Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13]([S:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=1[CH:26]=O)[CH3:14].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Cu](Cl)Cl.C(OCC)(=O)C.CN(C)C(=O)C>[CH2:13]([S:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[C:17]=1[C:26]1[S:12][C:3]2[C:2]([N:1]=1)=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=2)[CH3:14]
Reactant: CCSc1c(C=O)c(C(F)(F)F)nn1C
Reactant: Nc1cc(C(F)(F)F)cnc1S
Agent: Cl[Cu]Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCSc1c(-c2nc3cc(C(F)(F)F)cnc3s2)c(C(F)(F)F)nn1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 0.24 g of 3-amino-5-(trifluoromethyl)pyridine-2-thiol, 0.27 g of 5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde, 0.19 g of sodium sulfite, 0.33 g of copper(II) chloride (anhydrous) and 2 ml of N,N-dimethylacetamide was stirred at 150° C. for 8 hours. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were poured into the cooled reaction mixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate and then combined with the organic layer of the filtrate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, then the resulting residue was applied to a silica gel column chromatography to obtain 0.21 g of 2-(5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-6-trifluoromethylthiazolo[5,4-b]pyridine (Compound of Present Invention (27)).
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:28]=[C:29]([CH2:31][N:32]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH3:33])[CH:30]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][N:19]=1)=[O:16])([CH3:10])[CH3:9]>>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:28]=[C:29]([CH2:31][N:32]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH3:33])[CH:30]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)=[O:16])([CH3:10])[CH3:9]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(CN(C)S(=O)(=O)c3ccc(C)cc3)cc(OC(C)C)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)Cc2cc(OC(C)C)cc(C(=O)Nc3ccc(C(=O)O)cn3)c2)cc1

Procedure:
Standard ester hydrolysis (2M NaOH/THF), as described in Example A, of methyl 2-{3-isopropyloxy-5-[(N-methyl) 4-toluenesulfonylaminomethyl]benzoyl}amino-5-pyridine carboxylate gave the title compound as a pale yellow solid, 1H NMR δ (d6-DMSO): 1.23 (d, 6H), 2.40 (s, 3H), 2.58 (s, 3H), 4.13 (s, 2H), 4.62–4.72 (m, 1H), 7.70 (s, 1H), 7.41–7.52 (m, 4H), 7.73 (d, 2H), 8.31 (s, 2H), 8.84 (s, 1H), 11.16 (s, 1H) m/z 498 (MH)+, 496 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=O.[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([CH2:22][C:23](O)=[O:24])(=[O:21])=[O:20])=[CH:16][C:15]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([C:22]2[C:23](=[O:24])[O:11][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:20])=[O:21])=[CH:16][C:15]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CC(=O)O
Product: COc1ccc2cc(S(=O)(=O)Cc3ccc(OC)c([N+](=O)[O-])c3)c(=O)oc2c1
Yield: 75 %

Procedure:
A solution of 4-methoxysalicylaldehyde (1 mmol) and 2-(4-methoxy-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 75% yield of the title compound; m.p. 250-252° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(F)ccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1,4-difluorobenzene and isolated as white solid (7.0 mg, 38%). MS (m/e): 443.4 (MH+).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(=O)C>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccccc2)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
The suspension of 3-phenylglutaric acid (16.39 g) in acetyl chloride (28.6 ml) was heated to reflux with stirring for 2 h. Then precipitation of the product is completed by addition of petrol ether (70 ml) and cooling to rt. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-phenylglutaric anhydride (13.24 g) as colourless crystals.
