Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[C:15](Cl)=[O:16])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:20]=1)[C:15](=[O:16])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Reactant: Sc1ccccn1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Sc2ccccn2)cc(C(C)(C)C)c1
Reaction time: 5 h

Procedure:
To a stirred solution of 2-mercaptopyridine (2.78 g, 25.0 mmol) in CH2Cl2 (50 mL) was added a solution of 3,5-di-tert-butylbenzoyl chloride (6.31 g, 25.0 mmol) in CH2Cl2 (125 mL) over 10 min. After 5 h, TLC showed complete consumption of the 2-mercaptopyridine, then 2 N NaOH was added. The organic phase was isolated, washed with water, then dried (Na2SO4) and the solvent was removed to afford a white solid. The solid was recrystallized in hexane affording a white solid (5.05 g, 62%): mp 73-74° C.; 1H NMR δ 1.36 (s, 18H), 7.31-7.36 (m, 1H), 7.67-7.70 (m, 1H), 7.75-7.80 (m, 2H), 7.85-7.88 (m, 2H), 8.66-8.69 (m, 1H); 13C NMR δ 32.0, 35.7, 122.6, 124.2, 128.9, 131.4, 136.9, 137.7, 151.1, 152.3, 152.5, 190.8; Anal. Calcd for C20H25NOS: C, 73.35; H, 7.69; N, 4.28. Found: C, 73.40; H, 7.75; N, 4.23.
Reaction SMILES: [CH3:1][C:2]([NH:25][C:26]([NH2:28])=[S:27])([CH3:24])[CH2:3][NH:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:29][CH:30]1[CH2:36][CH2:35][O:34][C:33]2[CH:37]=[C:38]([Br:41])[CH:39]=[CH:40][C:32]=2[C:31]1=O>C(O)C>[BrH:29].[Br:41][C:38]1[CH:39]=[CH:40][C:32]2[C:31]3[N:28]=[C:26]([NH:25][C:2]([CH3:24])([CH3:1])[CH2:3][NH2:4])[S:27][C:30]=3[CH2:36][CH2:35][O:34][C:33]=2[CH:37]=1
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Reactant: CC(C)(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(N)=S
Solvent: CCO
Product: Br
Product: CC(C)(CN)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Yield: 68 %

