Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C=C[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:36][O:37][C:38](=[O:67])[C:39](C1C=CC(C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=CC=1)([CH3:41])[CH3:40].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:67])[C:39]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:31][CH2:32]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:11][CH:12]=1)([CH3:41])[CH3:40]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.118 g, 0.39 mmol), triethyl amine (10 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by work up and flash column chromatography over silica gel (230-400 mesh) using 1%-4% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow amorphous solid (0.125 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=[O:21])[C:16]2=[CH:17][N:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH2:13][O:12]1.CO.Cl>C1COCC1.C(Cl)(Cl)Cl>[OH:12][CH2:13][CH2:14][C:15]1[C:16]([C:11]([NH:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:21])=[CH:17][N:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OCCc2ccncc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cnccc2CCO)cc1
Temperature: 0 °C
Yield: 103.4 %

Procedure:
(4-Methoxyphenyl) methanamine (6.57 mL, 50.676 mmol) was added to a solution of 3,4-dihydro-1H-pyrano[3,4-c]pyridin-1-one (I-65c: 750 mg, 5.068 mmol) in THF (15 mL) and the resulting reaction mass was refluxed for 48 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was cooled to 0° C., neutralized with 1N HCl and extracted using DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1.5 g of the product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.CCN([CH:36]([CH3:38])[CH3:37])C(C)C.C1(C(Cl)=O)CC1>C(Cl)Cl>[CH:36]1([C:6]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:38][CH2:37]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1ccc(C2=CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the title compound from Example 9 Step A (301 mg, 1.00 mmol) in DCM (6 mL) was added TFA (3 mL). After 15 min, the reaction mixture was concentrated in vacuo, and the crude TFA salt was used without further purification. To a solution of the crude TFA salt in DCM (5 mL) were added DIEA (263 μL, 15.1 mmol) and cyclopropanecarbonyl chloride (274 μL, 3.01 mmol), and the resulting mixture was allowed to stir at room temperature. After 45 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude amide, which was used without further purification: LCMS m/z 270.5 [M+H]+. To a solution of the crude amide in MeOH (10 mL) was added NaBH4 (171 mg, 4.52 mmol), and the mixture was stirred at room temperature. After 20 min, the reaction mixture was concentrated in vacuo and was redissolved in EtOAc. The mixture was washed with sat aq NH4Cl, and the organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. The crude alcohol was used without further purification: LCMS m/z 272.5 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]([CH3:29])[CH2:24][C:25]([O:27]C)=[O:26])=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]([CH3:29])[CH2:24][C:25]([OH:27])=[O:26])=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of methyl 2-[[(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl](methyl)amino]acetate (Preparation 40) (180 mg, 0.44 mmol) in 1,4-dioxane (4 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (42 mg, 1 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. The mixture was then treated with hydrochloric acid (2M), diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCb to afford the title compound as a white foam (95 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=O)[CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)NC(=O)NNc1cc(Br)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Nc1nnc2cc(Br)ccn12
Temperature: 100 °C

Procedure:
A heterogeneous mixture of 1-(4-bromopyridin-2-yl)-4-isopropylsemicarbazide (0.315 g, 1.15 mmol) in phosphorous oxychloride (1.06 mL, 11.5 mmol) was heated at 100° C. for 2 h. The homogenous solution was allowed to cool to RT. Toluene (10 mL) was added and removed in vacuo (3×). DCM (20 mL) and saturated sodium bicarbonate (aq.) was added to the solid and stirred. The off-white solid was collected by filtration and washed with DCM to give 7-bromo-N-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine. MS (ESI, pos. ion) m/z: 255.2 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[C:11]([N:15]1[C:19](O)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]1)([CH3:14])([CH3:13])[CH3:12]>O>[C:11]([N:15]1[C:19]([Cl:3])=[C:18]([CH:8]=[O:9])[C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Yield: 51.6 %

Procedure:
462.0 g (3.0 moles) of phosphorus oxychloride was added to 87.7 g (1.2 moles) of N,N-dimethylformamide with ice-cooling. Thereto was added, at room temperature, 208.2 g (1.0 moles) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixture was refluxed for 10 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water, a 5% aqueous sodium hydroxide solution and water in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 131.5 g (yield: 21.7%) of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Reaction time: 20 h

