Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]3[CH2:13][CH:12]([C:2]1=2)[CH2:11][CH2:10]3.[NH2:14][C:15]1[C:16]([CH3:45])=[C:17]([C:21]2[N:22]=[C:23]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[C:41](=[O:42])[N:40]([CH3:43])[CH2:39][CH2:38][N:37]4[CH3:44])=[CH:32][CH:31]=3)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C=O)C>[CH3:44][N:37]1[CH2:38][CH2:39][N:40]([CH3:43])[C:41](=[O:42])[CH:36]1[C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:23]2[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=[C:21]([C:17]3[C:16]([CH3:45])=[C:15]([NH:14][C:6]([C:5]4[S:1][C:2]5[CH:12]6[CH2:13][CH:9]([C:3]=5[CH:4]=4)[CH2:10][CH2:11]6)=[O:8])[CH:20]=[CH:19][CH:18]=3)[N:22]=2)=[CH:31][CH:32]=1
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Reactant: O=C(O)c1cc2c(s1)C1CCC2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)C2CCC3C2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Temperature: 60 °C
Yield: 44.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 1e (100 mg, 0.515 mmol), 1p (203 mg, 0.469 mmol), N,N-diisopropylethylamine (242 mg, 1.88 mmol) and anhydrous DMF (2 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 249 mg, 0.563 mmol) was added, and the reaction was heated at 60° C. for 16 h. After this time, the reaction was diluted with water (10 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (20 mL), and the solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was eluted with a gradient from 0% to 20% of methanol in ethyl acetate, and the fractions containing 1q were collected to afford, after concentrating under reduced pressure, a 44% yield (127 mg) of 1q as an off-white solid: mp 178-179° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.35 (s, 1H), 7.85 (d, 1H, J=8.0 Hz), 7.77 (d, 2H, J=8.5 Hz), 7.59 (s, 1H), 7.42 (s, 1H), 7.29-7.22 (m, 4H), 6.76 (s, 1H), 3.68 (td, 1H, J=11.5, 4.5 Hz), 3.62-3.60 (m, 2H), 3.58 (s, 3H), 3.47 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.91 (s, 3H), 2.64 (m, 1H), 2.39 (s, 3H), 2.13 (s, 3H), 1.98-1.90 (m, 3H), 1.67 (dt, 1H, J=9.0, 2.5 Hz), 1.10 (dd, 2H, J=12.5, 3.5 Hz); MS (ESI+) m/z 609.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A stirring solution of methyl 2-(4-tert-butylbenzoylamino)benzoate (10.4 g, 33.4 mmol) and THF (200 mL) was treated with 1 M aqueous lithium hydroxide (40 mL) and methanol (80 mL). After stirring over night at room temperature, the mixture was treated with 1 M aqueous HCl (40 mL) and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (400 mL) and brine (100 mL). The organic phase was separated, then dried with MgSO4, filtered and concentrated in vacuo to give 9.69 g (98%) of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1O)=[O:25]>CO.ClCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)=[O:25]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)c1sccc1O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sccc1OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 44 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-thiophene-2-carboxylic acid methyl ester (20 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 32 mg (44%) of the titled compound. ESI-MS m/z 432 (MH+), 430 (M−H−).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(O)=[O:40]>C(O)CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH2:36][OH:40])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCCCc1nc2cccc(C(=O)OCCO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of ethyl 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.72 g) in ethylene glycol (15 ml) was added, while stirring at room temperature, sodium hydride (60% oil, 0.25 g) and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ice-water (100 ml), which was made acidic with formic acid. Precipitates then formed were dissolved in ethyl acetate (100 ml) and the solution was washed with water, dried and concentrated to dryness to give a crystalline product. The crystals were recrystallized from acetone to afford colorless crystals (0.49 g, 66%), m.p. 145°-147° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)O1.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1)=[O:26]>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:30]2[CH:31]=[CH:32][C:27]([C:25]([OH:26])=[O:24])=[N:28][CH:29]=2)=[CH:16][N:17]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)nc2)cn1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.442 g, 2.0 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (0.518 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0 mL) and toluene (3.0 mL). The resulting mixture was heated at 120° C. for 3 h. The organic solvents were removed under reduced pressure. The residue was diluted with water, and adjusted with 1N HCl to pH=4. The precipitates were collected by filtration, washed with water and EtOAc, and dried to give the desired product (0.25 g, 58%). LCMS: (M+H)=217.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:37]2[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([N:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]4=[O:60])=[N:30][CH:31]=3)=[CH:40][N:39]=[CH:38]2)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(CO)ccc1C#N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of [2-(2-cyano-5-hydroxy-methylphenoxy)-ethyl]-carbamic acid tert-butyl ester from step 3 (248 mg, 0.85 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (450 mg, 0.85 mmol) in CH2Cl2 (4.5 ml) was added DIEA (325 μl, 1.87 mmol) followed immediately by the addition of Tf2O (215 μl, 1.27 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (4.5 ml) and heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography with 0 to 4% MeOH(NH4OH5%) in CH2Cl2 to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]#[N:18].[C:19](Cl)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CCOC(C)=O.[Zn]>[C:19]([C:14]1[NH:13][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[C:16]([C:17]#[N:18])[CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)c(-c2cc(C(F)(F)F)ccc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a mixture of 2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (450 mg, 1.66 mmol) in toluene (3 mL) was added acetyl chloride (0.176 mL, 2.49 mmol) at room temperature, under nitrogen, and zinc (217 mg, 3.32 mmol). The mixture was allowed to stir for 3 h at 80° C. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (0 to 10% EtOAc/hexane) to afford the title compound (386 mg, 74%).
