Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:36]([F:39])([F:38])[F:37])[N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][C@H:16]([NH:27]C(OC(C)(C)C)=O)[CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:10][C:9]=12)=[O:4].[ClH:40]>C(OCC)(=O)C>[ClH:40].[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:36]([F:39])([F:37])[F:38])[N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][C@H:16]([NH2:27])[CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 94.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (0.12 g, 2.12 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 1 (0.12 g, yield 94.3%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH:22]([CH3:24])[CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)N1CCc2nn(C(C)C)c(-c3ccc(F)cc3)c2CC1

Procedure:
The title compound (92 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and acetone as in Example 35. MS (ESI): exact mass calculated for C19H26FN3, 315.21; found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.39 (m, 2H), 7.33-7.30 (m, 2H), 4.40 (m, 1H), 3.78-3.74 (m, 2H), 3.68-3.63 (m, 1H), 3.36-3.21 (m, 4H), 2.99-2.94 (m, 1H), 2.80-2.76 (m, 1H), 1.54-1.37 (m, 12H).
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(CN)CCCC1
Reaction time: 24 h

Procedure:
To a solution of methyl 1-cyanocyclopentanecarboxylate (15 g, 98 mmol) in MeOH (250 mL) was added RaNi (3 g). The reaction was charged with H2 at 50 psi and shaken in the Parr shaker for 24 h. The RaNi catalyst was removed by filtration through a layer of celite. The solvent was removed under vacuum. The crude product was dissolved in 1N NaHSO4 (100 mL) and then washed with Et2O (2×100 mL). The organic layer was dried over magnesium sulfate and then filtered. The solvents were removed under reduced pressure to provide the amine in 77%; 1H NMR (300 MHz, CD3OD) δ3.75 (s, 3H), 3.12 (s, 2H), 2.14×2.07 (m, 2H), 1.83×1.65 (m, 6H). MS [M+H]+470.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4][NH:3]1.[H-].[Na+].[CH3:20]I.[Cl-].[NH4+]>C1COCC1.CN(C=O)C>[CH3:20][N:3]1[C:2](=[O:1])[CH:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4]1
Reactant: COC(=O)NC1Cc2ccccc2CNC1=O
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)NC1Cc2ccccc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 176 mg (0.75 mmol) of product 1 (methyl (3-oxo-2,3,4,5-tetrahydro-1-H-2-benzazepin-4-yl)carbamate, which can be prepared according to WO 02/057257 and the content of the description of which is incorporated herein by reference), dissolved in a mixture of 2 ml of dry THF and 2 ml of dry DMF is added dropwise at room temperature to a suspension of 36 mg (0.9 mmol) of 60% NaH dispersed in oil, suspended in 2 ml of anhydrous THF, under an inert atmosphere. At the end of the addition, 159 mg (1.5 eq.) of methyl iodide are added. The reaction mixture is then stirred at room temperature for 2 hours, and 10 ml of saturated ammonium chloride solution are then added, while cooling the reaction medium in an ice bath. The mixture is extracted with 3×10 ml of ethyl acetate. The organic phases are combined, washed with 2×10 ml of saturated NaCl solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue obtained is chromatographed on silica gel, eluting with a 90/10 dichloromethane/methanol mixture. 82 mg (44%) of the expected product 2 are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[CH:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([C:21]2([O:29][CH3:30])[CH2:26][CH2:25][O:24][C:23]([CH3:28])([CH3:27])[CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([C:21]4([O:29][CH3:30])[CH2:26][CH2:25][O:24][C:23]([CH3:27])([CH3:28])[CH2:22]4)[CH:18]=[CH:19][CH:20]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2ccc(CBr)cc2c1
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Product: COC1(c2cccc(OCc3ccc4ccc(F)cc4c3)c2)CCOC(C)(C)C1
Yield: 99.8 %

