Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCCNCCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.42 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(4-(naphthalen-2-yloxy)butyl)amine solid, m.p. 117° C., (yield 0.67 gm, 93.6%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=1[F:33]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=2[F:33])=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)c1cnc(Cl)c(F)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
nBuLi (14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirred solution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0° C. After 20 minutes, the reaction mixture was cooled to −78° C. and a solution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10 mL) was added. After 20 minutes, a solution of 4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem. 1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After quenching the reaction mixture with 10% HCl (20 mL), it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride yielded 3.21 g (72%) of clean desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC(F)=CC=2)(=O)=O)N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)S(=O)(=O)c1ccc(F)cc1
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1ccc(F)cc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and 4-fluorophenylsulfonyl chloride, according to the general working procedure 106 mg of 2′-(4-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 130° C. MS (ES+): m/e=490 (M+1).
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:25][N:26]=[C:27]3[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][C:28]=23)[CH:21]=[CH:22][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:25][N:26]=[C:27]3[CH:32]=[CH:31][C:30]([CH:33]([C:14]4[S:15][CH:16]=[C:12]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=5)[N:13]=4)[OH:34])=[CH:29][C:28]=23)[CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(-c2cscn2)cc1
Reactant: O=Cc1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc2noc(-c3cccc(Cl)c3)c2c1)c1nc(-c2ccccc2)cs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
BuLi (0.118 mol) was added dropwise at −70° C. under N2 flow to a solution of 4-phenyl-thiazole (0.097 mol) in THF (205 ml). The mixture was stirred at −70° C. for 1 hour. A solution of intermediate (13) (0.0692 mol) in THF (205 ml) was added dropwise. The mixture was stirred at −70° C. for 2 hours, brought to -30° C. over a 90-min period, poured out into NH4Cl 10% and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (39.5 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 20–45 μm). The pure fractions were collected and the solvent was evaporated. A part (1.5 g) of the residue (18 g, 62%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 1.5 g (84%) of 3-(3-chlorophenyl)-α-(4-phenyl-2-thiazolyl)-2,1-benzisoxazole-5-methanol (intermediate 14), mp. 136° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[CH:7]([N-:9][CH:10]=[O:11])=[O:8].[Na+]>C(#N)C>[CH:7]([N:9]([CH2:2][C:3](=[O:6])[CH2:4][CH3:5])[CH:10]=[O:11])=[O:8]
Reactant: CCC(=O)CBr
Reactant: O=C[N-]C=O
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)CN(C=O)C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of bromobutan-2-one (10 g, 66 mmol), and sodium diformylamide (6.8 g, 72 mmol) in acetonitrile (50 mL) was stirred at room temperature for 3 hours, then warmed to 35° C. for 2 hours. The mixture was stirred for a further 48 hours at room temperature, then filtered, washing through with additional acetonitrile (50 mL). The filtrate was evaporated under reduced pressure to afford the title compound as a clear oil, 9.1 g.