Reaction SMILES: [Li+].[Br-].Br[C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:22])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:9][N:10]2[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1.[Br-].[CH2:24]([Zn+])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1C(=O)CCC1.C1COCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH2:24]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:22])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:9][N:10]2[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CC(=O)N1CC(C)(c2ccccn2)c2ccc(Br)cc21
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC(C)(c2ccccn2)c2ccc(Cc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a degassed solution of LiBr (165 mg, 1.9 mmol) and (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (8 mg, 0.012 mmol) in NMP (3 mL) under N2 were added a solution of 1-(6-bromo-3-methyl-3-pyridin-2-yl-2,3-dihydro-indol-1-yl)-ethanone (400 mg, 1.2 mmol) in THF (3 mL) and benzylzinc bromide (0.5 M in THF, 3.8 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 h and then partitioned between brine and EtOAc. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. Chromatography (50% EtOAc in Petrol) gave the title compound (350 mg) as a colourless gum. MS: [M+H]+=343.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[C:18](=O)[CH2:19]Br>>[F:14][C:15]1[CH:16]=[C:17]([C:18]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:19]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)c(F)c3)cs2)c1
Yield: 70 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3,4-difluorophenacyl bromide to obtain-methyl 3-[4-(3,4-difluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 70%. Colorless prisms. Melting point: 147 to 148° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl.CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:20](=[O:21])[CH2:19][Cl:18]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-proline methyl ester.HCl (8.04 g, 43 mmol) in CH2Cl2 (86.0 ml) at 0° C. was added NEt3 (12.0 mL, 86 mmol), followed by chloroacetyl chloride (1.1 equiv, 3.72 g, 47 mmol) dropwise via syringe. The reaction mixture was allowed to warm to room temperature with stirring. After 16 h, the mixture was diluted with sat. aqueous NaHCO3 and the organic layer was removed. The aqueous portion was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford N-chloroacetyl-L-proline methyl ester as a light brown oil (7.85 g, 38 mmol). A portion of the resulting oil (5.25 g, 26 mmol) was dissolved in butanone (51 mL) at RT and NaN3 (3.67 g, 51 mmol) was added in one portion. The reaction vessel was fitted with a reflux condenser and the heterogenous mixture was heated at 80° C. for 20 h. The resulting mixture was cooled to room temperature, filtered and concentrated in vacuo to afford N-azidoacetyl-L-proline methyl ester as a light red oil (5.37 g, 25 mmol). A portion of the oil (1.97 g, 9 mmol) was dissolved in anhydrous PhMe (38 mL) and PPh3 (2.55 g, 10 mmol) was added in one portion. After gas evolution steadied, the reaction mixture was heated at 90° C. for 20 h. The reaction mixture was concentrated in vacuo and triturated with a 1:1 mixture of Et2O/hexanes in order to remove the desired diketopiperazine product from the bulk of phosphine oxide byproduct. The trituration solution was concentrated and the resulting residue was purified by flash column chromatography on silica gel (elution: 1% MeOH to 10% MeOH in 1:1 EtOAc/PhMe+1% NEt3). The resulting diketopiperazine lactim ether product, (S)-1-methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-4(3H)-one (13), (1.43 g, 8 mmol, 80% yield, 3 steps) was obtained as a light yellow oil: TLC (60% EtOAc in hexane), Rf: 0.20 (CAM); [α]D25=+102 (c 2.07, CH2Cl2); IR (film): 2951, 2984, 2889, 2360, 2107, 1685, 1457, 1322, 1263, 1022, 751, 673, 625, 573 cm−1; 1H NMR (400 MHz, CDCl3) 4.21 (dd, J=9.5 Hz, 1.6 Hz, 1H), 4.11 (d, J=4.9 Hz, 1H) 4.03 (m, 1H), 3.68 (s, 3H), 3.65 (m, 1H) 3.47 (m, 1H), 2.25 (m, 1H), 2.03 (m, 1H), 1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.8, 56.5, 53.3, 52.3, 44.2, 29.3, 22.2; Exact mass calcd for C8H12N2O2 [M+Na+], 191.0791. Found 191.0790.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][O:24][CH3:25])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39][CH3:40])=[O:38])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COCC1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)OC)c3)nc3scnc23)c1