Procedure:
Using the procedure described in Example 5, 7-fluoro-2-bromomethylnaphthalene (0.23 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.21 g) to give 4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,2-dimethyltetrahydropyran (0.35 g, 86%), as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][C:18]1(OC)[CH2:22][CH2:21][C:20]([CH3:25])(OC)O1>>[CH3:17][C:18]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[C:20]([CH3:25])=[CH:21][CH:22]=1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reactant: COC1(C)CCC(C)(OC)O1
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
13.5 mmol of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione were reacted with 13.5 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Sn:11](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:20]([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A THF solution (100 mL) of furan (6.8 g) was cooled to -78° C. under N2 atmosphere. Butyl lithium (1.6 M×62.5 mL, 100 mmol) was added dropwise through dropping funnel in 1 hr. After stirred at -78° C. for 1 hr, the reaction mixture was warmed gradually to room temperature and stirred for 30 min. The mixture was again cooled to -78° C. and added dropwise a THF solution (25 mL) of Bu3SnCl (32.5 g, 100 mmol) with stirring. The mixture was warmed gradually to room temperature and stirred for 10-12 hrs and then concentrated. Distillation (92° C., 0.5 torr) yielded 31.3 g (87.7 mmol) of 2-(tributylstannyl) furan (87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:28]([C:25]3[CH:24]=[CH:23][C:22]([S:21][CH3:20])=[CH:27][CH:26]=3)(=[O:29])=[O:30])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH:7]=1
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Yield: 33.9 %

Procedure:
Using the method of Example 17.4, 2-(3-chloro-5-pyridyloxy)-5-aminobenzotrifluoride (0.394 g) and 4-methylthiobenzenesulfonyl chloride (0.34 g ) [H. Burton, et al. J. Chem. Soc. 1948, 604-605] were combined to provide, after flash chromatography and trituration with hexane/ether, the title compound as crystals (0.22 g). mp 109.5-111° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: CNCc1ccncc1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccncc1)C(=O)Nc1ccccc1
Yield: 81 %

Procedure:
4-(Methylaminomethyl)pyridine (5 g), dry chloroform (500 ml) and phenyl isocyanate (5 g) were stirred together at room temperature for 2 hours. The chloroform was then evaporated in vacuo and the resultant oil was redissolved in the minimum quantity of chloroform and chromatographed on a "Florisil" (Trade Mark) (100 g) column using chloroform containing gradually increasing quantities of methanol (up to 2.5%) as eluting solvent. Appropriate fractions (identified by t.l.c.) were combined and evaporated in vacuo to give 1-methyl-1-(4-pyridylmethyl)-3-phenylurea as an oil (8.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1)=[CH:10][C:9]([NH2:17])=[CH:8][CH:7]=3.P(Cl)(Cl)(Cl)=O.[CH:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=O.C(Cl)(Cl)Cl.CO>O1CCCC1>[N:25]1([CH:23]=[N:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11]([C:12](=[O:16])[NH:13][C:14]=3[CH:15]=2)=[CH:10][C:9]([N:17]=[CH:23][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:8][CH:7]=4)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CN1CCCC1
Reactant: Nc1ccc2c(c1)[nH]c(=O)c1cc(N)ccc12
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]c2cc(N=CN3CCCC3)ccc2c2ccc(N=CN3CCCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A suspension of 3,8-diamino-6-(5H)-phenanthridone (500 mg) in tetrahydrofuran (5 ml) was added to a mixture of phosphorus oxychloride (0.75 ml) and N-formylpyrrolidine (2.5 ml) and tetrahydrofuran (5 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 50° C. for 1 hour and worked as described in Example 8, paragraph 1. Yield 52%, melting point 280° C. (decomposition) (CHCl3 /methanol).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8]N)[CH:3]=1.[C:11]([OH:18])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.S(=O)(=O)(O)O>O>[CH3:16][C:14]1[NH:8][C:4]2[C:5]([C:13]=1[CH2:12][C:11]([OH:18])=[O:17])=[CH:6][CH:7]=[C:2]([CH3:10])[CH:3]=2
Reactant: CC(=O)CCC(=O)O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2c(CC(=O)O)c(C)[nH]c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.1 %

