Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[C:32]([F:33])=[CH:31][C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C@H:15]3[C@H:20]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH2:19][CH2:18][C:17](=O)[N:16]3[C:10]=2[CH:9]=1.Cl>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[C:32]([F:33])=[CH:31][C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C@H:15]3[C@H:20]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1
Reactant: COC(=O)N[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Borane-tetrahydofuran complex (1.0 M in THF, 970 mL, 970 mmol) was added dropwise to a stirred solution of methyl (±)-(cis)-(7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (105.2 g, 242 mmol) in THF (1 L). The resulting mixture was stirred at ambient temperature for 3 h. Subsequently, hydrochloric acid (1M) was added dropwise until evolution of gas ceased (±550 mL). The resulting mixture was stirred for 1 h and then diluted with ethyl acetate; the organic layer was washed with water and brine. After drying (MgSO4) the solvent was evaporated under reduced pressure to yield the crude title compound (98.5 g, 97%). (m/z)=421+423 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=O)(C)(C)C.N1C=CC=CC=1.[C:24](Cl)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:24]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: NCCCC[C@H](NC(=O)C=Cc1ccccc1)C(=O)O

Procedure:
Nε-t-Butoxycarbonyl-L-lysine (2.58 g) was dissolved in 50 ml of dimethylformamide, and 30 ml of anhydrous pyridine was added to the solution. To the mixture was added a solution of cinnamoyl chloride in chloroform (1.665 g/20 ml) was added, and the reaction was carried out at 40° C. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 3.6N HCl/dioxane (33 ml) and, after 4 hours of standing, the solution was concentrated under reduced pressure to give the desired compound (2.43 g; hereinafter referred to as compound B).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CCOC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(=O)O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
5-(2-((4-(3-Ethoxycarbonylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic acid methylamide (271 mg, 0.54 mmol, Production example 43-3) was dissolved in tetrahydrofuran (3.0 ml) and methanol (1.5 ml); 4N lithium hydroxide (0.54 ml) was added; and the reaction mixture was stirred at room temperature for 3.5 hours. 1N hydrochloric acid (2.2 ml) was added thereto while the stirred at room temperature. After the precipitated crystals were filtered off, the crystals were washed with water and diethyl ether sequentially, and dried under aeration to yield the title compound (170 mg, 0.35 mmol, 66%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:54])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:54][CH:46]([CH3:45])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CC(N)Cc1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)Cc4ccccc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (1,1,3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-methyl-2-phenylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methyl-2-phenylethyl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.43 min, MH+ 412.
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].S(=O)(=O)(O)O.[OH-].[NH4+]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14]([CH:17]([CH3:18])[CH3:19])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)C1(C)N=C(c2ccc(C(C)(C)O)cn2)NC1=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: C=C(C)c1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 6.4 g of 2-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-4-isopropyl-4-methyl-2-imidazolin-5-one is added with stirring and cooling (ice) 30 ml concentrated sulfuric acid. The mixture is stirred at room temperature for a further 30 minutes, then poured onto 100 ml ice. The pH of this mixture is adjusted to 4 with concentrated ammonium hydroxide and extracted with 3×200 ml ether. The combined extracts were washed with saturated brine, dried and concentrated to give 5.71 g yellow solid. Recrystallization from ether-hexane gave analytically pure 2-(5-isopropenyl-2-pyridyl)-4-isopropenyl-4-methyl-2-imidazolin-5-one, mp 123°-125° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([O:15][C:19]2[N:20]=[N:21][CH:22]=[CH:23][C:24]=2[N:25]2[CH2:30][CH2:29][CH:28]([CH:31]([OH:33])[CH3:32])[CH2:27][CH2:26]2)[CH2:14]1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)C1CCN(c2ccnnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: COC(C1C=COC=1C)=O.[Br:11]N1C(=O)CCC1=O.[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]([Br:28])[O:25][C:24]=1[CH3:29])=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]([Br:28])[O:25][C:24]=1[CH2:29][Br:11])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)oc1C
Agent: COC(=O)c1ccoc1C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)oc1CBr
Temperature: 0 °C