Procedure:
4-Hydroxyphenylsulfonamide (3.46 g, 20 mmol) is dissolved in DMF (40 mL) and treated with tert-butyl-dimethylsilylchloride (3.31 g, 22.0 mmol) and imidazole (1.50 g, 22.0 mmol) at room temperature. After 20 hr, the reaction mixture is diluted with EtOAc (100 mL) and washed with 1.0 N HCl (2×50 mL). The organic phase is dried (MgSO4), filtered, and concentrated to yield an oil. The crude oil is purified by Biotage column chromatography (40M SiO2 column, eluted at 75 mL/min with 1:1 hexanes:EtOAc). A white solid is obtained (4.24 g, 15.4 mmol, 77%). ESI-MS m/e 288.1 (M++H); mp 117–118° C.; 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.89 (d, 2H), 4.86 (br s, 2H), 0.97 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=1)=[C:3]([CH3:20])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (44.0 mg, 0.130 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, MeOH) δ ppm 7.90 (1H, br. s.), 7.52-7.62 (1H, m), 7.49 (1H, ddd, J=9.6, 1.8, 1.7 Hz), 6.98-7.11 (2H, m), 3.81-3.87 (4H, m), 3.70 (2H, t, J=7.2 Hz), 3.26-3.30 (4H, m), 2.57 (2H, t, J=6.6 Hz), 2.13 (3H, s), 2.08 (2H, quin, J=6.9 Hz). Mass Spectrum (ESI) m/e=458.2 (M+1).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[CH:1]1([NH:5][C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[C:23]([NH:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][CH:21]=[C:20]([CH:31]4[CH2:33][CH2:32]4)[N:19]=3)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CCC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCC2)n1
Yield: 24 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclobutylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (24%) as yellow powder.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].[C:14]([O:24]C(C)C)(=O)[CH2:15][CH2:16][C:17]([O:19]C(C)C)=O.Cl>C(O)(CC)(C)C.CO.O>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[NH:13][C:17](=[O:19])[C:16]2[C:15]=1[C:14](=[O:24])[NH:13][C:12]=2[C:8]1[S:7][CH:5]=[CH:2][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)OC(=O)CCC(=O)OC(C)C
Reactant: N#Cc1cccs1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCC(C)(C)O
Product: O=C1NC(c2cccs2)=C2C(=O)NC(c3cccs3)=C12
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
As a specific example embodiment, potassium tert-butoxide (67.4 g, 0.60 mol) and tert-amyl alcohol (400 mL) are added to a nitrogen-protected oven-dried three-neck round-bottom flask equipped with a mechanical stirrer, a thermometer and a reflux condenser. The mixture is heated to 105° C. for 1.5 h and to this mixture is added 2-thiophenenitrile (55.2 g, 0.50 mol) and the stirring continued at 105° C. for 30 min. A mixture of diisopropyl succinate (40.4 g, 0.20 mol) in tert-amyl alcohol (60 mL) is added dropwise over a period of 3 h with rapid stirring. The mixture is then stirred at 105° C. for a further 2 h, then cooled to 50° C., at which point a mixture of methanol (300 mL) and water (80 mL) is added. The reaction mixture is heated at reflux for 45 min before cooling to room temperature. The mixture is poured over 500 g of ice, then concentrated hydrochloric acid (35% aq) (150 mL) and methanol (750 mL) are added and the mixture is stirred for 45 min. The mixture is filtered and the solid is washed with methanol (200 mL). The solid is then suspended in water (1 L) and stirred for 30 min before being filtered again. This suspension in water, stirring and filtration is repeated a further three times. After filtering for the last time, the solid is oven dried at 80° C. for 16 h, then dried under vacuum to give the product, 3,6-bis(thiophen-2-yl)-2H,5H-pyrrolo[3,4-c]pyrrole-1,4-dione, (49.7 g, 82% yield) as a red solid. This compound is used without further purification. 1HNMR (d6-DMSO, 300 MHz): δ 7.27 (2H, t, J=3.0), 7.89 (2H, dd, J1=6.0, J2=3.0), 8.23 (2H, d, J=3.0), 11.00 (2H, s); 13CNMR (d6-DMSO, 75 MHz): δ 113.6 (2C), 127.1 (2C), 128.3 (2C), 130.5 (2C), 136.6 (2C), 142.6 (2C), 168.2 (2C); m/z (EI+) 300.0 [M]+; Anal. Calc. for C14H8N2O2S2: C, 55.98; H, 2.68; N, 9.33; S, 21.35.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([OH:7])[CH3:6].FS([C:21]([F:26])([F:25])C(O)=O)(=O)=O.O>C(#N)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([O:7][CH:21]([F:26])[F:25])[CH3:6]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(C)O
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(C)OC(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-3-hydroxy-butyric acid methyl ester (630 mg, 2.70 mmol) and copper(I) iodide (105 mg, 0.55 mmol) in acetonitrile at 45° C. was added a solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) by syringe pump over 45 minutes. The reaction was then stirred at 45° C. for 30 minutes. Another solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) was added by syringe pump over 45 minutes at 45° C. The reaction was stirred for 30 minutes at 45° C. after the second syringe pump addition was complete. Water was carefully added to quench the reaction, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography (10% ethyl acetate/hexanes) to yield 2-tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester (276 mg, 36%). 1H-NMR: 400 MHz, (CDCl3: 6.16 (t, JHF=74.0 Hz, 1H), 5.23-5.16 (br, 1H), 4.86-4.80 (m, 1H), 4.40 (br d, J=9.8 Hz, 1H), 3.76 (s, 3H), 1.46 (br s, 9H), 1.36 (d, J=6.4 Hz, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][I:17]>CC(C)=O>[I-:17].[CH2:14]([O:13][C:11]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N+:5]([CH3:16])[CH:4]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Reactant: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c[n+](C)c2n(c1=O)CCC2
Product: [I-]
Yield: 74 %

