Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C)=[N-].N(N[C:7](N)=O)=O.[OH-].[K+].[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:18](=[O:26])[CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21][C:22]=1[OH:23]>C(O)(=O)C.CCOCC>[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:22](=[O:23])[CH2:21][C:20]([CH3:24])([CH3:25])[CH2:19][C:18]=1[O:26][CH3:7]
Reactant: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Reactant: NC(=O)NN=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC1=C(C2CCCS2)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 500 parts by volume of an ether solution of diazomethane prepared using 47 parts of N-nitroso urea and 140 parts by volume of a 40% aqueous solution of potassium hydroxide in a conventional manner, 17.7 parts of 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one was added little by little over a period of 20 minutes. After stirring for 15 hours at room temperature, the unreacted diazomethane was decomposed by the addition of 5 parts of acetic acid and washed with 1 N aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution followed by drying. After removing ether by distillation, the residue was passed through a column containing a silica gel using a solvent mixture of chloroform and benzene (1:3) as a spreading agent. Upon recrystallization of the raw product from a solvent mixture of benzene and n-hexane, 2-(2-tetrahydrothienyl)-3-methoxy-5,5-dimethyl-2-cyclohexen-1-one was obtained in the form of colorless scale-like crystals. The melting point was 111° to 112° C. The yield was 5.7 parts.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15](O)[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:15]2[CH:14]=[CH:13][C:12]([C:21](=[O:23])[CH3:22])=[C:11]([OH:10])[C:16]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: OCc1cccc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 44.2 %

Procedure:
Combine (6-bromo-pyridin-2-yl)-methanol (1.00 g, 5.32 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.033 g, 5.32 mmol) and tri-n-butylphosphine (1.46 mL, 5.85 mmol, Aldrich Chemical Co.) in tetrahydrofuran (5.3 mL), add 1,1′-(azodicarbonyl)dipiperidine (1.48 g, 5.85 mmol, Aldrich Chemical Co.). After 12 hours at ambient temperature, add diethyl ether (white precipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography to obtain the title compound as a white solid (854 mg, 2.35 mmol): MS (m/z): 286 (M−Br+1).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][NH:14][C:15]2=S)([CH3:4])([CH3:3])[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][N:14]=[C:15]2[NH:23][NH2:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1cccc2c(=S)[nH]ncc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCC(O)COc1cccc2c(NN)nncc12
Yield: 100 %

Procedure:
A stirred mixture of 5-(3-t-butylamino-2-hydroxypropoxy)-1(2H)-phthalazinthione (0.5 g), ethanol (50 ml) and hydrazine hydrate (15 ml) was heated under reflux for 21 hours. Ethanol and excess of hydrazine were removed by evaporation under reduced pressure to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine (0.5 g, 100%) which was treated with 1.0N sulphuric acid (3.26 ml). Evaporation under reduced pressure gave the crude salt which was crystallised from aqueous methanol to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine sulphate hydrate (0.45 g, 65%, m.p. 274°-276°, decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:21])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2ccc(O)cc2N1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Temperature: 15 °C
Yield: 96.1 %

Procedure:
Step R1-1: To a suspension of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (200 g) in CHCl3 (2.0 L) was added pyridine (212 g) at room temperature over 10 minutes. Tf2O (344 g) was added to the mixture over 35 minutes, keeping the temperature below 10° C. After the mixture was allowed to warm to 15° C. over 1 hour, the reaction mixture was cooled to 0° C. and quenched by addition of water (2.0 L). The organic layer was separated, washed with aqueous saturated KHSO4 and water twice, dried over Na2SO4 and concentrated to obtain 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as a pale yellow solid (346 g).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>CC(N(C)C)=O>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:15])=[O:16])[CH2:10][C:11]([O:13][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])=[O:12]
Reactant: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: O=C(CC(CN1C(=O)C=CC1=O)S(=O)(=O)O)ON1C(=O)CCC1=O