Reaction SMILES: Cl.[CH:2]([NH2:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](O)=[O:11]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([NH:5][CH:2]([CH3:4])[CH3:3])=[O:11]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(F)c(Cl)c1
Yield: 81 %

Procedure:
Using isopropylamine hydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (81% yield) as a white solid. ESI-MS: m/z 216 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[I-:32].[Na+]>CC(C)=O>[I:32][CH2:6][C@H:7]([NH:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@H](COS(C)(=O)=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CI)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of methyl (2S)-3-[(methylsulfonyl)oxy]-2-(tritylamino)propanoate CII (22 g; 0.05 mol) in acetone (700 mL) was added sodium iodide (150 g; 1.0 mol) and stirred at r.t. for one week under argon. The acetone was evaporated and the residue was dissolved in diethyl ether (1.5 L). The solids were filtered and the solvent reduced to 1 L before washing with 10% aq Na2S2O3 (3×) and water (200 mL). The solvent was removed under reduced pressure and the residue purified on a silica gel column (10:1→2:1 hexane/EtOAc) and then crystallized from hexane. The methyl (2R)-3-iodo-2-(tritylamino)propanoate CIII was obtained as yellow foam (21 g; 0.045 mol; 89% yield). 1H NMR (CDCl3) [2.25-2.28 (m, 1st rotamer), 2.89 (d, J=10 Hz, 2nd rotamer), 1H], [2.54 (dd, J=13 Hz, J=6 Hz), 3.21 (dd, J=10 Hz, J=8 Hz), 1st rotamer, 1H], [2.69 (dd, J=12 Hz, J=8 Hz), 3.35 (dd, J=10 Hz, J=3 Hz), 2nd rotamer, 1H], [3.31 (s, 1st rotamer), 3.77 (s, 2nd rotamer), 3H], [3.48 (ddd, J=10 Hz, J=7 Hz, J=3 Hz, 2nd rotamer), 4.39 (dd, J=8 Hz, J=6 Hz, 1st rotamer), 1H], 7.18-7.22 (m, 3H), 7.29 (dd, J=8 Hz, J=7 Hz, 6H), [7.45 (d, J=8 Hz, 1st rotamer), 7.50 (d, J=8 Hz, 2nd rotamer), 6H].
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[NH:5][C:6]([NH2:8])=[O:7])#[N:2].[CH3:9][Si:10]([CH3:13])([CH3:12])Cl.[Cl-].[Li+]>C[Si](C)(C)N[Si](C)(C)C>[CH3:9][Si:10]([CH3:13])([CH3:12])[N:8]([Si:10]([CH3:13])([CH3:12])[CH3:9])[C:6]([NH:5]/[CH:4]=[CH:3]\[C:1]#[N:2])=[O:7]
Reactant: N#C/C=C\NC(N)=O
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: C[Si](C)(C)N(C(=O)N/C=C\C#N)[Si](C)(C)C

Procedure:
83 g of cis-2-cyanovinyl urea was dissolved in 200 ml hexamethyldisilazane and 5 ml of trimethylchlorosilane and 1 g of lithium chloride were added. N2 was bubbled and the solution was refluxed until clear. Hexamethyldisilazane was then distilled off and N,N-bistrimethylsilyl-(cis-2-cyanovinylurea) was obtained, which was then dissolved in 200 ml anhydrous dichloromethane. To the solution, 1 g of CdCl2 was added and the solution was stirred with N2 bubbling.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]#[C:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][N:27]=[C:28]=[S:29]>CN(C=O)C>[F:24][C:25]([F:31])([F:30])[CH2:26][NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]#[C:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC#CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 23.2 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobut-2-ynylthio)pyrimidine (1.2 g.), 2,2,2-trifluoroethylisothiocyanate (0.85 g.) and DMF (10 ml.) was stirred at 70° for 72 hours. The mixture was evaporated to dryness, and the residue stirred with N aqueous HCl and then filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobut-2-ynylthio)pyrimidine (0.4 g.), m.p. 124-127°.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21](O)(=[O:39])[CH2:22]CCCCCC/C=C/CCCCCCCC.C(O)(=O)CCCCCCC/C=C\C/C=C\CCCCC.C(O)(=O)CCCCCCC/C=C\C[C@@H](CCCCCC)O.C(Cl)C(OC(N)=O)CCl>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:20][CH2:22][CH2:21][OH:39]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Agent: NC(=O)OC(CCl)CCl
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOCCO

Procedure:
Surface-active dispersing agents in the form of oxyalkylated esters of unsaturated higher fatty acids are preferred. Oxymethylated and/or oxyethylated esters are especially preferred. In this, case, a glyceride type ester is preferred. This ester can be a mono-, di- and tri-glyceride. The oxyalkylated forms of the esters which can be used in accordance with the invention are obtained, in particular, from esters of unsaturated higher fatty acids which can undergo an oxyalkylation, particularly an oxyethylation. Particularly useful fatty acids are oleic acid, elaidic acid, linoleic acid and ricinoleic acid. The oxyethylated glyceride of ricinoleic acid, which can be advantageously used in the form of ethoxylated castor oil is of particular value for the purposes of the present invention. Castor oil consists of 80 to 85% of the glyceride of ricinoleic acid, and in addition the glycerides of oleic (7%), linoleic (3%), palmitic (2%) and stearic (1%) acids. Ethoxylated castor oil is marked by a good solubility in fatty acids, polar solutions and water. The oxyethylated castor oil may be that produced commercially by BASF (trademark: Emulphor EL). This castor oil is a yellow oil, having a freezing point below +20° C., and which is soluble in fatty acids, waxes, castor oil, polar solvents (e.g., trichloroethylene, xylene) and water.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[CH:21]=[C:20]([N:15]3[CH2:14][CH2:13][CH:12]([N:10]4[C:9](=[O:18])[NH:8][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:11]4)[CH2:17][CH2:16]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:37]=1
Reactant: O=c1[nH]c(-c2ccccc2)nn1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
378 mg (1.00 mmol) 5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one, 289 mg (1.00 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.0 mmol) DIPEA were stirred overnight in 10 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[N:19]O)[C:9]1[CH:18]=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[CH:11][CH:10]=1>CCOCC>[C:8](#[N:19])[C:9]1[CH:18]=[CH:17][C:12]([C:13]#[N+:14][O-:15])=[CH:11][CH:10]=1
Reactant: ON=C(Cl)c1ccc(C(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#Cc1ccc(C#[N+][O-])cc1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a 300 ml, three-necked, round bottomed flask equipped with a magnetic stirrer, a thermometer, and a 125 ml dropping funnel topped with a drying tube was added triethylamine (6.1 g, 60 mmoles) and ether (150 ml). The solution was cooled to -5°C in an ice/salt bath and a solution of terephthalhydroximoyl chloride (4.7 g, 20 mmoles) in ether (75 ml) was added dropwise at -5°C with rapid stirring over a period of 20 minutes. The resulting white suspension was stirred an additional 40 minutes at -5°C. Cold distilled water (30 ml) was then added and the suspension was stirred an additional 20 minutes at 0°to -5°C and was then filtered on a sintered glass filter. The nearly white solid was washed thoroughly on the filter with cold distilled water (3 × 25 ml) and cold ether (3 ×0 25 ml) and was then dried in a vacuum desiccator for 2 1/4hours (0.7 mm Hg) to yield 3.1 g (95%) of nearly white, fluffy terephthalonitrile oxide (TPNO). (As a word of caution, the dry material decomposed explosively when heated to 155°C in air).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN1CCN(CCCCN)CC1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available 4-(4-methylpiperazin-1-yl)butan-1-amine, the title compound was obtained, MS (Found M+1=413. 1H NMR (CD3OD, 300 Hz): 8.32-8.30 (d, 1H J=8.2 Hz), 8.30-7.85 (m, 1H), 7.58-7.57 (d, 1H), 7.47-7.44 (m, 1H), 7.34-7.32 (m, 1H), 4.00 (s, 3H), 3.92-3.89 (t, 2H, J=6 Hz), 2.54-2.51 (b, 4H), 2.41-2.29 (m, 6H), 2.25 (s, 3H), 1.85-1.77 (m, 2H), 1.60-1.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:20])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cc2c1OCCN2
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc2c1OCCN2

Procedure:
A mixture of 12 g of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid, 200 ml of methanol, and 10 ml of concentrated sulfuric acid was heat-refluxed for 24 hours with stirring. The liquid reaction mixture was concentrated in vacuo. To the residue were added an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the resulting organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was clitilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and ethanol to give 9.2 g of methyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate. Melting point: 60°-61° C.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[H-].[Na+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[O:24]([CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCCCCCC(Br)C(=O)O
