Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]4)[CH2:15]2)[CH2:21]3)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO.[CH2:28](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]4)[CH2:15]2)[CH2:21]3)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:28])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
A solution of 5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzoic acid (3.53 g, 9.57 mmol), 4-dimethylaminopyridine (0.23 g, 1.90 mmol), and methanol (3.87 mL, 95.70 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.67 g, 19.10 mmol). The reaction mixture was stirred for 24 hours at ambient temperature; diluted with ethyl acetate (200 mL) and washed with water (100 mL), saturated ammonium chloride (100 mL), and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate) to provide the title compound (0.65 g, 18%): 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=7.9 Hz, 1H), 6.59 (d, J=12.6 Hz, 1H), 3.85 (s, 3H), 3.56 (s, 2H), 3.23 (s, 2H), 2.11 (br s, 1H), 1.74-1.40 (m, 14H); MS (ES+) m/z 383.1, 385.1 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: CCCc1cc(O)nc(NCC)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1cc(Cl)nc(NCC)n1
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of 2-ethylamino-4-hydroxy-6-propylpyrimidine (1.81 g, 10 mM) and phosphorus oxychloride (15 ml) was heated at 100° C. for 18 hours. The excess of phosphorus oxychloride was removed under reduced pressure and the residual was decomposed with ice-water (50 ml). The solution was made basic with concentrated aqueous ammonia and extracted with ethyl acetate (3×50 ml). The extracts were combined, dried and the solvent evaporated to give 4-chloro-2-ethylamino-6-propylpyrimidine (1.79 g; 90% yield) as an oil which was used without purification.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(C(C)C)C(C)C)C.[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])[CH3:33]>C1C=CC=CC=1>[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:39])(=[O:34])[CH3:33]
Reactant: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCCN(C(=O)c1ccccc1OC(C)=O)c1ccccc1-c1ccccc1
Yield: 73.5 %

Procedure:
15.0 g of ethyl 5-(biphenyl-2-yl)aminovalerate is reacted, analogously to Example 47b), with 6.6 g of ethyldiisopropylamine and 10.0 g of o-acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 g (73.4% of theory) of ethyl 5-[o-acetoxy-N-(biphenyl-2-yl)-benzamido]valerate as a viscous non-distillable oil. The saponification of this ester yields 9.1 g (63.2% of theory) of 5-[o-hydroxy-N-(biphenyl-2-yl)benzamido]valeric acid, MP 138° to 139°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23]O)[C:19](=[O:25])[CH:18]([CH2:26][C:27]([OH:29])=[O:28])[S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:31].[CH2:34](O)[CH3:35]>C(OCC)C>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][Br:31])[C:19](=[O:25])[CH:18]([CH2:26][C:27]([O:29][CH2:34][CH3:35])=[O:28])[S:17]2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C2SC(CC(=O)O)C(=O)N2CCCO)cc(C(C)(C)C)c1O
Reactant: CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCOC(=O)CC1SC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N(CCCBr)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-hydroxypropyl)-5-carboxymethyl-1,3-thiazolidin-4-one (2.45 g) in diethyl ether (30 ml) was added phosphorus tribromide (3.45 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise ethanol (30 ml) under cooling with ice, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 100 ml of ice-water, and the product was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane, 20:80) and then recrystallized from chloroform/n-hexane to afford 1.50 g (51%) of the title compound as colorless crystals. mp 154-155° C. NMR (CDCl3) (200 MHz) δ: 1.26 (3H, t, J7.1 Hz), 1.43 (18H, s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m), 3.2-3.6 (4H, m), 4.17 (2H, q, J=7.1 Hz), 4.1-4.4 (1H, m), 5.33 (1H, s), 5.53 (1H, s), 7.14 (2H, s)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH:29]=3)=[CH:5][C:4]=2[N:3]=1.O>C(O)(=O)C.O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cncc(CO[Si](C)(C)C(C)(C)C)c4)cnc3c2n1CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOCc1nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1-{4-amino-7-[5-(tert-butyldimethylsilanyloxymethyl)pyridin-3-yl]-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.37 g, 2.55 mmol) in acetic acid (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was stirred at 60° C. for 18.5 hours and allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was diluted with saturated aqueous sodium bicarbonate (30 mL). Dichloromethane was added, but an oil was present that remained insoluble in both phases. Both phases were decanted away from the oil, which was dissolved in methanol. The aqueous phase was then separated and extracted with dichloromethane (30 mL) and ethyl acetate (2×30 mL). Silica gel was added to the combined dichloromethane, ethyl acetate, and methanol fractions, and the solvent was removed under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in dichloromethane). The resulting material was concentrated from acetonitrile to form a solid, which was triturated with acetonitrile (30 mL), isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven to provide 530 mg of 1-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 212-214° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH2:32])[NH:28][C:27](=[O:33])[CH2:26]2>>[NH2:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:27](=[O:33])[NH:28]2)=[CH:24][C:23]=1[F:22]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(N)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 50 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 50%) as a red solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29](O)[CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:33]([C:32]1[CH:27]=[CH:28][C:29]([O:25][C:24](=[O:26])[C@H:12]([CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:30][CH:31]=1)([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
N-carbobenzoxy-β-benzyl-L-aspartic acid (12 Kg) and p-nitrophenol (5.1 Kg) are dissolved in ethyl acetate (20-30 L) and the solution is cooled to below 5° C. Dicyclohexyl-carbodiimide (7.6 Kg) is dissolved in ethyl acetate (8-12 L) and added, maintaining the temperature below 5° C. The solution is stirred at reduced temperature for two hours and then for three hours at 20°-30° C. The dicyclohexylurea byproduct is removed by filtration and washed with ethyl acetate (20-30 L). The filtrate is concentrated in vacuo below 60° C. The concentrate is dissolved in a mixture of hot isopropyl alcohol (25-40 L) and distilled water (2-5 L) and cooled below 25° C. The solids are collected on a filter, rinsed with isopropyl alcohol and dried below 40° C. Melting point=76°-79° C.; specific rotation=-15° to 18° (C=1, DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[CH:12][S:13](=O)[C:9]=2[CH:8]=1)=[O:6].C([O-])([O-])=[O:21].[K+].[K+].Cl[CH2:27][CH2:28][O:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=1.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:16]=[CH:15][C:10]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:44]=[CH:43][C:33]([O:34][C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[C:12](=[O:21])[S:13][C:9]=2[CH:8]=1)=[O:6]
Reactant: O=C(c1cccc(Cl)c1)c1ccc2c(c1)S(=O)C=N2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCCl)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1
Temperature: 120 °C