Yield: 74.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoic acid (110 mg, 0.418 mmol), EDC (240 mg, 1.25 mmol) and N-hydroxysuccinimide (58 mg, 0.504 mmol) was stirred in 10 ml of DMA for overnight, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2/HAc (100:900:1 to 100:600:1) to afford 112 mg (75%) of the title product. 1H NMR (DMF-d7) 6.93 (s, 2H), 4.06 (dd, 1H, J=4.8, 13.1 Hz), 3.80 (dd, 1H, J=10.7, 13.9 Hz), 3.35 (dd, 1H J=3.3, 17.8 Hz), 3.25 (m, 1H), 3.10 (dd, 1H, J=2.2, 16.4 Hz), 2.87 (m, 4H); 13C NMR 172.27, 170.88, 169.29, 135.55, 55.28, 40.22, 32.69, 26.66; ESI MS m/z− 261.70 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(CO)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Br)cc(CO)c1
Reaction time: 16 h

Procedure:
To 3-bromo-5-(hydroxymethyl)benzoic acid (7.0 g, 30 mmol) in 20% methanol/benzene (100 mL) is added trimethylsilyldiazomethane (2M in hexanes), and the reaction is stirred 16 h. The reaction is concentrated under reduced pressure to afford the title compound. ESI MS m/z 244.0 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)(=O)C.[CH3:16][NH:17][NH2:18]>C(OC)(C)(C)C>[CH3:16][N:17]1[C:5]([OH:6])=[CH:4][C:3]([CH:2]([F:11])[F:1])=[N:18]1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
166 g (1 mol) of ethyl difluoroacetoacetate are initially charged in 500 ml of methyl tert-butyl ether, and 60 g of acetic acid are added. After the mixture has been cooled to 5° C., 119 g of methylhydrazine are added in 40% aqueous solution. The mixture is stirred at 22° C. for a further 20 h. The phases are separated, and the organic phase is washed with 200 ml of water and dried over MgSO4. After the solvent has been removed under reduced pressure, 140 g of the product are obtained as a yellow solid with an m.p. of 133° C. and a purity of 96%. Yield 91%.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:28]O2)[N:21]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([O:14][C:12]([C@@H:11]1[CH2:28][C@H:26]1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: Fc1cccc(C2CO2)n1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a suspension of NaH (60% oil dispersion, 320 mg, 8 mmol) in toluene (10 mL) was added dropwise t-butyl diethylphosphonoacetate (1.92 g, 7.6 mmol). The resulting mixture was stirred at rt for 10 min., then a solution of 2-fluoro-6-oxiranyl-pyridine (530 mg, 3.8 mmol) in toluene (5 mL) was added dropwise to the reaction mixture. The resulting mixture was then heated at reflux for 12 h. The mixture was cooled to rt and diluted with EtOAc and washed with NH4Cl (saturated) and water. The EtOAc layer was dried (Na2SO4). The solvent was removed and the residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (165 mg). MS (MH+ 238).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([F:12])[CH:3]=1.[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19]>O1CCOCC1>[F:12][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C:15]2=[O:19])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:11]
Reactant: O=C1CCc2c(F)cc(Br)cc21
Reactant: O=C1NCC[C@@H]1O
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-4-fluoro-indan-1-one (Enamine, 453 mg), (S)-3-hydroxy-pyrrolidin-2-one (200 mg) and 1,4-dioxane (3 mL) was purged with argon. Cesium carbonate (645 mg), N,N′-dimethyl-ethylene-diamine (2.24 mL) and copper(I) iodide (38 mg) were added and the mixture was heated to 80° C. for 3 hours. After cooling to r.t. the mixture was filtered and the filtrate evaporated. The residue was purified by SGC (eluent: heptane/EA 1:1 with 0 to 20% MeOH) to provide the title compound. MS ESI+: m/z=250 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH2:19])[C:7]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(=[O:29])[CH3:28]>O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH:19][C:27](=[O:29])[CH3:28])[C:7]=2[CH:20]=1
Reactant: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step E is dissolved in a mixture of water/dichloromethane (2/3); 2 eq. of potassium carbonate are then added and 2 eq. acetyl chloride are added dropwise. After stirring for 2 hours at ambient temperature, the 2 phases are separated; the organic phase is washed with 1M HCl and then with water, until the washing waters are neutral, and is then dried over MgSO4 and evaporated. The residue obtained is purified by chromatography on silica gel.