Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 2-(1,3-benzothiazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in methanol (15 mL) was added sodium hydroxide (30.0 mg, 0.75 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted pH to 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 2-(1,3-benzothiazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (80 mg, 82%).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1nnc(Cc2cccnc2)c(=O)[nH]1
Yield: 70.9 %

Procedure:
3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (2.34 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.88 g) were heated together on an oil bath (160°-70° ). The cooled mixture was triturated with boiling methanol and the solid was recrystallised from dimethylformamide to give the title compound as a colourless solid (2.53 g) m.p. 232°-233°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][Cl:28].O>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:17][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: ClCCCBr
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCCCl)ccc3c2s1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.00 mg, 4.08 mmol), cesium carbonate (5.30 g, 16.3 mmol), and DMF (40 mL) was stirred at 50° C. for 10 minutes. A portion (0.05 mL) of a solution (1.1 mL) of 1-bromo-3-chloropropane (705 mg, 4.48 mmol) in DMF was added every 7 minutes. After 2 hours the reaction mixture was poured into water (225 mL). The mixture was stirred for 30 minutes and then filtered. The isolated solid was dried to provide 785 mg of 7-(3-chloropropoxy)-2-ethylthiazolo[4,5-c]quinolin-4-amine as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 105 °C
Yield: 87.3 %

Procedure:
To the ester of Step C (26 mmol) was added methanol (10 mL), tetrahydrofuran (45 mL), and 1 N sodium hydroxide (33 mL). The solution was refluxed vigorously in an oil bath at 105° C. for one hour. The volatile solvents were evaporated and the solution was chilled in ice. Hydrochloric acid (2.0 N) was added until the pH was −1. The product was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, filtered and evaporated to a white solid. This was recrystallized in ethyl acetate and hexane to afford 5.5 g of the title compound (86%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:10]2[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])[CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])=O.[NH2:37]OS(O)(=O)=O.CO>O>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:4][C:3]=2[CH:1]=[N:37]1
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Reactant: NOS(=O)(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (190 mg, 0.39 mmol) in water (5 mL) was added aminooxysulfonic acid (83 mg, 0.48 mmol) and methanol (5 mL). The resulting solution was stirred overnight at 25° C. Then the reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (50 mg, 26%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(NC(C)C)(C)C.C[Si](C)(C)[C:32]#[C:33][C:34]1([CH3:38])[CH2:37][O:36][CH2:35]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:38][C:34]1([C:33]#[C:32][C:2]2[C:3]([O:8][CH:9]3[CH2:12][N:11]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:37][O:36][CH2:35]1
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CC1(C#Cc2nccnc2OC2CN(c3ccc4ccccc4n3)C2)COC1
Temperature: 85 °C
Yield: 12.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (288 mg, 0.249 mmol), copper(i) iodide (190 mg, 0.998 mmol) and 2-(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 0.998 mmol) were combined in a microwave vial which was degassed and backfilled with nitrogen (procedure was repeated three times). DMF (1663 μL) was added followed by diisopropylamine (2097 μL, 14.96 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (840 mg, 4.99 mmol). The tube was sealed and heated to 85° C. for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water. The aqueous layer was back extracted with EtOAc (3×) and the combined organic phase was dried over Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 2-(3-(3-((3-methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinoline (45 mg, 0.121 mmol, 12.11% yield) as orange powder. 1H NMR (400 MHz, chloroform-d) δ ppm 1.76 (s, 3H) 4.28 (dd, J=9.88, 4.21 Hz, 2H) 4.47 (d, J=5.48 Hz, 2H) 4.67 (dd, J=9.59, 6.65 Hz, 2H) 4.97 (d, J=5.48 Hz, 2H) 5.52-5.62 (m, 1H) 6.63 (d, J=8.80 Hz, 1H) 7.21-7.41 (m, 2H) 7.45-7.65 (m, 1H) 7.76 (d, J=8.22 Hz, 1H) 7.90 (d, J=8.80 Hz, 1H) 8.03 (d, J=2.74 Hz, 1H) 8.17 (d, J=2.54 Hz, 1H). ESI (M+1) 373.1; calc for C22H20N4O2 372. (PDE10 IC50=0.0446 nM).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:6][C:7]([O:10][CH2:13][CH:15]2[O:17][CH2:16]2)=[CH:8][CH:9]=1)[OH:11]
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC2CO2)cc1O

