Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[O:12][CH3:13].[CH2:15](I)[CH3:16]>CN(C)C=O>[CH2:15]([N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[C:11](=[O:14])[O:12][CH3:13])[CH3:16]
Reactant: CCI
Reactant: COC(=O)Nc1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)c1ccccc1C
Reaction time: 4 h

Procedure:
5.1 g (0.2 mol) of sodium hydride are added a little at a time to 30 g (0.18 mol) of methyl N-(o-methylphenyl)-carbamate (Example 1a) in 200 ml of dimethylformamide. After the evolution of gas has ceased, 30 g (0.2 mol) of ethyl iodide are added drop-wise, the reaction mixture being lightly cooled in a water bath. A white solid is precipitated. After about 4 hours, the reaction mixture is diluted with water and the aqueous phase is extracted three times with ether. The organic phase is dried over MgSO4 and evaporated down. The residue is distilled. 32.5 g (0.17 mol=93%) of the title compound are obtained as a colorless oil. bp.0.5 =74° C.; 1H-NMR (CDCl3 ; δ (ppm): 7.2 (m, 3H, aromatic); 7.1 (m, 1H, aromatic); 3.8 (m, 1H, N--CHA); 3.6 (s, 3H, OCH3); 3.5 (m, 1H, N--CHB); 2.2 (s, 3H, CH3); 1.1 (t, 3H, CH3)
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[C:7]2[N:6]=[C:5]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:4]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C.[C:42](O)(=[O:46])[C@@H:43]([CH3:45])[OH:44].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:30]([C:4]1[C:5]([CH:24]2[CH2:25][CH2:26][N:27]([C:42](=[O:46])[C@H:43]([OH:44])[CH3:45])[CH2:28][CH2:29]2)=[N:6][C:7]2[N:8]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[C:3]=1[NH2:2])(=[O:32])[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(C2CCN(C(=O)[C@@H](C)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone hydrochloride (0.5 mmol), DIEA (350 μL, 2 mmol) in DMF (5 mL) was added a solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (1 mL). The reaction was stirred at rt for 20 min. Another solution of solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (2 mL) was added and stirred for 5 minutes. LC-MS indicated the reaction was complete and reaction mixture was directly purified by HPLC to furnish the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(=O)O)NC(OCC1C=CC=CC=1)=O>>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Product: COC(=O)[C@H](N)Cc1ccccc1
Yield: 62.3 %

Procedure:
Example 17 was repeated except for using DL-phenylalanine methyl ester instead of L-phenylalanine methyl ester to obtain 756 mg of an addition compound of N-benzyloxycarbonyl-L-aspartyl L-phenylalanine methyl ester and D-phenyl alanine methyl ester (1:1) (melting point: 105° to 111° C.; yield: 62.3% based on N-benzyloxycarbonyl L-aspartic acid).
Reaction SMILES: [Br:1]Br.[C:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: BrBr
Reactant: COC(=O)CC(=O)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)C(=O)OCc1ccccc1
Yield: 97.5 %

Procedure:
Bromine (17.6 g, 0.11 mol) was added to a stirred solution of benzyl methyl malonate (20.8 g, 0.10 mol) in carbon tetrachloride. After 30 minutes the solvent was removed under reduced pressure to give 28 g of product (85% pure by gc, containing 7% benzyl methyl malonate) which was used without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:1]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([Cl:9])[S:11][C:12]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1nc2ccc(OCc3ccccc3)cc2s1
Temperature: 70 °C
Yield: 93.9 %