Procedure:
Following the Example 356, 1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea was reacted with 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in ethanol under reflux for 18 hours to give N2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diamine hydrobromide. Yield 68%. MS (ESI+): 368.0
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:13])[C@H:7]([C@H:9]([CH2:11][CH3:12])[CH3:10])[NH2:8])([CH3:4])[CH3:3].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN1C(=O)N(C)CCC1.O>[CH3:4][C:2]([O:5][C:6](=[O:13])[C@H:7]([C@H:9]([CH2:11][CH3:12])[CH3:10])[N:8]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N(CCO[Si](C)(C)C(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
L-isoleucine 1,1-dimethylethylester (23.00 g; 122.8 mmol), (2-Bromoethoxy)-(1,1-dimethylethyl)dimethylsilane (30.26 g, 126.5 mmol) and Na2CO3 (26.18 g; 247.0 mmol) were stirred in DMPU (Aldrich art. 25,156-9) (300 mL) at 90° C. for 20 h. The intermediate product was not isolated, but after cooling the mixture to roughly 40° C., tert-butyl bromoacetate (commercial product) (19.0 mL; 130 mmol) and further Na2CO3 (27.00 g; 254.7 mmol) were added, then heating at 90° C. was restored. More tert-butyl bromoacetate (2.0 mL; 14 mmol) was added after 4 h and heating prolonged for another 2 h. The mixture was cooled to 0° C., then water (600 mL) was cautiously added (exothermic solubilization). Once clear, the solution was extracted with diethyl ether (4×250 mL); the combined organic layers were washed with water (3×250 mL), brine (250 mL), at last dried over Na2SO4. After removal of solvents in vacuo, the residual oil was purified by flash chromatography (n-hexane/iPr2O 95:5). The desired compound was obtained (42.25 g; 91.90 mmol). Yield 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C.O>C(#N)C>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
4-Methoxybenzenesulfonyl chloride (341 mg, 1.7 mmol) was added to a solution of 1-(-2′,4′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol) and triethylamine (418 μL, 3 mmol) in acetonitrile. The reaction progress was monitored by LCMS and after 2 hours the reaction appeared to be complete. Water was added and the resulting solid was collected by filtration. The solid was dissolved in dichloromethane and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the title compound (473 mg, 78%) as a white solid, m.p. 154-155° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Li])CCC.S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][CH3:18])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COC[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidine-2-carboxylic acid (820 mg, 3.34 mmol) in 11 mL THF was cooled in a −10° C. bath and treated with n-butyl lithium (1.6M in hexanes, 6.5 mL, 10.36 mmol) and kept cold for 1 hour, then dimethyl sulphate (0.380 mL, 4.01 mmol) was added. The temperature was held at −5° C. to 5° C. and then the reaction mixture was held in the −20° C. freezer overnight. The reaction was quenched cold, with water. Next, the mixture was concentrated under reduced pressure to remove THF. The aqueous mixture was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to give 788 mg crude product, which was then purified by silica gel chromatography to give 199 mg clean product, 140 mg recovered starting material, and 317 mg of a mixture of starting material and product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][N:20]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([NH:27][C@@H:25]([C:22]1[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=1)[CH3:26])=[O:7]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Br)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 3-bromo-5-(5-methylpyridin-2-yl)benzoic acid (250 mg, 0.86 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (141 mg, 1.03 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (651 mg, 1.71 mmol), N,N-diisopropylethylamine (0.60 mL, 3.42 mmol), and N,N-dimethylformamide (6 mL). The reaction mixture was stirred at room temperature overnight, and then washed with brine and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:20](=[O:21])[O:22][CH2:23][CH3:24])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
3,5-Dichloro-4-(3,5-dichlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solventis then removed to yield the desired product ethyl [3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]carbamate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[N+:24]([O-])=O)=O)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:24][C:18]=2[CH:19]=1
Reactant: CN1CCC(C(=O)c2ccccc2Nc2ccc(F)cc2[N+](=O)[O-])CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCC(C2=Nc3cc(F)ccc3Nc3ccccc32)CC1

Procedure:
The general procedures of Example 6 are repeated. The compound o-(4-fluoro-2-nitroanilino)phenyl 1-methyl-4-piperidyl ketone is reduced and cyclized with phosphorus oxychloride to give 8-fluoro-11-(1-methyl-4-piperidyl)-5H-dibenzo[b,e][1,4]diazepine base, which is converted to the fumarate salt.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:17]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)NCc2ccccn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of 3.0 g of product from Example 95, 13.5 g of acetic anhydride, 0.081 g of 4-N,N-dimethylaminopyridine, 3.34 g of triethylamine and 25 ml of methylene chloride is heated, in a sealed tube, at 100° C. for 54 hours. The reaction is concentrated in vacuo, dissolved in methylene chloride, washed with saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 20% ethyl acetate/hexane) to give 1.42 g of the desired product as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:9][N:8]([CH3:10])[C:7](=O)[CH:6]([CH3:12])[CH2:5][CH2:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:4][CH2:5][CH:6]([CH3:12])[CH2:7][N:8]([CH3:10])[CH2:9]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCC(C)C(=O)N(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC1(c2cccc(OC)c2)CCC(C)CN(C)C1
Yield: 89.9 %

Procedure:
Epimer `B` of 6-ethyl-6-(m-methoxyphenyl)-1,3-dimethylhexahydro-2H-azepin-2-one [Example 1 (ii) (a); 2.8 g.] in dry ether (20 ml.) was reduced with lithium aluminium hydride (1 g.) according to the procedure of Example 2. After work up, the colourless oil was distilled affording the title compound (2.39 g.), b.p. 106°-110° C. 0.1mm.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][NH:13]2>C(Cl)Cl>[CH3:9][N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][N:13]2[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Nc1ccc(Cl)nn1
Solvent: ClCCl
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc(N)nn1
Temperature: 200 °C