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: COc1ccc(CNc2cnc(C#N)c(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile (15 g, 49.02 mmol) was taken up in DCM (30 mL) and TFA (50 mL) was added. The resulting reaction mixture was stirred at room temperature for 3 h (until done by LC-MS). The solvent and TFA were removed in vacuo and MeOH was added to the residue. The beige solid that was not soluble in MeOH was filtered and washed with MeOH. The filtrate was evaporated to dryness and the residue was partitioned between EtOAc and a saturated solution of sodium bicarbonate. The organic layer was washed two more times with a saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in DCM and hexanes with swirling until a yellow solid precipitated. This solid was filtered and washed with hexanes to afford 7.2 g of 5-amino-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, 1H), 7.28 (d, 1H), 6.99 (bs, 2H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6]C1=O.[OH-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>CN(C)C=O>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10](=[O:11])[C:3]([C:2]2[CH:1]=[CH:10][CH:3]=[CH:2][CH:1]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:6][C:7]1=[O:8])([OH:27])=[O:26]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: O=C(O)CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CCCCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
The DppE amide of 1-(4-carboxybutyl)-5-ethyl-5-phenyl barbituric acid (DPPE-phenobarbital) was prepared as outlined in FIG. 2. The sodium salt of phenobarbital (compound A) (2 mmoles) formed by treating phenobarbital with sodium hydroxide was reacted with the methyl ester of 5-bromovaleric acid (2.200 mmoles) in 5 ml of N,N-dimethyl formamide, for 4 hrs at 96° C., to form the methyl ester of 1-(4-carboxybutyl)-5-ethyl-5-phenyl barbiturate (compound B). The product was purified by column chromatography at a yield of about 77%.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:8])[CH3:7])(=[NH:3])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=O>C(#N)C.ClCCl>[CH3:2][C:1]1[N:4]([NH:5][C:6](=[O:8])[CH3:7])[CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:30])[C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1
Reactant: CC(=N)NNC(C)=O
Reactant: Cc1ccc(-c2c(C(=O)CBr)cnn2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)Nn1cc(-c2cnn(C)c2-c2ccc(C)cc2)nc1C
Temperature: 80 °C

Procedure:
N′-Ethanimidoylacetohydrazide (147 mg, 1.28 mmol) and sodium bicarbonate (99%, 181 mg, 2.13 mmol) were added to a solution of 2-bromo-1-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (250 mg, 0.853 mmol) in acetonitrile (9 mL), and the mixture was heated at 80° C. for 3 hours. The reaction was allowed to cool to room temperature, and was then diluted with dichloromethane and filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (Eluant: 10% methanol in dichloromethane) to provide the product as a yellow oil. Yield: 236 mg, 0.763 mmol, 89%. LCMS m/z 310.5 (M+1). 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 2.10 and 1.77 (2 s, 3H), 2.25 and 2.36 (2 s, 3H), 2.44 and 2.46 (2 s, 3H), 3.69 and 3.72 (2 s, 3H), 6.21 (s, 1H), 7.22-7.33 (4H, m, assumed; partially obscured by solvent peak), 7.96 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O-:16])=[O:15])[CH3:12].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][Cl:10])=[O:15])[CH3:12]
Reactant: CCCCC(CC)C(=O)[O-]
Agent: ClCc1ccccc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)C(=O)OCc1ccccc1CCl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a glass-made three-necked flask (volume: 500 ml) with a condenser, 66.5 g (380 mmol) of α,α′-dichloro-o-xylene, 66.5 g of N,N-dimethylformamide and 63.2 g (380 mmol) of sodium 2-ethylhexanoate were added. After the mixture was heated and stirred at 120° C. for one hour, the reaction mixture was analyzed by the gas chromatography. The conversion of α,α′-dichloro-o-xylene, the yield of [2-(chloromethyl)phenyl]methyl 2-ethylhexanoate (based on sodium 2-ethylhexanoate), and the molar ratio of the [2-(chloromethyl)phenyl]methyl 2-ethylhexanoate produced to the diester compound as a by-product are shown in Table 1 below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:39](=[O:41])[CH2:38][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CCc1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-propionamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-(4-fluorophenyl)propionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 588.2 [M]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:26][CH:27]=1
Reactant: OCc1cc(Cl)cs1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)cs4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 5.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chlorothiophen-2-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (12 mg) as a white solid.