Yield: 59.5 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.53 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (153 mg, 0.58 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (112 mg, 1.06 mmol) in 5 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give methyl 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (150 mg, 59%) as a yellow sold. 1H NMR (300 MHz, CDCl3): δ 9.13 (s, 1H), 8.82 (s, 1H), 8.68 (d, 1H, J=7.8 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.06 (s, 1H), 7.54 (t, 1H, J=7.8 Hz), 7.35 (s, 1H), 7.28 (t, 1H, J=7.2 Hz), 7.16 (d, 1H, J=7.8 Hz), 6.49 (d, 1H, J=7.5 Hz), 3.96 (brs, 4H), 3.57-3.50 (brs, 2H), 3.32 (s, 3H), 3.25-3.19 (m, 2H), 2.11-2.02 (m, 5H). LC-MS: 476 [M+H]+, tR=1.93 min. HPLC: 98.15% at 214 nm, 97.85% at 254 nm, tR=5.24 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.30 (1H, br), 11.21 (1H, br), 10.20 (1H, br), 8.52 (1H, d, J=4.2 Hz), 8.26 (1H, br s), 7.75 (1H, t, J=7.6 Hz), 7.36-7.24 (5H, m), 7.15 (2H, t, J=8.9 Hz), 4.62 (2H, br m), 4.04 (2H, s); ES+ MS: 405 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][O:7][CH3:8])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25](I)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:1][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([NH:6][O:7][CH3:8])=[O:5])[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Reactant: CONC(=O)c1ccc(F)cc1N
Product: CONC(=O)c1ccc(F)cc1Nc1cc(Nc2cn(C)nc2C)ncc1C(F)(F)F
Yield: 39.3 %

Procedure:
2-amino-4-fluoro-N-methoxybenzamide (90 mg, 0.49 mmol) and N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (110 mg, 0.29 mmol) were reacted according to the procedure of example 14.01. After chromatography, the solvent was evaporated to dryness, the residue triturated in tBuOMe and the resulting precipitate was collected by filtration and dried to a constant weight to afford the title compound (50 mg, 39.6%) as a white solid. NMR Spectrum: (DMSO-d6) 2.08 (s, 3H), 3.70 (s, 3H), 3.71 (s, 3H), 6.71 (bs, 1H), 6.93 (ddd, 1H), 7.36 (dd, 1H), 7.66 (dd, 1H), 7.87 (s, 1H), 8.24 (1, 1H), 8.52 (s, 1H), 9.99 (bs, 1H), 11.95 (s, 1H); Mass spectrum: MH+ 439
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH3:33])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(C)C2=O)cc1

Procedure:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione (Example 100) is reated with sodium hydride in DMF, followed by methyl iodide to give the title compound as colorless crystals, mp 113-11 5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cc2c(nn1)CCCCCC2
Solvent: O
Product: NNc1cc2c(nn1)CCCCCC2

Procedure:
11.7 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 60 cc of hydrazine hydrate are reacted in accordance with the process described in Example 1. The orange-coloured solution is completely concentrated, and the remaining crystalline crude title compound is washed with water. M.P. 145°-148° (decomp., from absolute ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][N:22]=1.[CH2:32](I)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].CC(C)([O-])C.[K+]>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][N:22]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CCCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-{2-[(3-Chloro-5-methoxycarbonylpyridin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (5.14 g) was obtained using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5 g) synthesized in Example 7 and 2,3-dichloro-5-(methoxycarbonyl)pyridine (3.41 g) as starting materials and by an operation similar to that of Example 265-1. The obtained compound (5.14 g) and heptyl iodide (1.86 mL) were dissolved in N,N-dimethylformamide (40 mL), potassium tert-butoxide (1.34 g) was added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=9:1) to give the title compound (2.59 g) as a yellow oil.