Procedure:
6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:3]([OH:5])[CH3:4].P(=O)(O)(O)O>C(OC(=O)CC)(=O)CC>[C:3]([O:5][CH:3]([C:2]([CH3:1])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4])(=[O:5])[CH2:2][CH3:1]
Reactant: CC(C)=CCC(C)(C)C(C)O
Agent: CCC(=O)OC(=O)CC
Agent: O=P(O)(O)O
Product: CCC(=O)OC(C)C(C)(C)CC=C(C)C

Procedure:
From 46.8 g of 3,3,6-trimethyl-hept-5-en-2-ol, 70 ml of propionic anhydride and 0.1 ml of phosphoric acid analogously to Example 7.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=2)[C:5]1=[O:26])(=O)C>O1CCCC1.[C].[Pd]>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][O:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH3:18])[CH2:11][CH:6]1[NH:7][C:8](=[O:10])[CH2:9][NH:4][C:5]1=[O:26]
Reactant: COCCOCOc1cc(C=C2NC(=O)CN(C(C)=O)C2=O)ccc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCOCOc1cc(CC2NC(=O)CNC2=O)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of 1-acetyl-3-[[3-[(2-methoxyethoxy)methoxy]-4-methylphenyl]methylene]-2,5-piperazinedione (2.0 g) in tetrahydrofuran (20 ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.2 g) at room temperature under atmospheric pressure for 3 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved into tetrahydrofuran (30 ml) and thereto was added hydrazine monohydride (1.5 ml). After being stirred for 1 hour at room temperature, the mixture was concentrated under reduced pressure. The residue was triturated with isopropyl alcohol and the resulting solid was collected by filtration to give 3-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-2,5-piperazinedione (1.75 g).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[NH:7][C:8]([CH3:13])=[CH:9][C:10](=[O:12])[CH:11]=1.[C:14](O)(=[O:16])C>[OH-].[Na+]>[CH3:5][C:6]1[NH:7][C:8]([CH3:13])=[CH:9][C:10](=[O:12])[C:11]=1[CH:14]=[O:16]
Reactant: Cc1cc(=O)cc(C)[nH]1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)c(C=O)c(C)[nH]1

Procedure:
Chloroform (12 ml) was added in 1 ml portions over a period of 2 hours to a refluxing solution of 2,6-dimethyl-4-(1H)-pyridone (6.2 g) in 4M aqueous sodium hydroxide (112 ml). The solution was heated under reflux for 6 hours, cooled and acidified to pH 6 with acetic acid. Volatile material was removed by evaporation and the residue was extracted with methanol (3×100 ml). The extracts were concentrated and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v), to give 2,6-dimethyl-3-formyl-4(1H)-pyridone (B) (2.1 g) as a solid, m.p. >100° C. (decomposition); NMR (d6 -DMSO): 2.2(s,3H), 2.5(s,3H), 6.1(s,1H), 10.25(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][CH2:15][CH2:16]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: ClCCCCCl
Reactant: CCOC(=O)Cc1cccs1
Product: CCOC(=O)C1(c2cccs2)CCCC1

Procedure:
Thiophen-2-yl acetic acid ethyl ester (1) was dialkylated as described in Example 1, Step 1, using 1,4-dichlorobutane to obtain the title compound (31).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[NH4+].[NH4+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]2(CC(O)=O)[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>CCN(CC)CC.CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([C:14]2([C:1]([NH2:27])=[O:4])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CC1(c2cccc(Br)c2)CC1
Reactant: O=C([O-])[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C1(c2cccc(Br)c2)CC1