Reaction SMILES: [CH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)=O.C1C2(CCN(C(OC(C)(C)C)=O)CC2)[CH2:17][CH:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:15]1>>[CH2:6]1[C:3]2([CH2:17][CH:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:15][CH2:1]2)[CH2:4][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Product: CCOC(=O)C1CC2(CN1)CN(C(=O)OC(C)(C)C)C2
Yield: 93 %

Procedure:
This compound was prepared from 1,1-dimethylethyl 3-formyl-1-azetidinecarboxylate (650 mg, 3.5 mmol) in 93% yield in an analogous fashion to Intermediate 131 in Example 19.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(N)cc(Cl)c1N
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCOCC2)cc(Cl)c1N
Temperature: 180 °C
Yield: 91 %

Procedure:
2,5-Diamino-3-chloro-benzonitrile (387 mg), bis-(2-bromoethyl)ether (0.35 mL) and N,N-diisopropyl-ethylamine (1.25 mL) were mixed in N,N-dimethylformamide (4 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (20 mL) was added and the crude mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo to furnish 0.50 g (91%) of the title compound as a brown solid. LC-MS (m/z) 238 (MH+); tR=2.31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2.97 (m, 4H), 3.69 (m, 4H), 5.59 (s, 2H), 7.04 (d, 1H), 7.29 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3
Yield: 46.9 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (136 mg, 47%) was prepared via coupling of the appropriate tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (250 mg, 0.608 mmol) with 2,4-dichlorophenyl boronic acid (116 mg, 0.608 mmol) using the procedure described in Example 450 Step A.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)O1>>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2[C:7]3[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=3[C:5]3[C:4]4[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: Nc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1
Yield: 57 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in example 7 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine according to the procedure described in example 8 gave 4-(4-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (16) (I, Ar=4-aminophenyl) in a 57% yield; mp 256–258° C. 1H NMR δ [(CD3)2SO] 11.60 (s, 1H), 10.92 (s, 1H), 9.19 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 2H), 5.29 (br s, 2H). Found: C, 68.09; H, 4.34; N, 11.03. C20H13N3O3.1/2H2O requires C, 68.17; H, 4.00; N, 11.92.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([NH:13][CH2:14][C@@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:13]2[CH2:14][C@H:15]([C:16]([O:18][CH3:19])=[O:17])[O:20][C:21]2=[O:22])[CH:3]=1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A mixture of methyl (2R)-3-[(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 8, 0.84 g, 2.96 mmol) and 1,1′-carbonyldiimidazole (0.48 g, 2.96 mmol) in acetonitrile is stirred and heated at 60° C. overnight. The reaction is diluted with ethyl acetate, washed with 2N HCl and saline, and evaporated under reduced pressure. The resulting solid is triturated with methanol to give pure product as a white solid (0.88 g, 96%); MS for C13H11FN2O6 m/z 311 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([OH:17])[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([NH:31][C:32]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:24][C:25]=4[O:29][CH3:30])[O:13]2)=[CH:5][CH:4]=1.[CH:69]1[CH:74]=[CH:73][C:72]([CH2:75][O:76][C:77](Cl)=[O:78])=[CH:71][CH:70]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:77](=[O:78])([O:17][C@H:16]1[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([NH:31][C:32]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24][C:25]=3[O:29][CH3:30])[O:13][C@@H:12]1[CH2:11][O:10][C:9]([C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[O:76][CH2:75][C:72]1[CH:73]=[CH:74][CH:69]=[CH:70][CH:71]=1
Reactant: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](O)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](OC(=O)OCc5ccccc5)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of nucleoside 3 (2.52 g, 2.75 mmol) in anhydrous DCM (8 mL) was added DMAP (1.01 g, 8.2 mmol) and the solution was cooled at 0° C. in an ice-water bath. Cbz-Cl (0.77 g, 4.2 mmol) was added via a syringe to the mixture and resulted in a cloudy reaction mixture. The mixture was stirred at room temperature for 24 hours and sat. NaHCO3 (10 mL) was added. The mixture was partitioned in DCM and water. The organic layer was dried over Na2SO4 and concentrated to a white foam solid. The residue was purified via column chromatography (10˜60% EtOAc in hexanes) to afford 2.74 g product, 4, as a white foam solid (yield, 95%). 1H-NMR (CDCl3): δ 7.87 (s, 1H), 7.41-7.16 (m, 24H), 6.79-6.75 (m 8H), 6.28 (s, 1H), 5.65 (br, 1H), 5.15 (s, 2H), 4.28 (d, 1 H), 3.79-3.71 (m, 15H), 3.55-3.52 (m, 1H), 3.39-3.36 (m, 1H), 0.93 (br, 3H).
