl-].[NH4+]>O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[OH:19])[NH:15][C:14]=12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: -15 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 141) (1.7 g, 5.1 mmol) in tetrahydrofuran (25 mL) was added 3.0 M phenylmagnesium bromide in Et2O (2.0 mL, 6 mmol) dropwise at −78° C. under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium bromide in Et2O (2.0 mL, 6 mmol) was added. The reaction mixture was stirred for another 1.5 h warming to −15° C. The reaction mixture was poured into a saturated ammonium chloride solution, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated sodium chloride, and dried over sodium sulfate. Filtration and concentration provided the crude material, which was purified by Biotage chromatography (10-30% ethyl acetate in hexanes) to provide [7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanol (1.32 g, 62%) as a yellow foam: mp 53-61° C.; 1H NMR (500 MHz, CD3OD) δ4.60 (4H, q, J=23.2, 15.4 Hz), 5.95 (1H, s), 6.25 (1H, s), 7.05 (1H, d, J=5.7 Hz), 7.15-7.40 (15H, m), 7.62 (1H, d, J=5.7 Hz); ESI MS m/z 420 [C28H25N3O+H]+; HPLC (Method A) >99% (AUC), tR=19.2 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.[CH3:37][NH:38][CH3:39]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19]([N:38]([CH3:39])[CH3:37])[N:18]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CNC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(N(C)C)n2)cc1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (204 mg, 0.356 mmol) and dimethylamine solution in water (0.4 mL, 3.02 mmol) in NMP (1 ml). The reaction was stirred and heated in a oil bath at 90° C. for 10 min. The mixture was diluted with water. The resulting white ppt was collected by filtration, washed with water, then MeOH, and dried to give the crude product. MS (ESI, pos. ion) m/z: 538/540 (1:1) (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH3:33])[S:27]([CH3:30])(=[O:28])=[O:29])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(NS(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(C)S(C)(=O)=O
Yield: 89.5 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}methanesulfonamide (60.4 mg, 0.124 mmol) in N,N-dimethylformamide (1.2 mL) was added sodium hydride (60%, 6.0 mg, 0.15 mmol. After the resultant mixture was stirred at room temperature for 30 min, methyl iodide (0.010 mL, 0.16 mmol) was added. The resultant mixture wad stirred at room temperature for 30 min, diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (55.6 mg, 0.111 mmol, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3]1.CC(C)([O-])C.[K+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:5]2[C:4]3[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN1CCc2c([nH]c3ccccc23)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1ccc(Cn2c3c(c4ccccc42)CCN(C)C3)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 33.2 %

Procedure:
A round bottom flask fitted with reflux condenser containing 2-methyl-2,3,4,9-tetrahydro-1H-b-carboline (16) (0.30 g, 1.62 mmol) and potassium tert-butoxide (0.22 g, 1.92 mmol) was vacuum purged and filled with argon, followed by addition of DMSO (5 mL). After stirring at 120° C. for 20 min, 4-bromomethyl-benzoic acid methyl ester (0.37 g, 1.62 mmol) was added and the mixture was stirred at 120° C. for 3 h. The reaction was quenched by addition of water (30 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. The product was purified by MPCC (0 to 5% gradient of MeOH in CH2Cl2), which gave 180 mg (33%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.95 (d, 2H, J=8.2 Hz), 7.54 (m, 1H, J=7.6 Hz), 7.18-7.11 (m, 4H), 7.15 (d, 2H, J=8.1 Hz), 5.25 (s, 2H), 3.89 (s, 3H), 3.53 (s, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.5, 141.9, 137.4, 130.4, 126.0, 122.8, 120.2, 118.6, 109.4, 106.7, 52.2, 51.3, 49.7, 46.6, 45.56, 42.1, 18.5. ESI-HRMS (m/z): [M+H]+ calcd. for C21H22N2O2, 335.1727. found, 335.1724.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].CO.[OH-].[K+]>O>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])=[N:13][NH:12]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1n[nH]c(=S)s1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-phenylalanine methyl ester (EXAMPLE 1; 528 mg, 1.56 mmol), MeOH (20 mL), H2O (5.0 mL) and KOH (350 mg, 6.24 mmol) is stirred at room temperature for 16 hours. The solution is concentrated (to remove the MeOH), acidified with 10% HCl, and extracted with EtOAc (3×20 mL). The organic layers are dried (MgSO4), filtered, and concentrated to give 490 mg (97%) of the title compound (mp 130° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[CH:15])=[CH:10][N:9]=2)=[C:4]([CH3:16])[CH:3]=1.I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]#[C:15][C:18]3[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[N:12][CH:13]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: C#Cc1cnc(-c2ccc(Cl)cc2C)cn1
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Product: Cc1cc(Cl)ccc1-c1cnc(C#Cc2ccc(OCCN3CCC(C)(O)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product was prepared analogously to Example 48.1c from 200 mg (0.88 mmol) of 2-(4-chloro-2-methylphenyl)-5-ethynylpyrazine and 316 mg (0.88 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (stirring the reaction mixture overnight at RT). Yield: 30 mg (7% of theoretical); C27H28ClN3O2 (M=461.983); calc.: molpeak (M+H)+:462/464 (Cl); found: molpeak (M+H)+:462/464 (Cl); HPLC-MS: 5.43 minutes (method G; Zorbax-Bonus).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:15]1[CH:20]=[C:19]2[C:21]([C:24]([C:26](Cl)=[O:27])=[O:25])=[CH:22][NH:23][C:18]2=[CH:17][CH:16]=1>>[NH:23]1[C:18]2[C:19](=[CH:20][CH:15]=[CH:16][CH:17]=2)[C:21]([C:24](=[O:25])[C:26]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)=[O:27])=[CH:22]1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Product: O=C(C(=O)N1CCC(Oc2ccc(F)cc2)CC1)c1c[nH]c2ccccc12

Procedure:
By following the manipulative procedure described in Example 4(b), 4-(p-fluorophenoxy)piperidine is reacted with indole-3-glyoxyloyl chloride to give 1-(indol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine as an off-white solid. The solid is recrystallized twice from a methanol and water mixture to give white needles of the glyoxamide, m.p. 205°-207° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: CC(=O)N1CSC[C@H]1C(=O)O
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 301 mg (0.77 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 7.5 ml of dichloromethane, 135 mg (0.77 mmol) of (R)-3-acetylthiazolidin-4-carboxylic acid, 342 mg (0.77 mmol) of BOP reagent and 0.15 ml (0.86 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 309 mg of 2-(((R)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]Br.[H-].[Na+].C(OCC)C>CN(C)P(=O)(N(C)C)N(C)C>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 100 ml of hexamethylphosphoric acid triamide at 35°. The mixture is allowed to cool to 20°, first 11.2 g of 2-bromoacetaldehyde-dimethylacetal and then, in portions, 2.9 g of 50% strength sodium hydride suspension (in mineral oil, de-oiled with hexane) are added, the reaction temperature being maintained at 25°-30° by cooling. The mixture is then stirred at room temperature for 1 hour, poured onto ice, the oil which separates is brought into solution with diethyl ether, and the organic phase is removed. The aqueous phase is extracted by shaking again with 200 ml of diethyl ether. The organic phases are combined, washed with 200 ml of 2 N sodium hydroxide solution, dried over magnesium sulphate and concentrated by evaporation. The oily crude product is crystallised from hexane and made into a slurry with methanol. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal having a melting point of 60°-61° is obtained.