Procedure:
Ammonium carbonate (7.97 g 83.0 mmol) was added to a suspension of 1-(3-bromophenyl)cyclopropylacetic acid (2.00 g, 8.30 mmol), HOBt (1.68 g, 12.4 mmol) and EDCl.HCl (2.39 g, 12.4 mmol) in Et3N (5 mL) and DMF (25 mL) and the mixture was stirred at room temperature overnight. EtOAc (150 mL) was added and the organic layer was washed with sat. NaHCO3 solution (100 mL), 0.5 M citric acid solution (3×100 mL), water (100 mL), brine (50 mL) and dried (Na2SO4). The volatiles were removed in vacuo to yield the title compound A58 as a white solid (1.78 g, 89%). LCMS-A: rt 5.807 min; m/z 241 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[S:5][CH2:6][C:7](O)=[O:8].P(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]2[C:7](=[O:8])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: O=C(O)CSc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C1CSc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of m-chlorothiophenoxyacetic acid (5.00 g, 24.7 mmol) in chlorobenzene (25 ml) was added phosphorous trichloride (2.90 ml) at room temperature, and the reaction was allowed to proceed with vigorous stirring at 100° C. for 2 hours. After cooling to room temperature, anhydrous aluminum chloride (3.70 g, 27.7 mmol) was added thereto, and the reaction was allowed to proceed at room temperature for 30 minutes, followed by stirring at 100° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into ice-water and separated with a separatory funnel. The aqueous layer was extracted with toluene (150 ml×2). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to give 6-chloro-2,3-dihydro-benzothiofuran-3-one (2.83 g, 15.3 mmol; yield, 62%), m.p., 123.8° C.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[S:17][N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH:9]1[CH:10]=[C:11]([C:13]2[S:17][N:16]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=2)[CH:12]=[N:8]1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)ns3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Nc2nsc(-c3cn[nH]c3)n2)nc1
Yield: 18.8 %

Procedure:
According to Scheme 2 Step 4: A solution of N-(5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-3-yl)pyridin-2-amine (69 mmol, 25 mg) in TFA (686 μL) was microwaved for 5 minutes at 120° C. The reaction mixture was neutralized with a solution of NaOH (1 M) and was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 90:9:1) as eluent to yield 5-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amine (13 mmol, 3.3 mg, 19%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([O:15][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=1)[CH2:17][NH2:18])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([O:15][CH:12]([CH3:14])[CH3:13])[C:19]1[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)OC(C)C)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)OC(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=368.1, tR (minutes, Method D)=0.64
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5]C)(C)C.Cl.CN(C)CCCN=C=NCC.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:33][CH:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:35]=3)[CH2:31][C:30]2=[O:48])[CH:26]=[CH:27][CH:28]=1.[CH2:49]1[CH2:53][O:52][CH2:51][CH2:50]1>>[CH:43]1([O:42][C:36]2[CH:35]=[C:34]([CH:32]3[CH2:33][N:29]([C:25]4[CH:24]=[C:23]([NH:22][C:51](=[O:52])[C:50]5[CH:49]=[CH:53][CH:9]=[C:7]([N:4]([CH3:5])[CH3:1])[CH:8]=5)[CH:28]=[CH:27][CH:26]=4)[C:30](=[O:48])[CH2:31]3)[CH:39]=[CH:38][C:37]=2[O:40][CH3:41])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COc1ccc(C2CC(=O)N(c3cccc(NC(=O)c4cccc(N(C)C)c4)c3)C2)cc1OC1CCCC1
Reaction time: 30 h

Procedure:
A mixture of carboxylic acid (0.02 mmol), diisopropylethylamine (0.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.024 mmol, 1.2 eq) in dry THF was stirred for 20 min before the addition of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one (0.02 mmol). The reaction mixture was then stirred for 30 h. Concentration under reduced pressure and purification by column chromatography on silica gel gave the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c1C

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide to give the title compound.
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])=[N-].[C:28]([OH:31])(=[O:30])[CH3:29].O1CCOCC1>>[C:28]([O:31][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])(=[O:30])[CH3:29]
Reactant: [N-]=[N+]=CC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reactant: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 100 °C

Procedure:
(S)-2-[[(S)-2-(Diazoacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (3.63 g) was dissolved in acetic acid-1,4-dioxane (1:1, 36 ml), and the mixture was heated at 100° C. for 10 minutes. The reaction mixture was concentrated, added with methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.47 g) (see Table 1).