Procedure:
By refluxing 34 g of 2,4-dihydroxybenzoic acid methyl ester with 185 g of epichlorohydrin and 35 g of potassium carbonate for 2 to 3 hours, and chromatographing the crude product on 100 g of silica gel (elution with toluene), 4-(2,3-epoxypropoxy)salicylic acid methyl ester having a melting point of 53°-55° is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8]([C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:6]1[CH:7]=[C:3]([CH2:2][NH:12][C:11]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:8][CH3:9])[N:4]=[CH:5]1
Reactant: ClCc1cscn1
Reactant: CCc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCc1cscn1
Temperature: 100 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
In 200 ml dry dimethylformamide was added 10.2 g 4-chloromethylthiazole, 10.26 g 2-ethyl-6-methylaniline and 10.54 g of potassium carbonate. The mixture was stirred at 100° C. for 3 days and filtered. The filtrate was stripped, dissolved in methylene chloride, washed with water, dried and stripped again. The crude product was chromatographed with methylene chloride through a 200-g silica-gel column to give 7 g of product.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[S:16][N:15]=[C:14]([CH3:17])[N:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:17][C:14]1[N:13]=[C:12]([N:11]([CH3:10])[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[S:16][N:15]=1
Reactant: CNc1nc(C)ns1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nsc(N(C)C(=O)C2CCCCC2)n1

Procedure:
Cyclohexane carboxylic acid chloride (9.92 g, 0.068 mol) was added slowly to a solution of 5-methylamino-3-methyl-1,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and the mixture heated under reflux for 11/2 hours, cooled and washed with 2N hydrochloric acid, saturated solution sodium hydrogen carbonate and water; dried over magnesium sulphate, filtered and evaporated down to yield yellow oil which crystallised upon standing. This was recrystallised twice from petroleum ether 60°-80° C. to yield off-white crystals of N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-methylcyclohexane carboxamide. Yield 8.23 g, (63.8%), m.p. 96° C.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Reactant: COc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1NC1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 75 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-methoxyphenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 75%. Melting point: 184-185° C. (ethyl acetate-hexane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(C(F)F)COCC(N)=N3)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (44.47 g, 91.0 mmol) was dissolved in 450 ml DCM and mildly chilled with a rt water bath. TFA (150 ml) was added. The reaction was slightly exothermic. The mixture was stirred for 1.5 h at rt. The volatiles were removed with vacuum at rt. The residue was taken up in DCM and the procedure repeated twice. The residue was taken up in 3 L EtOAc and washed with 10% aqueous Na2CO3 and brine. The organic phase was dried with sodium sulfate and partially evaporated. iPrOH was added and the mixture chilled. The title compound was collected as snow-white crystals. Yield 30.56 g.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClCCl.O=[Pt]=O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: C[C@H]1N[C@@H](c2ccccc2)COC1=O
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1.70 g, 9.0 mmol, 1.0 equiv.) in anhydrous dichloromethane (60 mL) under an atmosphere of nitrogen was added PtO2 (170 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by recrystallisation in dichloromethane, diethyl ether and hexane to furnish the title compound as white needles (1.26 g, 74%); m.p. 81.0-82.0° C. (lit. m.p. 81.0-82.0° C.); v(max)(KBr) 3314 (N—H), 2981 (C—H), 1736 (C═O), cm−1; δH (250 MHz, CDCl3) 7.43-7.26 (5H, m, Ph); 4.42-4.23 (3H, m, CHCl2), 3.88 (1H, q, /6.76 Hz, CHCH3), 1.80 (1H, br, NH), 1.50 (3H, d, J 6.76 Hz, CH3); δc (62.5 MHz, CDCl3) 170.7, 138.1, 129.3, 129.1, 127.5, 75.4, 58.2, 55.4, 19.0; m/z (CL, NH3), 192 (MH+, 30%), 147 (68%), 132 (64%), 104 (100%), and 91 (10%); HRMS for C11H13NO2 requires 192.1025 found 192.1019. [α]D20 +88.8 (c 0.96 CHCl3) (lit. [α]D20 +92.3 (c 0.84 CHCl3)).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C.C(#N)C.[Pd]>[C:15]1(=[O:16])[CH:10]2[CH2:9][NH:8][CH2:12][CH:11]2[CH2:13][NH:14]1
Reactant: O=C1NCC2CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: CCO
Solvent: CC#N
Product: O=C1NCC2CNCC12
Reaction time: 16 h

