Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([CH2:12][C@H:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1>O.CO>[CH:7]1([CH2:12][C@H:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:24])=[O:2])[CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of sodium periodate (1.07 g, 4.98 mmol) in water (10 mL) was added a solution of (R)-3-cyclopentyl-2-(3-methylsulfanyl-phenyl)-propionic acid (700 mg, 2.65 mmol) in methanol (15 mL) and the reaction was stirred at 25° C. for 1 h. The reaction mixture was filtered through a pad of celite and the solids were washed with methanol and chloroform. The filtrate was concentrated and azeotroped with benzene to remove any traces of water to yield (R)-3-cyclopentyl-2-(3-methylsulfinyl-phenyl)-propionic acid as a white solid which was then dissolved into methanol (20 mL). To this stirred solution was slowly added potassium permanganate (630 mg, 3.98 mmol) in water (6 mL) and the reaction stirred at 25° C. for 1 h. The reaction mixture was filtered through a pad of celite and the solids washed with methanol. Concentrate the filtrate to yield (R)-3-cyclopentyl-2-(3-methylsulfonyl-phenyl)-propionic acid (705 mg, 90%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[NH2:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][C@H:55]([OH:58])[CH2:54]2)=[C:48]([C:61]2[N:62]([CH3:66])[N:63]=[CH:64][CH:65]=2)[CH:47]=1>C1COCC1>[OH:58][C@H:55]1[CH2:56][CH2:57][N:53]([CH2:52][CH2:51][O:50][C:49]2[CH:59]=[CH:60][C:46]([NH:45][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)=[CH:47][C:48]=2[C:61]2[N:62]([CH3:66])[N:63]=[CH:64][CH:65]=2)[CH2:54]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CC[C@H](O)C1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CC[C@H](O)C1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of HATU (183 mg, 0.482 mmol), triethylamine (100 μl, 0.741 mmol) and 4-trifluoromethyl benzoic acid (92 mg, 0.482 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, (S)-1-{2-[4-Amino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidin-3-ol (112 mg, 0.370 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 58 mg, 33% yield). 1H NMR (DMSO-d6, 400 MHz) δ 1.67-1.74 (m, 1H), 1.78-1.90 (m, 1H), 2.09-2.18 (m, 1H), 2.88-2.97 (m, 1H), 3.31-3.37 (m, 1H), 3.47-3.61 (m, 2H), 3.69 (s, 3H), 4.31-4.36 (m, 4H), 6.31 (s, 1H), 7.24-7.28 (m, 1H), 7.50 (s, 1H), 7.75 (s, 1H), 7.90 (d, J=8.84 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.34 Hz, 2H), 9.93-10.11 (m, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2, found 475.3 (MH+).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=3)[C:7]([C:15]#[N:16])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(OB([O-])[O-])(C)C.[Li+].CC([N-]C(C)C)C.[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[CH:35][C:34]=1[NH2:40].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:40][C:34]1[CH:35]=[CH:36][C:37]([C:6]2[N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:13]3[C:8]([C:7]=2[C:15]#[N:16])=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=3)=[CH:38][C:33]=1[Cl:32]
Reactant: Nc1ccc(I)cc1Cl
Reactant: N#Cc1cn(C2CCC2)c2cc(O)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in anhydrous THF (40 mL) at 0° C. was added LDA (16.2 mL, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirred at 0° C. for 15 min and then at room temperature for 1 h. After cooling the reaction mixture to 0° C. a solution of 2-chloro-4-iodo-phenylamine (3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition of PdCl2(dppf) (0.3 g, 0.4 mmol) and aq. K2CO3 (14 mL, 2.0 M). The mixture was warmed to room temperature and continued to stir overnight. The reaction was diluted with water and then extracted with ethyl acetate. The organic layers was dried, concentrated and triturated with chloroform to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.1 g, 64%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(C)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-methoxybenzothiazole (12.0 g) is dissolved in pyridine (250 ml) and thereto is added dropwise acetoxyacetyl chloride (7.9 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water and then with diethyl ether, dried and recrystallized from ethanol to give the title compound (15.3 g) having the following physical properties.