Procedure:
Benzyl bromide (0.921 g, 5.39 mmol) was added to a mixture of 2-chlorobenzo[d]thiazol-6-ol (1.00 g, 5.39 mmol) and cesium carbonate (1.76 g, 5.39 mmol) in CH3CN (15 mL). After 2 h at rt the reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×75 mL) and brine (75 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% EtOAc in Hexanes gradient), yielding 1.396 g (94%) of the title compound as a reddish, waxy solid. LC-MS: RT=10.51 min., [M+H]+=275.9. Rf=0.41 in 10% EtOAc/Hexanes.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[Br-].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:21])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)CBr
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
Magnesium (5.2 g, 199 mmol) is suspended in anhydrous THF (60 mL) under nitrogen. A small crystal of iodine is added. 1-Bromo-2,2-dimethylpropane (25 g, 165 mmol) is dissolved in anhydrous THF (90 mL) and a portion of the solution is added to the magnesium. The mixture is heated to reflux temperature to initiate the reaction. The rest of the bromide solution is added dropwise. After the addition is complete the mixture is refluxed for 4 h. The Grignard reagent is allowed to cool to room temperature and added dropwise to a solution of methyl-4-formylbenzoate (15 g, 91.5 mmol) in THF which has been cooled in an ice bath. After the addition is complete the resulting solution is stirred at room temperature for 2 h. The reaction is quenched with MeOH, worked up and concentrated to give 8.07 g (37%) of the titled compound as a yellow oil. 1H NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](Cl)=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[C:8]=1[C:32](=[O:33])[CH2:31][C:30]([CH3:36])([CH3:35])[CH3:29])[CH3:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
3-[5-Methoxy-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (Example 5, Step 4; 0.133 g, 0.33 mmol) was dissolved in dichloroethane (5 mL). 3,3-Dimethyl-butyryl chloride (0.12 mL, 0.86 mmol) and aluminum chloride (0.137 g, 1.03 mmol) were added, and the reaction was heated to 80° C. under N2 for 1.5 hours. The reaction mixture was cooled to room temperature and quenched with saturated potassium sodium tartrate tetrahydrate solution. The mixture was extracted with EtOAc three times, the combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K+].[Br-]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:3])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CN1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-methylpiperazine, yield 81%. White crystals, m.p. 237-240° C.; 1H NMR (DMSO-d6): δ11.67 (br s, 1H), 7.50, 7.45, 7.24, 7.20 (AB-system, d=7.47 and 7.22; J=8.84 Hz, 4H), 4.40-3.91 (br, 2H, 3.77-2.92 (br m, 6H+water), 2.77 (s, 3H); IR (KBr): ν 1717 (C═O) cm −1.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=O)C.O.[NH2:30][NH2:31]>C(O)C>[NH:30]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=[O:3])[NH2:31]
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(=O)NN)cc1
Yield: 41.5 %

Procedure:
In this example, 4 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 30 ml of ethanol and 6.1 g of 85% hydrazine hydrate is added thereto. The mixture is heated under reflux for2 hours. The solvent is distilled away from the reaction solution under reduced pressure. The residue is recrystallized from tetrahydrofuran-etherto obtain 1.6 g of 1-(4-hydrazinocarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol. (Yield: 42%)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CC(C)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([O:13][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2ccc(O)c(O)c2c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(CC)c2ccc(OCc3ccc(OC)cc3)c(O)c2c1=O
Yield: 20.9 %

Procedure:
To a suspension of ethyl 1-ethyl-5,6-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5 g, 18.03 mmol) and potassium carbonate (8.72 g, 63.1 mmol) in Acetone (120 mL) at r.t. was added 4-methoxybenzyl chloride (7.37 mL, 54.1 mmol) and KI (0.599 g, 3.61 mmol). The mixture was heated under reflux for 2 days. After cooling, the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between DCM and water, and the organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with EtOAc/hexanes (0-100%) to afford ethyl 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.5 g, 3.77 mmol, 20.9% yield) as a light yellow solid that contained some PMB-ester. LCMS: (M+H)+: 398.3.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37]>C1COCC1.CCOC(C)=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (492 mg, 0.97 mmol) in THF (1 ml) was treated with a solution of 2M methylamine in THF (7 ml, 14.4 mmol) and stirred at 40° C. in a sealed vessel for 75 minutes. The reaction mixture was allowed to cool to room temprature and dissolved in EtOAc (100 ml) which was washed with sat. NaHCO3 (100 ml) solution followed by brine. The organic extract was dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (337 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Li+].[Li+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCCCl)cc1
Reaction time: 2 h

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous lithium carbonate (740 mg, 10 mmol), 15 ml of dimethylsulfoxide, and 15 ml of 1,2-dichloroethane are combined and heated to reflux. HPLC shows the reaction is at equilibrium at about 2 hours with a product to starting material ratio of 22.7:68.7.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1)=[O:5]
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (144 mg, 0.48 mmol) and 3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (109 mg, 0.48 mmol) in N,N-dimethylacetamide (2 mL) was treated with triethylamine (0.168 mL, 1.21 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (256 mg, 0.68 mmol). The resulting mixture was stirred at ambient temperature for 5 hours, before being filtered and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a white solid (118 mg, 52.1% yield); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.62 (2H, m), 1.73-1.83 (3H, m), 1.91-1.99 (1H, m), 3.10-3.18 (1H, m), 4.40 (2H, s), 4.54-4.60 (1H, m), 5.03-5.11 (2H, m), 7.26-7.37 (5H, m), 7.45-7.50 (2H, m), 7.83-7.93 (2H, m), 8.02 (1H, d), 8.30 (1H, d), 12.13-12.59 (1H, br s); m/z (LC-MS, ESI+), RT=2.14 (M+H 470.9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)C1(CCCNCc2ccccc2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(CCCNCc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 132.7 %