Procedure:
A mixture of 3-tolylhydrazine hydrochloride (1 g), levulinic acid (1.3 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 80° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate and the organic layer was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the obtained residue and vigorously stirred therewith, and then dichloromethane was added and the mixture was again vigorously stirred. The aqueous layer was collected, rendered acidic with concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Methanol (20 ml) and concentrated sulfuric acid (1 ml) were added to the obtained residue, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, water was added, and then extraction was performed with dichloromethane. The organic layer was collected and dried over sodium sulfate, and then concentrated under reduced pressure. A 2-(2,6-dimethyl-1H-indol-3-yl)acetic acid methyl ester component was purified from the obtained residue by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate. A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained 2-(2,6-dimethyl-1H-indol-3-yl)acetic acid methyl ester, and the mixture was heated to reflux for one hour. The reaction mixture was allowed to cool, water was added, and then the mixture was rendered acidic with concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulfate, and then concentrated under reduced pressure to obtain 0.13 g of the title compound as a colorless powder (13% yield).
Reaction SMILES: ClCCl.I[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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]>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8]3)[CH:23]=1
Reactant: OB(O)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(I)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ncc2cc(-c3cccnc3)ccc21
Temperature: 100 °C
Yield: 52.7 %

Procedure:
[1,1′-Bis(diphenylphosphino)-ferrocene)dichloropalladium(II) 1:1 complex with dichloromethane (204 mg, 0.25 mmol) was added to a mixture of 5-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (Preparation #17a, 1.87 g, 5.00 mmol), pyridine-3-boronic acid (737 mg, 6.00 mmol), and Cs2CO3 (4.89 g, 15.0 mmol) in 1,2-dimethoxy-ethane (16 mL) and water (3.2 mL) under a nitrogen atmosphere. The reaction was heated at about 100° C. overnight, cooled, concentrated and extracted with CH2Cl2 (about 30 mL). The extracts were adsorbed onto silica and purified over a silica gel column eluting first with heptane:EtOAc (85:15) and then with heptane:EtOAc (3:2) to yield 5-pyridin-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (857 mg, 53%) as an oil. RP HPLC (Table 1, Method e) Rt=3.04, m/z: (MH)+ 326.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:9]([O:8][C:7](=[O:13])[NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:2]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 97.5 %