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.Cl.[CH3:19][NH:20][CH3:21].C(N(CC)CC)C.[BH4-].[Na+]>CO.O1CCCC1>[CH3:19][N:20]([CH2:1][C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:21]
Reactant: COC(=O)C1=Cc2cccc(C=O)c2OCC1
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1=Cc2cccc(CN(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
The mixture of methyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (1.0 g), dimethylamine hydrochloride (0.7 g), triethylamine (1.2 ml) and 4 Å molecular sieves (1.0 g) in methanol (20 ml) and tetrahydrofuran (10 ml) was stirred at ambient temperature for 3 hours. To the mixture was added sodium borohydride (0.33 g) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The solvent was removed by concentration. The residue was dissolved in a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted pH 10 with 20% aqueous potassium carbonate and extracted with a solution of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 2,3-dihydro-9-dimethylaminomethyl-1-benzoxepin-4-carboxylate (0.74 g).
Reaction SMILES: ClC([O:4][CH3:5])Cl.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[O:4]
Reactant: Cc1ccccc1C
Reactant: COC(Cl)Cl
Product: Cc1ccc(C=O)cc1C

Procedure:
The above reaction of Example 68(A) is repeated except that o-xylene and dichloromethyl methylether are the starting materials. Using the same reaction conditions and techniques, there is obtained 3,4-dimethylbenzaldehyde.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1CCCCC1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:23][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(NCCO)c1ccccc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(NCCCl)c1ccccc1

Procedure:
40.2 g. of N-(β-hydroxyethyl)-benzene sulfonamide was slurried in 100 ml. of carbon tetrachloride containing 5 drops of piperidine. Then, 47.6 g. of sulfonyl chloride was added over 10 minutes, keeping the temperature at 20°-25° C. during the addition. The reaction was completed by heating on a steam bath for 1 hour. The mixture was concentrated on the steam bath, dissolved in benzene and washed twice with dilute aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the benzene evaporated on the steam bath with air. The product was crystallized from benzene cyclohexane to yield 28.0 g. of product, m.p. 58°-62° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:19]>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
To a solution of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.22 g) in water (30 ml) was added a suspension of adenosine deaminase in aqueous ammonium sulfate (0.44 ml, containing 4.4 mg of the enzyme). The reaction mixture, which initially had a pH of 7.0, was heated at 37° C. for 18 hours, at which time the pH was 8.5 and TLC (silica gel plates developed in 15% methanol - 85% chloroform) indicated a single product different from starting material. The reaction mixture was thoroughly chilled in an ice bath and the resulting white solid removed by filtration and thoroughly washed with cold water. The product was dried at 100° C./0.1 mm Hg for 16 hours to give 0.20 g of 9-(2-hydroxyethoxymethyl)guanine. 1/4 H2O, the structure of which was confirmed by m.p., TLC, U.V., NMR and mass spectroscopy analysis. Recrystallization from methanol gave the anhydrous 9-(2-hydroxyethoxymethyl)guanine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][C:14](=O)[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[OH:16])[CH2:6][CH2:5]2.B.CSC.CO.Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][CH2:14][CH:15]([OH:16])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:6][CH2:5]2
Reactant: O=C(NCC1CCc2cc(O)ccc2C1)C(O)c1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CCC(CNCC(O)c1ccc(Cl)cc1)C2

Procedure:
A solution of the compound obtained in step (i) above (3.2 g, 0.0092 mol) in anhydrous tetrahydrofuran (65 ml) is heated to the reflux temperature under nitrogen atmosphere and a 10M solution of borane-methyl sulfide (2.8 ml, 0.028 mol) and anhydrous tetrahydrofuran (10 ml) are then added thereto. The mixture is refluxed for 4 hours, methanol (30 ml) is slowly added thereto and refluxing is prolonged for an additional hour. lN HCl (60 ml) is then added thereto and the mixture is refluxed for 1 hour, and concentrated under reduced pressure. The residue is taken up in ethyl acetate, the organic solution is washed with ammonium hydroxide and then with water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure affording a solid which is washed with isopropyl ether (2.3 g). M.p. 150°-153° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.BrC1C=C([F:36])C(C)=C(CC(O)=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]3)[C:12]=2[OH:13])[CH:7]=1
Reactant: Cc1c(F)cc(Br)cc1CC(=O)O
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)c(F)cc1C)=C2O
Product: CON1CCC2(CC1)NC(=O)C(c1cc(Br)cc(F)c1C)=C2O

Procedure:
3-(5-Bromo-3-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound F3) was prepared analogously to the synthesis of 3-(5-bromo-4-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (preparation example P5, step P5.5) starting from (5-bromo-3-fluoro-2-methyl-phenyl)-acetic acid (preparation example P7, step P7.2) by making use of the procedures described under step P5.4 and step P5.5. The title compound F3 was obtained as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(OCC)=O.C(#N)C.N>C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:14]1(=[O:23])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: NCCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
A solution of 5-amino-1-pentanol (5.00 g, 48.5 mmol) in benzene (150 ml) was treated with N-carboethoxyphthalimide (11.0 g, 50.2 mmol) and stirred at room temperature for 5 h. Concentration in vacuo and flash chromatography (25% ethyl acetate/petroleum ether) yielded III-33 (9.6 mg, 84% yield) as a clear, colorless oil: UV (9.65×10-4M, acetonitrile) λmax 292.0 (ε212), 242.4 (226) nm; IR (CHCl3) 3460 (br), 2940 (s), 2860 (s), 1770 (s), 1710 (s), 1610 (s), 1470 (s), 1440 (s), 1400 (s), 1370 (s), 1190 (m), 1170 (m), 1130 (m), 1050 (s), 960 (m), 890 (m), 875 (m), 790 (m), 720 (s) cm-1 ; 1H NMR (500 MHz, CDCl3) δ7.72-7.70 (m, 2 H), 3.69 (t, J=7.2 Hz, 1 H), 3.64 (t, J=6.5 Hz, 1 H), 2.17 (br s, 1 H), 1.74-1.59 (m, 2 H), 1.46-1.40 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ169.39, 133.78, 131.96, 123.05, 62.34, 37.74, 32.03, 28.22, 22.93; high resolution mass spectrum (Cl, NH3) m/z 234.1108 [(M+H)+ ; calcd for C13 H15NO3 : 234.1129].
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].C(OC(=O)[NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1)(C)(C)C>>[NH2:33][C:34]([CH3:45])([CH3:46])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:41][CH:42]=1
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 29 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CS(C)=O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:9]([CH3:12])[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]2=[O:16]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3)cc21

Procedure:
2.55 (0.01 mol) of 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3.5 cm3 of morpholine (0.01 mol) and 34 cm3 of DMSO were heated at 110° C. for 7 hours, whilst stirring. The reaction product precipitated after heating for 5 hours. After cooling, the mixture was diluted with water (100 cm3) and the solid was filtered off, washed with water and recrystallised from DMF (45 cm3). 1 g of 6-fluoro-1-methyl-7-morpholino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 316° C. (decomposition), was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[O:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)=[CH:7]2.[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:7][C:8](=[O:9])[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:11]=1[C:10]([NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=1[F:26])=[O:12]
Reactant: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc2cccc(Cl)c12