Procedure:
To a solution, heated at 80° C. for 2 hours, of 6-(3′-chlorobenzoyl)-benzothiazolinone (1.8 g) in the presence of K2CO3 (1.72 g) in 20 ml of DMF there is added ethyl 2-[4-(2-chloroethoxy)phenoxy]-2-methylpropanoate (1.96 g). The reaction mixture is heated at 120° C. for 5 days, cooled, hydrolysed using 100 ml of water and rendered alkaline using 1N NaOH. The precipitate obtained is filtered off and then recrystallised from cyclohexane to yield the title compound in the form of a white powder.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][CH3:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[O:26][CH3:27]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: COc1cc(B(O)O)ccc1Cl
Product: COc1cc(-c2c(-c3cc(C#N)ccn3)ncn2C)ccc1Cl

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-methoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H13ClN4O, 326. Found, 325, 327.
Reaction SMILES: NC1C=CC=CC=1.O=[S:9](Cl)Cl.[NH2:12][C:13]1[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=1[NH2:19]>C1(C)C=CC=CC=1>[N:19]1[S:9][N:12]=[C:13]2[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=12
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)c1ccc(N)c(N)c1
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc2nsnc2c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To a solution of aniline (1.86 g, 20 mmol) in 50 mL of toluene was added SOCl2 (2.6 g, 22 mmol) dropwise at 0° C. and the mixture was then refluxed for 2 h. After cooling to rt, 1-(3,4-diaminophenyl)propan-1-one (1.65 g, 10 mmol) was added. The mixture was refluxed for 2 h, cooled, concentrated, and purified by flash chromatography to give the desired product (960 mg, 50%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.15 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Product: O=C(O)CCC(=O)OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Yield: 75 %