Procedure:
The title compound was prepared as described by Khatuya (Tetrahedron Letters (2001), 42(14), 2643-2644.). 2-Methyl-furan-3-carboxylic acid methyl ester (5.0 g, 35.7 mmol) was dissolved in N,N′-dimethylformamide (10 mL) and cooled to 0° C. N-bromosuccinimide (NBS) (15.88 g, 89.2 mmol) was added in portions. Approximately 6.5 grams of NBS were added over 45 minutes at which point it was determined by HPLC that complete formation of 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester had occurred. The reaction was allowed to warm to room temperature and the remainder of the NBS was added over 1.5 hours. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was extracted with ether and the combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The N,N′-dimethylformamide was removed under high vacuum and the material was absorbed onto silica gel and passed through a column of silica gel using 5% ethyl acetate in hexanes as the eluent. The title compound was obtained as a very pale greenish, waxy solid (4.86 g, 46%). 1H NMR (300.132 MHz, DMSO) δ 6.93 (s, 1H), 4.93 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:23]([O:25]C)=[O:24])[C:7]2[CH:8]=[N:9][N:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]=2[CH:12]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7]2[CH:8]=[N:9][N:10]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C(=O)O)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Lithium hydroxide (0.774 g, 32.3 mmol) was added to a stirred suspension of methyl 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carboxylate (5.51 g, 13.46 mmol) in tetrahydrofuran (50 ml) and water (15 ml) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured onto 2N HCl (800 ml) with stirring. The precipitate formed was filtered off under vacuum and dried at 50° C. in a vacuum oven for 18 h to give the title compound as a yellow solid (3.5 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].I[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN1CCCC1=O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Sc2ccccc2C(=O)O)c1
Temperature: 165 °C

Procedure:
First, 2-(3-methoxyphenylthio)benzoic acid was prepared. A stirred mixture of thiosalicylic acid (3.57 g, 23 mmol), 3-iodoanisole (5.42 g, 23 mmol), potassium carbonate (7.04 g, 51 mmol), copper powder (0.29 g, 5 mmol), and N-methylpyrrolidinone (75 mL) was deaerated by sparging with nitrogen for 10 min, heated at 165° C. for 2 h, and then cooled to ambient. The reaction mixture was poured onto a mixture of 500 g of ice plus 40 mL of concentrated HCl. The resulting precipitate was collected, washed with water, and dried. The precipitate was dissolved in acetone and filtered through Celite, then concentrated to deposit a crude product. The product was purified by recrystallization from aqueous ethanol. A tan powder was obtained, mass: 4.60 g (76% of theory).
Reaction SMILES: C([Li])(C)(C)C.I[C:7](=[CH2:16])[CH2:8][C@@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>CCCCCC.C(OCC)C>[CH3:14][C:11]1([CH3:15])[O:10][C@H:9]([CH2:8][C:7]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH2:16])[CH2:13][O:12]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(I)C[C@@H]1COC(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl lithium in hexane (1.7M, 7.65 mL) was added dropwise to a solution of (R)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane (1.21, 6.5 mmol) in diethyl ether (12 mL) at −78° C., and the reaction stirred at −78° C. for 30 min. Sulfuryl dichloride (SO2Cl2, 538 μL, 6.5 mmol) was added, the mixture warmed to room temperature and the solvents removed under reduced pressure. The product was used in the next step with no further purification.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11].Cl[C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[NH4+].[Cl-]>C1COCC1.[Cu](Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]([CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:20]
Reactant: COCCOCCCCBr
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCOCCCCC(=O)CCC(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
A 5 L 3-neck round bottom flask was fitted with a thermocouple probe, a 2 L dropping funnel, an inlet argon, and a mechanical stirrer. After the addition of magnesium (65.6 g, 2.7 mol), entire system was flame dried. Then, 100 mL of dry THF and 5 mL of neat 43 was added dropwise with vigorous stirring over a period of 5 minutes. When the temperature was arised to 30° C., the flask was placed in an ice bath and a solution of 43 (234 g, 1.08 mol) in THF (1 L) was added dropwise to maintain the temperature below 15° C. The mixture was stirred for 1 h at rt. The Grignard solution was titrated to 0.71 M (0.71 mol, 66%). The freshly Grignard solution was transferred in a 1 L dropping funnel. A 5 L 3-neck round bottom flask was fitted with this charged dropping funnel, an argon inlet, and a magnetic stirrer. Dry THF (0.8 L), copper chloride (3.5 g, 0.036 mol), and methyl 4-chloro-4-oxobutyrate (88 mL, 0.71 mol) were introduced into the 5 L flask and the mixture was cooled at 0° C. The Grignard solution was added dropwise over a period of 1.5 h at 0° C. After the addition, the mixture was strirred for 0.5 h at 0° C. A solution of saturated aqueous NH4Cl (1 L) was added and the mixture was extracted with ethyl acetate (3×1 L). The combined organic phase was washed with a 5% aqueous NH4OH solution (2×1 L) and brine (3×1 L), dried over magnesium sulfate, and rotary evaporated to give 121 g (65%) of crude product 44. 1H NMR (400 MHz, CDCl3) δ 1.91 (quintuplet, J=7.1 Hz, 2H), 2.56-2.66 (m, 4H), 2.76 (t, J=6.5 Hz, 2H), 3.42 (s, 3H), 3.57 (m, 4H), 3.70 (m, 5H), 4.71 (s, 2H) ppm.
Reaction SMILES: S(Cl)(Cl)=O.ClCC1C=C(NC(C2C=CC=CC=2)C(OC)=O)C=CC=1.[N-]=[N+]=[N-].[Na+].[N:29]([CH2:32][C:33]1[CH:34]=[C:35]([NH:39][CH:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:41]([O:43][CH3:44])=[O:42])[CH:36]=[CH:37][CH:38]=1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:29][CH2:32][C:33]1[CH:34]=[C:35]([NH:39][CH:40]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:41]([O:43][CH3:44])=[O:42])[CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(Nc1cccc(CN=[N+]=[N-])c1)c1ccccc1
Agent: [Pd]
Agent: COC(=O)C(Nc1cccc(CCl)c1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(Nc1cccc(CN)c1)c1ccccc1

