Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH3:10].C[O-].[Na+]>>[C:3]([CH:2]([CH2:9][CH3:10])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CCBr
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: CCC(C(C)=O)C(=O)OC
Yield: 56.8 %

Procedure:
465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under nitrogen to 720 g of 30% sodium methylate solution. The reaction mixture was subsequently boiled at reflux. After distilling off the methanol the residue was poured onto ice-water, the mixture was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation there were obtained 328 g of methyl 2-acetylbutyrate, b.p. 77°-79°/15 Torr.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]([OH:25])=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[N:18]1([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (5.00 g, 14.8 mmol) in methylene chloride (59 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (7.77 mL, 44.5 mmol) and tert-butyl 2-bromoacetate (4.34 g, 22.2 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, and the organic layer was extracted with methylene chloride. The resulting organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (S)-1-((9H-fluoren-9-yl)methyl) 2-(2-(tert-butoxy)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (Fmoc-Pro-HOGly-OtBu) (Compound SP631) (6.40 g, 14.2 mmol, 96%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.[CH3:14][N:15]([CH3:25])[C:16]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]([N:15]([CH3:25])[CH3:14])=[O:17])[CH:19]=2)[N:8]=1
Reactant: CN(C)C(=O)c1cccc(O)c1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1

Procedure:
In a similar manner, 2-methylthio-5-nitro-4,6-dichloropyrimidine was treated with 3-(dimethylaminocarbonyl)phenol in the presence of cesium carbonate to afford 2-methylthio-5-nitro-4-chloro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (M).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27]C)[CH:23]=3)[CH2:18]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>Cl>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[CH2:18]2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)CCC(CN1CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Product: Oc1ccc2c(c1)CCC(CN1CCN(Cc3ccccc3)CC1)C2
Yield: 127.4 %

Procedure:
2-(4-Benzylpiperazin-1-yl)methyl-6-methoxytetralin dihydrochloride (0.849 g) was added to conc. hydrochloric acid (20 ml) and the reaction mixture was heated under reflux for 6 hr and cooled. The resulting precipitate was collected and washed with ethanol, methanol, and diethyl ether to obtain the titled compound (0.523 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([F:13])([F:12])[F:11])=[C:4]([O:9][C:10]([F:11])([F:13])[F:12])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc(Br)ccc1SC(F)(F)F
Temperature: 23 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a stirred solution of 4-bromo-2-trifluoromethoxybenzenethiol (1.76 g, 6.44 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 283 mg, 7.08 mmol) in small portions and the reaction mixture was slowly warmed to 23° C. over 30 minutes. The reaction vessel was evacuated and flushed with trifluoromethyl iodide gas and finally a balloon of trifluoromethyl iodide gas was attached and continued the reaction at 23° C. till the gas is consumed. The reaction mixture was heated to 80° C. with stirring for 2 h, cooled to room temperature and stirred overnight. The reaction mixture was poured into 1.0 N HCl (100 mL) and extracted with ethyl ether. The combined organic layer was washed with brine (80 mL), dried MgSO4 and concentrated in vacuo to get the crude product. This was purified by silica gel column chromatography using pentane as a eluent to afford 4-bromo-2-trifluoromethoxy-1-trifluoromethylthiobenzene (1.12 g, 51%).
Reaction SMILES: C1(O[C:8](=[O:49])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:60]2[CH2:59][CH2:58][N:57]([CH:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH2:62][CH2:61]2)=[O:49])[CH:24]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 1-(1-methylpiperidin-4-yl)piperazine (73.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (56.4 mg, 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:24][CH:25]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Yield: 30.4 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.103 g, 0.68 mmol) to afford the title compound (0.042 g, 56%) as an off-white solid. MW=406.79. 1H NMR (DMSO-d6, 500 MHz) δ 10.24 (s, 1H), 8.33-8.25 (m, 2H), 7.74-7.58 (m, 4H), 7.33 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 6.88 (s, 1H), 3.39 (s, 2H), 2.70 (s, 1H); APCI MS m/z 407 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester (54.5 mg, 0.226 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150.6 mg, 0.452 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.23 mL, 0.23 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+].
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(Br)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=351.2/353.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-bromo-2-methyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([O:17][C:18]([N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].N1(C#N)CCCCC1>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:25][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: N#CN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1

Procedure:
4-Chlorophenylacetonitrile was reacted with three equivalents of sodium hydride and one equivalent of N-tert-butyloxycarbonyl-bis-(2-chloroethyl)amine in DMF, initially at room temperature and then at 60° C. to give, after work up, the N-protected piperidine nitrile title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=O>>[N:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][N:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: Nc1n[nH]cc1C(=O)c1nccs1
Reactant: CN(C)C=CC(=O)c1ccncc1
Product: O=C(c1nccs1)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
As described for Example 1, (3-amino-1H-pyrazol-4-yl)-2-thiazolyl-methanone was reacted with 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one to give the product as crystals, mp 323°-325° C.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)([CH3:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO.O1CCCC1>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)([CH3:16])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(Nc2ccccc2[N+](=O)[O-])CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(Nc2ccccc2N)CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
168 mg ferrum was added to 160 mL ammonium chloride in 5 mL water. A solution of 244 mg (1-benzyl-4-methyl-piperidin-4-yl)-(2-nitro-phenyl)-amine in 5 mL methanol and 5 mL tetrahydrofuran were added and the mixture was stirred at 70° C. under nitrogen. The mixture was filtered over Celite and water was added to the filtrate. The solution was extracted with ethylacetate. The organic layer was evaporated to yield 121 mg of the desired product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[I:34])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:41]([N:22]1[C:23](=[O:24])[C:18]2[C:17]([I:34])=[C:16]([C:8]3[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:14])[F:15])=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:7]=3)[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=2[CH:20]=[N:21]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(I)c2c(=O)[nH]ncc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(I)c2c(=O)n(Cc3ccccc3)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To 452 mg (0.749 mmol) of 2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 38-(b) and 126 mg of potassium carbonate was added 4 ml of dehydrated N,N-dimethylformamide, then 0.1 ml of benzyl bromide was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. Moreover, 36 mg of sodium hydride (55% dispersed material in mineral oil) and 0.1 ml of benzyl bromide were further added to the mixture, and the resulting mixture was stirred for 2 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=19:1→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 389 mg of the title compound as a pale yellowish foam. (Yield: 75%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccc1Cl)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccnc1N1CC2CCC(C1)N2
Temperature: 25 °C