Reaction SMILES: C[Si]([Br:5])(C)C.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:5])=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: C[Si](C)(C)Br
Reactant: COCCCOc1cc(CO)ccc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyl bromide (97 ml) is added dropwise to a solution of 4-methoxy-3-(3-methoxypropoxy)-benzyl alcohol (111.1 g) in chloroform (1.31 liters), the reaction temperature being maintained at 10°-25° C. by cooling with ice. When the addition is complete, the mixture is stirred for a further 10 minutes at room temperature and concentrated under reduced pressure. The residue is purified by FC on silica gel (ethyl acetate/hexane 1:3) and after recrystallisation from hexane the title compound (144.5 g) is obtained in the form of a white crystalline solid: m.p. 50-51° C. Rf (ethyl acetate/hexane 1:2)=0.34.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:39](=[O:41])[CH3:40])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A stirred solution of 6-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (1.25 g, 99%) as a white solid.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:9][N:8]([CH:10]([C:17]([OH:19])=[O:18])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:20])C(=O)C2=CC=CC=C12.CN(C)CCCN.CO>O>[NH2:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]([OH:19])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:20]
Reactant: O=C(O)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CN(C)CCCN
Solvent: O
Solvent: CO
Product: NC1CN(C(C(=O)O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
3-Phthalimido-1-(α-carboxybenzyl)-2-azetidinone (350 mg.) and N,N-dimethyl-1,3-propanediamine (310 mg.) were added to methanol (6 ml.), and the mixture was stirred at ambient temperature for 18 hours. Water (6 ml.) was poured into the reaction mixture under ice-cooling and then the mixture was adjusted to pH 5.8 to 6.0 with cation-exchange resin IRC-50 (Trade Mark, maker: Rohm & Haas Co.,) (20 ml.). The resin was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. Acetonitrile was added to the residue (190 mg.) obtained and then the mixture was stirred under ice-cooling for 2.5 hours. The powder was collected by filtration to give 3-amino-1-(α-carboxybenzyl)-2-azetidinone (120 mg.).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)=[N:13][CH:14]=1>ClCCl>[Cl:8][C:9]1[C:10]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)c(Cl)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to tert-butyl 4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (12 mg, 0.027 mmol) in dichloromethane (1 mL) and the mixture was stirred at r.t. for 2 hr. Solvent was removed in vacuo and the residue was redissolved in MeOH and adsorbed onto Isolute SCX-II acidic resin (500 mg). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were evaporated to dryness to give 5-(5-chloro-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (2 mg, 22%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cn[nH]c3)c2n1C
Temperature: 140 °C
Yield: 19.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.065 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 80 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 428 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.23 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 13.10 (1H, s), 8.28 (1H, s), 8.04 (1H, s), 7.83 (1H, s), 7.66-7.64 (1H, m), 7.60 (1H, dd, J=8.74, 4.77 Hz), 7.31 (2H, s), 7.12-7.06 (1H, m), 5.66-5.61 (1H, m), 3.66 (3H, s), 1.57 (3H, d, J=6.73 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH3:21].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: COCCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g, 4.5 mmole), 1-bromo-2-methoxyethane (0.7 g, 5 mmole) and K2CO3 (1.3 g, 9 mmole) in DMF (10 mL) was heated at 85° C. for 20 hr, diluted by ethyl acetate, washed by water, dried over MgSO4, filtered, concentrated under vacuum, purified by ISCO (silica gel, elute: 10% ethyl acetate in hexane) to give liquid product (316 mg, 25% yield). MS (ESI) m/z: Calc. 278.2 (M+). Found: 279.3 (M++1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C[C@@H]1CN(c2ccccn2)CCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
The product of Example 26A (0.79 g, 4.43 mmol) and N,N-dimethylformamide (15 mL) at 0° C. was treated with a solution of the 2-chloromethyl-1H-benzimidazole (0.70 g, 4.21 mmol) in N,N-dimethylformamide (15 mL). After 10 minutes, the mixture was treated with cesium carbonate (1.37 mmol, 4.21 mmol) and the cooling bath was removed. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1–3% methanol/dichloromethane gradient) to afford 0.50 g (39% yield) of the title compound as a light yellow solid. mp 151–153° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5; C, 70.33; H, 6.89; N, 22.78. Found: C, 70.10; H, 7.03; N, 22.63.