Procedure:
A solution of 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g; 33 mmol) in absolute ethanol (100 ml) is placed in a 250 ml autoclave and palladium-on-charcoal at 5% (1.5 g) is then added. After having purged with nitrogen, the autoclave is placed under 5-6 bar of hydrogen at 70° C. for 16 hours. After returning to 20° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The compound obtained is taken up in acetonitrile (15 ml) at reflux, filtered, under hot conditions, through paper and then crystallized. After crystallization, the solid obtained is filtered off, washed with acetonitrile (3 ml) and then with diethyl ether (20 ml) and, finally, dried under reduced pressure at constant weight. Hexahydropyrrolo[3,4-c]pyrrole-1-one, (1.3 g; 31%) is isolated, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCNC(=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 mg, 0.11 mmol) for 18 hours. The reaction was heated for 2.0 hours at 50° C., then additional potassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 mg, 0.11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 16 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(3-oxopiperazin-1-yl)ethoxy)benzamide. MS (Q1) 558 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][OH:11])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: OCCNc1ccc(F)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN(CCO)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-[(4-fluorophenyl)amino]ethan-1-ol (1.3 g, 8.39 mmol), methyl 4-bromobutyrate (2.28 g, 12.58 mmol), potassium carbonate (2.31 g, 16.77 mmol), and anhydrous N,N-dimethylformamide (6 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at 80° C. for 16 hours. Progress of the reaction was monitored by TLC using ethyl acetate:hexanes (1:1) (Rf product=0.5). Another aliquot of methyl 4-bromobutyrate (0.76 g, 4.20 mmol) was added and this was allowed to stir at 80° C. for 20 hours, until 2-[(4-fluorophenyl)amino]ethan-1-ol was consumed by TLC analysis. The reaction was partitioned using ethyl acetate (50 mL) and water (15 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated aqueous NaCl (3×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 20-100% ethyl acetate in hexanes to afford the title compound as an oil (1.1 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1
Reactant: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 142 mg (0.33 mmol) of the compound from example 1 were initially charged in THF (9.5 ml), the mixture was cooled to 0° C. and 13 mg (0.33 mmol) of sodium hydride (60% suspension in mineral oil) were then added. The mixture was stirred at 0° C. for 30 min, and 96 μl (0.67 mmol) of 2,2,2,-trifluoroethyl trichloromethanesulfonate were then added dropwise. The reaction mixture was stirred at RT overnight. The mixture was then diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase dichloromethane:methanol 60:1) and the product fractions were concentrated. The crude product obtained in this manner was re-purified by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient), then suspended in acetonitrile/water and finally dried by lyophilization. This gave 68 mg (40% of theory) of the title compound as a solid.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[BrH:10].N([O-])=O.[Na+]>O.C(OCC)C>[Br:10][C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)C[C@@H](Br)C(=O)O
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a 500 mL round bottom flask was added D-aspartic acid ((R)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-5° C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 5° C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25° C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (˜100 mL) and hexanes (˜10 mL) to obtain the product (16.58 g, 84 mmol, 45%) as a white crystalline solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].Br[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CC1C=CC=CC=1>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]3[N:6]=[C:2]4[N:3]([CH:8]=3)[CH:4]=[CH:5][S:1]4)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Nc1nccs1
Reactant: O=C(CBr)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cn5ccsc5n4)CC3)nc3ccccc32)cc1
Yield: 5.3 %

Procedure:
A mixture of 2 parts of 2-thiazolamine, 12.7 parts of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone, 6.4 parts of sodium carbonate and 135 parts of methylbenzene was stirred and refluxed for 3 hours using a water separator. The whole was filtered and the filtrate was evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 0.5 parts (5.3%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(imidazo[2,1-b]thiazol-6-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 222.7° C. (compound 149).