Procedure:
tert-Butyl(3R)-pyrrolidin-3-ylcarbamate (4.54 g, 24.4 mmol), 4-fluoronitrobenzene (3.78 g, 24 mmol) and potassium carbonate (3.54 g 25.6 mmol) in acetonitrile (70 ml) were heated under reflux for 18 hours. After evaporation under reduced pressure, the mixture was dissolved in DCM (200 ml), and washed with water (100 ml) and saturated sodium chloride solution (25 ml). The solution was dried and filtered. After evaporation under reduced pressure, chromatography on silica gel eluting with DCM gave the title compound (7.19 g, 97%). NMR: 1.39 (s, 9H), 1.87-1.98 (m, 1H), 2.09-2.21 (m, 1H), 3.15-3.23 (m, 1H), 3.32-3.44 (m, 1H), 3.45-3.51 (m, 1H), 3.53-3.61 (m, 1H), 4.09-4.21 (m, 1H), 6.57 (d, 2H), 7.21 (s, 1H), 8.01 (d, 2H); m/z (MH+—C4H8) 252.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[CH2:33][CH2:34][NH2:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:34][CH2:33][C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=4)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 68 was coupled with 3-flourophenethylamine following procedure F. LC-MS showed the product had the expected M+H+ of 506. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (m, 2H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 5.3 (m, 1H) 3.9 (m, 4H) 3.7 (m, 4H) 3.0 (m, 4H) 1.6 (m, 3H) 1.4 (s, 9H).
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12](=[S:35])[NH:13][C:14]1[S:15][C:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:18]=1)(=O)C1C=CC=CC=1.O>CO>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([NH:13][C:12]([NH2:11])=[S:35])[S:15][C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2nc(NC(=S)NC(=O)c3ccccc3)sc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(NC(N)=S)sc2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution of sodium hydroxide (0.36 g) in methanol (4.1 ml) was added to a solution of 2-(3-benzoylthioureido)-4,5-bis(4-methoxyphenyl)thiazole (4.3 g) and water (0.5 ml) in methanol (25 ml). The resulting mixture was stirred for 3 hours at 55°~60° C. The methanol was evaporated in vacuo and the residue was triturated with water. The precipitates were collected by filtration and dried to give 4,5-bis(4-methoxyphenyl)-2-thioureidothiazole (3.20 g).
Reaction SMILES: [OH:1]C1C=C(O)C=CC=1CC(O)=O.[CH2:13]1[CH2:18][CH2:17][CH:16]([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:15][CH2:14]1>C(OCC)(=O)C.CCCCCC>[CH:22]1([NH:21][C:20](=[O:1])[NH:19][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:18][CH2:17]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
1.5 g of 2,4-dihydroxyphenylacetic acid (1.8 mole) was dissolved in 20 mL of 50:50 v/v ethyl acetate and hexane. Then 1.5 mL of DCC (˜1.4 mmole) was added and the reaction continued for 1 hr at room temperature under argon that was bubbled into the solution. A white precipitate of dicyclohexyl urea formed during the reaction. After 3 hr. the urea precipitate was removed and 1.8 mL (5.6 mmol) of oleylamine (C18-content 80-90%; Fisher), was initially dissolved in 10 mL of hexane in the presence of 4-dimethylaminopyridine (0.5 g) and added to the reaction product of the 2,4-dihydroxyphenylacetic acid and DCC. The reaction continued at room temperature for 1 hr and then stored at −20° C. for one week.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[SH:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][S:16][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: SCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(SCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A solution of 2.78 g (10 mmol) of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate and 2.09 g (12 mmol) of 2-mercaptomethylnaphthalene in 100 ml of absolute acetonitrile was treated with 13.8 g (100 mmol) of anhydrous potassium carbonate and thereafter the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured on to ice-water and adjusted to pH 2-3 with concentrated hydrochloric acid; the aqueous phase was extracted three times with 200 ml of ethyl acetate each time, the organic phase was washed once with 200 ml of water, dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The crude product (5.5 g) was chromatographed on silica gel with hexane and ethyl acetate as the eluent. The product was recrystallized from ethyl acetate and hexane. There were obtained 2.27 g (61% of theory) of tert-butyl (3RS)-3-(naphthalen-2-ylmethylthio)-4-oxo-piperidine-1-carboxylate as a colourless solid; MS: 371 (M)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncnc(N[C@H](COC(=O)c3cccc(Br)c3)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of (S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline (49 mg, 0.15 mmol) in pyridine (2 ml) was added dropwise at 0-5° C. 3-bromobenzoylchloride (33 mg, 0.15 mmol). After 6 h stirring at room temperature the reaction mixture was poured into iced water and extracted with dichloromethane. The organic layer was dried and evaporated to dryness. The residue was purified by flash chromatography on silica gel using as eluant dichloromethane/methanol 95:5 to give pure title compound as a white solid in 71% yield (54 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41](F)(F)[CH:42]([F:44])[F:43])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:49][CH3:50])[N:27]=1.[CH2:51](N(S(F)(F)F)CC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:47][CH3:48])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([F:44])([F:43])[CH3:51])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:49][CH3:50])[N:27]=1
Reactant: CCc1cc(NC(CC)c2ccc(OC(F)(F)C(F)F)cc2)nc(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCc1cc(NC(CC)c2ccc(OCC(C)(F)F)cc2)nc(Cl)n1
Yield: 61.9 %

Procedure:
To a solution of 1.0 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-acetonyloxybenzyl)aminopyrimidine obtained in Example 17 dissolved in 50 ml of dried benzene was added 0.5 g of diethylaminosulfur trifluoride, and the mixture was refluxed by heating for 5 hours while stirring. After completion of the reaction, the mixture was poured into ice-cold water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=7:1) to give 0.6 g of the desired product as pale yellow oily liquid.