Procedure:
tert-Butyl 3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (419 mg, 1.29 mmol) in dry dichloromethane (5 mL) was treated with trifluoroacetic acid and stirred at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was treated with 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure to provide the title compound. MS (ESI) m/z: 224 (M+H)+; 1H NMR (CDCl3) δ 1.86 (m, 2H), 2.09 (m, 2H), 3.09 (d, 2H), 3,63 (m, 4H), 6.81 (dd, 1H), 7.56 (dd, 1H), 8.16 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)[CH2:4][CH2:3]1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].[Cl-].[NH4+].N>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:21]3[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3=[O:20])[N:12]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CN1CCN(c2nc(C=O)cs2)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN(c2nc(C=C3SC(=S)N(CC(=O)O)C3=O)cs2)CC1

Procedure:
The reaction described in Example 1 was repeated, but using 1.8 g of 2-(4-methyl-1-piperazinyl)thiazole-4-carbaldehyde, 1.2 g of rhodanine-3-acetic acid, 0.9 g of ammonium chloride, 0.9 ml of 28% v/v aqueous ammonia, and 40 ml of ethanol, giving the title compound as dark yellow needles.
Reaction SMILES: [NH3:1].[Si:2]([O:9][CH:10]([CH:23]=[CH2:24])[CH2:11][N:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20](Cl)[C:15]=2[C:14]([I:22])=[CH:13]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C1COCC1.O>[Si:2]([O:9][CH:10]([CH:23]=[CH2:24])[CH2:11][N:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([NH2:1])[C:15]=2[C:14]([I:22])=[CH:13]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C=CC(Cn1cc(I)c2c(Cl)ncnc21)O[Si](C)(C)C(C)(C)C
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: C=CC(Cn1cc(I)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Reaction time: 5 h

Procedure:
25% aqueous ammonia (9 ml) was added to a solution of 7-(2-(tert-butyldimethylsilyloxy)-3-butenyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.12 g) obtained in Step 3 in THF (7 ml). The mixture was stirred at 120° C. for 5 hours using a microwave reactor. The reaction mixture was cooled, and then diluted with water. The resulting precipitate was collected by filtration, washed with water, and then dried to obtain the title compound as a white solid (1.06 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35].C(=O)([O-])[O-].[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:34][C:30]1[C:29]([F:35])=[CH:28][CH:33]=[CH:32][C:31]=1[C:16]1[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Reactant: Fc1cccc(Br)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cccc(F)c2F)c1

Procedure:
Into a 5 mL microwave vial were charged with methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (250 mg, 0.71 mmol), 1-bromo-2,3-difluorobenzene (273 mg, 1.42 mmol), cesium carbonate (1.15 g, 3.54 mmol), tetra-n-butylammonium iodide (261 mg, 0.71 mmol), POPd (35 mg, 0.071 mmol), water (0.5 mL) and N,N-dimethylformamide (3 mL). The reaction mixture was subjected to microwave irradiation at 150° C. for 10 mins. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure to give the residue which was purified by silica gel column to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29](O)=[O:30])[NH:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:35][CH3:34])=[O:30])[NH:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4c[nH]c(C(=O)O)c4)c3)cc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylic acid (50 mg, 0.11 mmol), HATU (50 mg, 0.13 mmol), 2M methylamine/THF solution (0.1 ml, 0.2 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography with 3˜5% MeOH/CHCl3 to give 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-methyl-1H-pyrrole-2-carboxamide as white solid. Yield: 21 mg, 41%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:19][C:20]2[CH:41]=[CH:40][C:23]3[C:24]4[N:28]([CH2:29][CH2:30][O:31][C:22]=3[CH:21]=2)[CH:27]=[C:26]([C:32]2[N:33]([CH:37]([CH3:39])[CH3:38])[N:34]=[CH:35][N:36]=2)[N:25]=4)[CH3:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:37]([N:33]1[C:32]([C:26]2[N:25]=[C:24]3[N:28]([CH2:29][CH2:30][O:31][C:22]4[CH:21]=[C:20]([O:19][CH:17]([CH:14]5[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]5)[CH3:18])[CH:41]=[CH:40][C:23]=43)[CH:27]=2)=[N:36][CH:35]=[N:34]1)([CH3:38])[CH3:39]
Reactant: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A suspension of 4-{1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester (278 mg, 0.50 mmol) and 10% Pd/C (150 mg) in EtOAc (10 mL) was stirred under an atmosphere of H2 at RT for 1 h then heated at 50° C. for 3 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-piperidin-4-ylethoxy)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (211 mg, quantitative) as a colourless oil. LCMS: RT 2.26 min [M+H]+ 423.4