Procedure:
To a solution of 2-(3-benzylaminopropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.69 g) in chloroform (38 ml) cooled to 0° C. was added 4M hydrochloric acid-ethyl acetate (18 ml), and the mixture was stirred at room temperature for 3 hours. To the mixture was added additional 4M hydrochloric acidethyl acetate (20 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure, and then thereto was added saturated aqueous sodium bicarbonate solution (150 ml). The mixture was extracted with chloroform (100 ml×2, 75 ml×2) 4 times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (7.49 g).
Reaction SMILES: [OH:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([Si:24]([CH3:27])([CH3:26])[O:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(C)(C(=O)O)C(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A cooled (0° C.) solution of 2-(1-hydroxy-1-methyl-ethyl)-2-methyl-but-3-enoic acid (2.0 g, 12.6 mmol) and 2,6-lutidine (13.5 g, 126.4 mmol) in dichloromethane (150 mL) was treated with tert-butyldimethylchlorosilane (16.7 g, 63.2 mmol). After stirring for 1 h, the volatiles were removed in vacuo, the residue was taken in methanol (100 mL) and water (50 mL) and treated with potassium carbonate (20 g). After stirring for 16 h, the volatiles were removed in vacuo, the residue was diluted with water (50 mL), acidified to pH 2 with potassium hydrogen sulfate, and extracted with dichloromethane (3×25 mL). All the organics were combined and the volatiles were removed in vacuo to afford the title compound (3.288 g, 95%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 3H), 0.25 (s, 3H), 0.94 (s, 9H), 1.34 (s, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 5.29 (m, 2H), 6.17 (dd, J=17.6, 10.9 Hz, 1H), 10.99 (br s, 1H).
Reaction SMILES: S(=NC(N)=O)(=O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([Cl:28])[C:24]([NH:26][CH3:27])=[CH:25][C:18]=3[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:31][C:32](=O)[NH:33][S:34]([C:37]1[S:38][C:39]([Cl:42])=[CH:40][CH:41]=1)(=[O:36])=[O:35])C>>[Cl:42][C:39]1[S:38][C:37]([S:34]([NH:33][C:32]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:20](=[O:21])[C:19]4[CH:22]=[C:23]([Cl:28])[C:24]([NH:26][CH3:27])=[CH:25][C:18]=4[O:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:31])(=[O:36])=[O:35])=[CH:41][CH:40]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1Cl)C(=O)N(c1ccc(N)cc1)CO2
Agent: NC(=O)N=S(=O)=O
Product: CNc1cc2c(cc1Cl)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2

Procedure:
Analogues to the sulfonylurea formation described in Ex. 5, 3-(4-aminophenyl)-6-chloro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (Ex. 47) (44 mg, 0.15 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (59 mg, 0.22 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-chloro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)urea. RP-HPLC: 2.70 min; ES-MS (M+H)+=528.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.4 (s, 2), 6.2 (s, 1), 6.9 (d, 1), 7.1 (d, 2), 7.39 (d, 1), 7.48 (d, 2), 7.7 (s, 1).
Reaction SMILES: [CH2:1]1[C@H:5](N2C(=O)NC(=O)C=C2)[O:4][C@H:3]([CH2:14][OH:15])[C@H:2]1[OH:16].[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20]([NH2:27])[N:19]=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[CH:23]1[N:24]([C@@H:5]2[O:4][C@H:3]([CH2:14][OH:15])[C@@H:2]([OH:16])[CH2:1]2)[C:25]2[C:21](=[C:20]([NH2:27])[N:19]=[C:18]([Cl:17])[N:26]=2)[N:22]=1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
reaction of 2-deoxyuridine with 2-chloroadenine, in the presence of uridine phosphorylase (UPase) and purine nucleoside phosphorylase (PNPase) in an aqueous reaction medium possibly containing up to 40% v/v of an aprotic dipolar solvent, to obtain cladribine dissolved in said reaction medium; b) isolation of the cladribine by precipitation by means of concentration and alkalinisation of the reaction medium up to a pH of 11.5-12.5.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:4]=1)#[N:9]
Reactant: N#Cc1ccn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccn(CC(C#N)(C#N)CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
0.27 g of 1-chloromethyl-3-cyano-1H-pyrole and 0.34 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 3ml of N,N-dimethylformamide. 0.29 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.37 g of [(3-cyano-1H-pyrole-1-yl) methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (48), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:37])=[C:34](Br)[CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:37])=[C:34]([C:9]5[CH:10]=[CH:11][C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:7][CH:8]=5)[CH:35]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cnc2C)cc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-(4-(N-methylsulfamoyl)phenyl)pyridin-3-yl)cyclopropanecarboxamide was prepared from 4-(N-methylsulfamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.