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(Oc1ccccc1)C(=O)O
Reaction time: 17 h
Yield: 92 %

Procedure:
To 2-bromododecanoic acid (500 mg) dissolved in N,N-dimethylformamide (DMF, 10 ml) at 0° C. were added 60% sodium hydride (163 mg) followed by phenol (154 mg), and the mixture was stirred for 17 hours. Then, the solvent (DMF) was evaporated, and the residue was distributed into water and ethyl acetate. The ethyl acetate layer was dried and concentrated to give 2-phenoxydodecanoic acid (440 mg). To 2-phenoxydodecanoic acid (440 mg) dissolved in DMF were added para-nitrophenol (190 mg) and N,N'-dicyclohexylcarbodiimide (283 mg), and the mixture was stirred for 15 hours. Then, precipitates produced were removed by filtration, and 6-(4'-N-glycylspicaminyl-amino)purine hydrochloride (529 mg) and triethylamine (2.0 ml) were added to the filtrate. The mixture was further stirred for 15 hours. The DMF was evaporated from the reaction mixture, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK242 in the yield of 118 mg.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH3:3].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:3][CH2:2][CH2:1][NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[C:20]([CH:21]=[O:22])[CH:23]=1
Reactant: CCCNCCCC(=O)OC(C)(C)C
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCNCCCc1ccc(Br)cc1C=O
Temperature: 80 °C
Reaction time: 94 h
Yield: 52.3 %

Procedure:
To a solution of t-butyl 4-propylaminobutyrate (14.2 g, 70.7 mmol) in DMF (20 ml) were added 5-bromo-2-fluorobenzaldehyde (14.4 g, 70.9 mmol) and potassium carbonate (14.7 g, 106 mmol) at room temperature, and the mixture was stirred at 80° C. for 94 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1) to give yellow oil of t-but yl 4-(4-bromo-2-formylphenyl)propylaminobutyrate (14.2 g, 52%).
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH2:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Nc1ccc(I)cc1C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A magnetically stirred solution of 5 grams of 5-iodoisatoic anhydride (0.0173 mol), 5.85 grams of β-alanine benzyl ester tosylate (0.0173 mol), 35 mL pyridine, and 0.5 of dimethylaminopyridine (0.0041 mol) was heated to 80° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 100mL ethyl acetate and washed 2×50 mL of 10% cupric sulfate, 1×50 mL sat. sodium bicarbonate, 1×50 mL brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by column chromatography, using silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane (TLC, SIO2, 1:1 EtOAc/hexane, Rf =0.65, υν positive) to yield 1.85 grams (25%) of N-(2-amino-5-iodobenzoyl)-β-alanine benzyl ester. 1H NMR (CDCl3, δTMS) 7.54 (1H, d, 4JHH =2 Hz, Ar--H o--CON), 7.42 (1H, dd, 3JHH =9 Hz, 4JHH =2 Hz, Ar--H p--CON), 7.38-7.32 (5H, s, ArH Ph), 6.65 (1H, bt, 3JHH =6 Hz, CONH), 6.46 (1H, d, 3JHH =9 Hz, Ar--H m--CON), 5.16 (2H, s, OCH2), 3.68 (2H, q, 3JHH =6 Hz, NCH2), 2.69 (2H, t, 3JHH =6 Hz, CH2CO2). 13C NMR (CDCl3,δTMS) 172.4, 167.8, 148.2, 140.6, 135.6, 135.5, 128.7, 128.4, 128.3, 119.3, 118.1, 76.3, 66.7, 35.2, 34.0.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][N:22]=3)[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[O:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH:43]1[O:42][NH:41][C:27]([C:24]1[CH:23]=[N:22][C:21]([N:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:20]=3[CH2:19]2)=[N:26][CH:25]=1)=[O:28]
Reactant: O=C(O)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a stirred solution of 2-(9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylic acid (90 mg) in DCM (5 mL) was added EDCI (74 mg) at 0° C. and the reaction mixture was stirred for 20 min. NH2OTHP (30 mg) was added and the temperature was allowed to attain room temperature. After stirring at room temperature overnight, it was diluted with DCM. The organic layer was washed with water and then concentrated under vacuum. The residue obtained was purified by column chromatography to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (60 mg, 53% yield), m/e=484 (M+1).