Reaction SMILES: C[Mg]I.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.O>ClCCCl>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]I
Solvent: O
Solvent: ClCCCl
Product: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium iodide (3 M in diethyl ether, 30.7 mL, 92.02 mmol) was added over 20 min to a solution of 1H-indole (7.19 g, 61.35 mmol) in DCE (25 mL) under nitrogen at 0° C. 2,4-Dichloro-5-methylpyrimidine (10 g, 61.35 mmol) in DCE (20 mL) was then added slowly to the reaction mixture over 20 min at 0° C. and the reaction mixture was stirred for an additional 30 min at 0° C. The reaction mixture was then allowed to warm up to RT and stirred at 30 min. The reaction mixture was then cooled to 0° C. and water (50 mL) was slowly added. The resultant yellow solids were collected by vacuum filtration. The solids were then suspended in 10% aqueous citric acid solution (150 mL) and stirred for 10 min, filtered, then washed with water and diethyl ether to give the title product. (8.10 g, 54.2%) as a yellow solid.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([O:15]COC)[C:6]=1[CH3:19].Cl.O>CO>[CH3:19][C:6]1[C:7]([OH:15])=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CCCOc1ccc(OCOC)c(C)c1OCOC
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCOc1ccc(O)c(C)c1O
Yield: 98.8 %

Procedure:
A solution of 5b (580 mg, 2.15 mmol) in MeOH (17.9 mL) was treated dropwise with 3 M HCl (630 μL, 17.2 mmol), then heated to reflux for one hour. Water (20 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 6b as a red amorphous solid (387 mg, 99%). 1H NMR (CDCl3, 500 MHz) δ 6.51 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.6 Hz, 1H), 5.74 (s, 1H), 4.36 (s, 1H), 3.87-3.85 (m, 2H), 2.09 (s, 3H), 1.75-1.71 (m, 2H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 147.5, 143.8, 139.0, 109.8, 108.4, 103.8, 70.2, 21.6, 9.5, 7.3; IR (film) νmax 3520, 3360, 2966, 2880, 2359, 2341, 1636, 1236, 1068, 785, 750 cm−1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([NH:27][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[C:8]3[S:13][CH:12]=[CH:11][C:9]=3[N:10]=2)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)c1nc(NCCNC(=S)Nc2ccccc2)nc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with phenyl isothiocyanate (33 mg, 0.25 mmol), shaken at room temperature for 2 h, poured into water (20 mL) and the resulting yellow precipitate was filtered and dried in vacuo to give the title compound (44 mg, 61%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23].CC#N.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
To a N2-purged flask was added ′5-[1-(4-Hydroxy-3-methoxy-phenyl)-methylidene]-2-(4-methyl-piperazin-1-yl)thiazol-4-one (57 mg, 0.17 mmol), MeCN (5 mL), benzyl chloride (30 μL, 1.5 equiv), and K2CO3 (70 mg, 3 equiv). The reaction mixture was stirred at 70° C. for 6 h. The reaction mixture was diluted with EtOAc (100 mL), and the excess K2CO3 was removed by filtration through a fritted glass funnel. The product solution was washed with aq NH4Cl (50 mL×2) and H2O (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed (SiO2, DCM/MeOH 100:0 to 92:8) to provide pure title compound (20 mg, 28% yield). 1H NMR (DMSO-d6) δ 7.66 (1H, s), 7.44-7.52 (5H, m), 7.29 (1H, s), 7.23-724 (2H, m), 5.22 (2H, s), 3.96 (2H, t, J=4.6 Hz), 3.89 (3H, s), 3.70 (2H, t, J=4.6 Hz), 2.48-2.52 (4H, m), 2.29 (3H, s); MS (ESI) 424 (MH+).