Reactant: NCc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: O=C(Cc1cccc(Cl)c1C(=O)NCc1ccc(F)cc1F)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Alternatively, 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one (48 mg, 0.14 mmol) and 2,4-difluorobenzylamine (24 μL, 0.20 mmol) were combined in toluene (2.0 mL) in a round-bottomed flask under nitrogen. To the resulting mixture was added a solution of methyl aluminoxane (0.11 mL, of a 1.5 M solution in toluene, 0.16 mmol). The resulting yellow solution was then heated to reflux. TLC of the reaction mixture after 1 hour at reflux showed no 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one remaining. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (5 mL), and diluted with EtOAc (25 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. The crude solid was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 20% EtOAc/hexane. The main peak that eluted was collected to afford a compound of formula (W), 2-chloro-N-(2,4-difluorobenzyl)-6-[2-oxo-2-(4-phenoxyphenyl)ethyl]benzamide, (54 mg, 79% yield) as a white solid; 1H-NMR (400 MHz, CDCl3): δ 7.87-7.82 (2H, m), 7.46-7.41 (2H, m), 7.35-7.21 (4H, m), 7.14-7.10 (2H, m), 7.05-7.02 (1H, m), 7.01-6.96 (2H, m), 6.66-6.60 (1H, m), 6.53-6.47 (1H, m), 6.43 (1H, t, J=6.1 Hz), 4.49 (2H, d, J=6.1 Hz), 4.25 (2H, s); which could be used in the next step to produce a corresponding compound of formula (Id).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:11][O:10]1.[Na].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.ClCCl.CO>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:11][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: CC(c1cccnn1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1cccnn1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (1.15 g) with 1H-1,2,4-triazole sodium salt (0.80 g) in N,N-dimethylformamide (15 ml) according to the method of Example 1(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (50:1) as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.35 g), m.p. 134°-135° (from ether).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
To a solution of L-leucinol (1.00 g, 8.53 mmol) in methylene chloride (30 ml) were added chloroformic acid benzyl ester (1.46 ml, 10.2 mmol) and triethylamine (1.43 ml, 10.2 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed With saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamic acid benzyl ester (2.31 g, yield 100%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[N:4]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:3]1.[CH2:24]1[O:32][C:31]2[C:26](=[CH:27][CH:28]=[C-:29][CH:30]=2)[O:25]1.[Mg+2].[Br-]>O1CCCC1>[O:25]1[C:26]2[CH:27]=[CH:28][C:29]([C:20]([OH:22])([CH3:21])[CH2:19][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:1])([CH3:23])[CH2:3]3)=[CH:30][C:31]=2[O:32][CH2:24]1
Reactant: [c-]1ccc2c(c1)OCO2
Reactant: CC(=O)CN1CC(C)(C)Cn2c1nc(-c1ccncn1)cc2=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1(C)CN(CC(C)(O)c2ccc3c(c2)OCO3)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of 0.3 g (0.957 mmol) of 7,7-dimethyl-9-(2-oxo-propyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 2 ml of anhydrous tetrahydrofuran at −2° C. was added 2.1 ml (9.57 mmol) of a solution of 3,4-(methylenedioxy)phenylmagnesiumbromide (1M solution in tetrahydrofuran/toluene 50/50) during 20 min. After stirring for 15 min. at room temperature the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with dichloromethane and the extracts washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of ethyl acetate/cyclohexane in the proportions 50/50 to 100/0 to give 0.210 g (50%) of product. Mp.: 194-196° C.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:12]1([CH2:15][NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C1(CNCC)CCCC1>>[CH:12]1([CH2:15][N:16]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:2]2[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:14][CH2:13]1
Reactant: C1CC1CNCC1CC1
Reactant: O=Cc1cc(F)cc(F)c1F
Agent: CCNCC1CCCC1
Product: O=Cc1cc(F)cc(F)c1N(CC1CC1)CC1CC1

Procedure:
By using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5-(trifluoromethyl)benzaldehyde, and N,N-bis(cyclopropylmethyl)amine synthesized by the method described in International Patent Publication WO2006/073973 instead of N-(cyclopentylmethyl)-N-ethylamine, reactions and treatments were performed in the same manner as those of Step 3 of Example 1 to obtain 2-[bis(cyclopropylmethyl)amino]-3,5-difluorobenzaldehyde as a yellow oil.