Procedure:
1-Benzyl-3-(4′-hydroxymethylphenyl)indazole was reacted with succinic anhydride according the procedure described in Example 1 (d) to afford Compound 9 in a yield of 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][NH:22]2)=[CH:17][CH:16]=1)[CH3:14])=[O:11].[BH4-].[Na+].[CH3:27]O>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][N:22]2[CH3:27])=[CH:17][CH:16]=1)[CH3:14])=[O:11]
Reactant: CO
Reactant: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)N(C)CCC2
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of 3-(2-fluoro-phenyl)-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-acrylamide (39 mg, 0.12 mmol) in formic acid (3 mL) was treated at 23° C. with small portions of NaBH4 (136 mg, 3.6 mmol). The reaction mixture was stirred for 16 hours, then MeOH was added and the solvent evaporated. The residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with water, dried (MgSO4) and evaporated. The crude material was purified by chromatography (SiO2, 5% CH3CN in CH2Cl2) yielding 37 mg (91%) of the title compound as a tan solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4]CC1.[CH:29](=O)CC(C)C.CC(C)CCN.C([O:43][C:44](=[O:54])C(SC1SC(N)=NC=1)C)C>>[CH3:29][CH:5]([CH3:4])[CH2:6][CH2:1][N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:44]([OH:54])=[O:43])=[CH:13][N:14]=1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)CC=O
Agent: CC(C)CCN
Product: CC(C)CCN(CCC(C)C)C(=O)Nc1ncc(SCCC(=O)O)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, 3-methyl-butylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[N:22]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[OH-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:45][N:46](C)[OH:47].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:46]([O:47][CH3:32])[CH3:45])=[O:29])[C:12]([CH3:28])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[N:22]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of 3-[5-chloro-4-(6-fluoro-pyridin-2-ylmethoxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (180 mg, 0.43 mmol) in tetrahydrofuran (2 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to give a yellow solid which was used without additional purification. To a solution of the crude acid in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (105 mg, 0.65 mmol). After stirring at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (63 mg, 0.65 mmol) and triethylamine (0.12 mL, 0.86 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a colorless oil (85 mg, 44%). MS (M+H): 447
Reaction SMILES: C1(C2SC=C(CCO)N=2)C=CC=CC=1.ClC1C=CC(C2SC=C(CCO)N=2)=CC=1.[CH2:30]([C:32]1([CH2:48][C:49]([O:51]CC)=[O:50])[C:40]2[S:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)=[N:37][C:36]=2[CH2:35][CH2:34][O:33]1)[CH3:31]>>[CH2:30]([C:32]1([CH2:48][C:49]([OH:51])=[O:50])[C:40]2[S:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)=[N:37][C:36]=2[CH2:35][CH2:34][O:33]1)[CH3:31]
Reactant: CCOC(=O)CC1(CC)OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: OCCc1csc(-c2ccc(Cl)cc2)n1
Agent: OCCc1csc(-c2ccccc2)n1
Product: CCC1(CC(=O)O)OCCc2nc(-c3ccc(Cl)cc3)sc21

Procedure:
In the same manner but replacing 2-phenyl-4-(β-hydroxyethyl)thiazole with an equivalent amount of 2-(4-chlorophenyl)-4-(β-hydroxyethyl)thiazole the intermediate ester, ethyl 6,7-dihydro-4-ethyl-2-(4chlorophenyl)-4H-pyrano[4,3-d]thiazole-4-acetate (IV, R1 = Cl, R2 = CH2CH3, A= COOCH2CH3 and n= 1is obtained. Alkaline hydrolysis of the latter ester gives 6,7-dihydro-4-ethyl-2-(4-chlorophenyl)-4H-pyrano[4,3-d]thiazole-4-acetic acid (I; R1 = Cl, R2 = CH2CH3, R3 = COOH and n= 1), mp 190°-191° C., after crystallization from methanol. The ether extract obtained from the alkaline aqueous solution is purified to give the by-products 6,7-dihydro-4-ethyl-4-methyl-2-(4-chlorophenyl)-4H-pyrano[4,3-d]thiazole hydrochloride, mp 153°-154° C., after trituration with ether containing hydrogen chloride.
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=1)=[CH2:11].[OH-:25].[Na+].OO>O1CCCC1.O>[OH:25][CH2:11][CH2:10][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 5.65 g, 46.3 mmol) in anhydrous tetrahydrofuran was added to a solution of t-butyl 4-vinylbenzoate (8.47 g, 42.1 mmol) prepared in the Preparative Example 102 in anhydrous tetrahydrofuran in a nitrogen stream. The obtained mixture was stirred at room temperature for 3 hours. 15 ml of water and 17 ml of 3N NaOH were added to the reaction mixture successively, followed by the dropwise addition of 80% aqueous hydrogen peroxide at 50° C. or below. The obtained mixture was stirred as such for one hour and poured into water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=1:1) to give the objective compound. yield: 8.71 g
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) from Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90 mL). lodomethane (2.1 mL) is added and the mixture is stirred at room temperature for 1 h. The resulting suspension is poured into water (500 mL) and filtered. The crude solid is washed with water (50 mL) and diethyl ether (100 mL) and then is recrystallized from ethanol to afford 10.6 g (85%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:25])[NH2:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(N)=S)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 5 h

Procedure:
3,4,5-Trimethoxybenzamide (5.0 g) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (5.24 g) were added to toluene, and the mixture was stirred at 70° C. After 5 hours, the reaction mixture was cooled back to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to obtain yellow crystals, and the crystals were further recrystallized from ethyl acetate-hexane to obtain the title compound.