Procedure:
2.08 g. of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 5 ml. of acetone and to the solution 2.5 ml. of methyl iodide are added. After 24 hours the precipitated crystals are filtered and washed with acetone. 2.61 g. (74%) of 3-ethoxycarbonyl-1-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidinium iodide are obtained melting under decomposition at 212° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[F:22][C:23]([CH3:36])([C:29](=O)[C:30](OCC)=[O:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[F:22][C:23]([C:29]1[N:16]=[N:15][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][C:30]=1[OH:31])([CH3:36])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(=O)C(C)(F)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)(F)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.000 g (purity 67%, approx. 2.357 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 15 ml of absolute ethanol were initially introduced and admixed with 1.557 g (7.070 mmol) of diethyl 2-fluoro-2-methyl-3-oxobutanedioate (described in J. Med. Chem. 1966, 9, 149-151). The mixture was stirred at RT overnight and then concentrated. The residue was purified by preparative HPLC (mobile phase: methanol/water, gradient 30:70→95:5). This gave 230 mg of the target compound (purity 95%; 21% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C1C(=O)N([I:32])C(=O)C1>C(#N)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:17])[C:15]([I:32])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)N1CCc2ccc(O)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCc2cc(O)c(I)cc2CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Into a 100 ml flask, the product of step (c) (503 mg, 2.14 mmol) dissolved in acetonitrile (20 ml) and TFA (2 ml) was added. To this stirred solution, NIS (458 mg, 2.03 mmol) was added. After stirring for 30 minutes at room temperature, the reaction was diluted with water (200 ml) and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a yellow solid (616 mg). 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H); 6.77 (s, 1H); 5.42 (bs, 1H); 4.18 (q, J=7.2 Hz, 2H); 3.61-3.52 (m, 4H); 2.81-2.72 (m, 4H); 1.26 (t, J=6.9 Hz, 3H); MS: ESI (positive): 362 (M+H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7](OC)=[N:6]1)[C:2]#[C:3][CH3:4].[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH2:1]([CH:5]1[NH:6][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCC1CCCCC(OC)=N1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: CC#CCC1CCCCC(=N)N1
Product: Cl

Procedure:
The product of EXAMPLE 257 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O>[CH3:15][S:16]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](C)O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
24.11 G (0.2041 mol) of ethyl L-(+)-lactate and 50 ml of anydrous pyridine were stirred in an ice bath. 17.0 Ml (25.2 g, 0.220 mol) of methanesulfonyl chloride was added dropwise over a period of 20 minutes, and the mixture was stirred for 1 hour at the same temperature and for 1 hour at room temperature. 200 Ml of water was added, and extraction was performed with methylene chloride (50 ml, 3 times). The extract was washed with water (50 ml), then dried with anhydrous magnesium sulfate, and vacuum concentrated. The red-colored oily residue was vacuum distilled, and 32.20 g of ethyl (-)-2-methanesulfonyloxypropionate was obtained in the form of a colorless liquid with bp 97°-102° C./2 Torr. Yield 82.0%.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.[OH-].[Na+].O.CN(C=O)C>C(O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[N:3]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1c(S)nc2c(c1=O)CCCC2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2c(c1=O)CCCC2
Yield: 60.5 %

Procedure:
A solution of 2-mercapto-3-methyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone (980 mg), 4-(4-chlorobenzoyl) benzyl bromide (1.53 g), and 1N-sodium hydroxide/water (5.5 ml) in ethanol (10 ml)-DMF (5 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from methanol-ethyl acetate to provide the title compound as colorless solid (1.27 g).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C(N(CC)CC)C.Cl>ClCCl>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:9])=[O:6].[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCC(=O)O
Reaction time: 0.67 h

Procedure:
One mole of glutaric anhydride and one mole of N-hydroxysuccinimide were treated in dichloromethane with 1.2 equivalents of triethylamine. This reaction was stirred for 40 minutes, acidified by the addition of 0.5 N hydrochloric acid (HCl) (aqueous), and then extracted with ethyl acetate to form mono N-hydroxysuccinimide glutarate. This glutarate was then combined with 5 moles of thionyl chloride and stirred at room temperature for three hours. The resulting reaction mixture was dried to remove volatiles, and thereby form N-hydroxysuccinimidyl glutaryl chloride.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCOCC1>[CH2:20]([O:19][C:17]([CH2:16][N:10]1[CH2:11][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])=[O:18])[CH3:21]
Reactant: O=C1C[C@H](c2ccccc2)CN1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Temperature: 90 °C
Yield: 63.9 %

Procedure:
The solution of 4(R)-phenyl-2-pyrrolidinone (1) (345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80÷90° C. during 30 min and then cooled to room temperature. Ethyl bromoacetate (393 mg, 2.37 mM) was added and the reaction mixture was refluxed at 110÷120° C. for 6 hours. Obtained mixture was concentrated under reduced pressure. Residue was purified by column chromatography on silicagel with ethylacetate-hexane mixture 1:1, giving N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (338 mg, 64%). [α]D20=+4.60° (c=3, MeOH). 1H NMR (CDCl3), δ: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, quintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q, CH2CH3); 7.20-7.39 (5H, m, C6H5).