Procedure:
Equimolar amounts of methyl (R,S)-2-bromo-2-phenylacetate and 3-hydroxymethylaniline are reacted to give methyl N-(3-hydroxymethylphenyl)aminophenyl-acetate. By reaction with thionyl chloride to give methyl N-(3-chloromethylphenyl)aminophenylacetate and subsequent reaction with sodium azide, methyl N-(3-azidomethylphenyl)aminophenylacetate (“A”) is obtained. A solution of 9.2 g of “A” in 350 ml of ethyl acetate is hydrogenated for 35 minutes in the presence of 1 g of Pd/C (5%). After removing the catalyst and the solvent, methyl N-(3-aminomethylphenyl)aminophenyl-acetate) (“B”) is obtained as an oil, RT 19.5; FAB 271.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:25]([O-])C.[Na+].CI>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:25])([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 4 h

Procedure:
7.38 g (20 mmoles) of 3-chloro-4-(4-chloropyrazol-1-yl)phenylmalonic acid diethyl ester are dissolved in 20 ml of absolute ethanol; a solution of sodium ethanolate in ethanol (consisting of 470 mg of sodium in 20 ml of ethanol) is added; stirring is effected at 40° C. for half an hour and 2.84 g (20 mmoles) of methyl iodide are added. Boiling under reflux is effected for 4 hours; again, 2.84 g of methyl iodide are added, followed by heating for a further 2 hours, concentration, and taking up with diethyl ether. The ethereal phase is washed with sodium hydrogen sulphite solution and water, dried and concentrated. Methyl-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] malonic acid diethyl ester is obtained.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH:2]1[C:4](OCC)=[O:5].[NH3:14]>C(O)C>[C:4]([CH:2]1[CH2:3][N:1]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:5])[NH2:14]
Reactant: CCOC(=O)C1CN1C(=O)OCC
Reactant: N
Solvent: CCO
Product: CCOC(=O)N1CC1C(N)=O
Reaction time: 8 h

Procedure:
To 4.67 g. (0.025 mole) diethyl 1,2-aziridine-dicarboxylate in 30 ml. ethanol there is added the equimolar amount of gaseous ammonia dissolved in ethanol and the reaction mixture then left to stand overnight in a refrigerator. The reaction mixture is subsequently evaporated and the desired ethyl 2-carbamoyl-1-aziridine-carboxylate isolated by column chromatography (200 g. silica gel: elution agent acetone/toluene 1:1 v/v). There is obtained 1.4 g. (about 32% of theory) of the ester; m.p. 125°-128° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4])#[N:2].S(=O)(=O)(O)O.[CH3:19]O>>[C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])[CH3:4])#[N:2]
Reactant: CO
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)C#N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-(1-cyanoethyl)benzoic acid (2.0 g, 11 mmol) in methanol (20 mL) was added conc. sulfuric acid (0.2 mL), and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (1.9 g, 89%) as a colorless oil.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:31])=[CH:25][CH:24]=2)[N:9]=1)=[O:7])C.Cl>CO>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])=[CH:25][CH:24]=2)=[N:11][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:16]
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(C(=O)O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
1N KOH (10.5 ml, 5 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic acid ethyl ester (1.03 g, 1 eq.) in MeOH (10 ml) and the mixture was refluxed for 4 h. The mixture was cooled to 0° C. and carefully acidified with conc. HCl. The mixture was filtered and the precipitate was dried in vacuo, and a product was obtained as a white solid (0.93 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]=1[C:9]([O:11]CC)=O.C([O-])=O.[NH4+].[CH:18]([NH2:20])=O>O>[CH3:7][C:4]1([CH3:8])[C:3]2[C:9](=[O:11])[NH:20][CH:18]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1=C(N)CCC1(C)C
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCc2nc[nH]c(=O)c21
Temperature: 150 °C

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H) 1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).