Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:25]([O:28][C:29]([CH3:31])=[CH2:30])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C:29]1([CH3:31])[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])(=[O:27])[CH3:26]
Reactant: C=C(C)OC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Solvent: ClCCl
Product: CC(=O)OC1(C)CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Yield: 17 %

Procedure:
Two solutions of p-nitrobenzyl 2-azidocarbapen-2-em-3-carboxylate (52 mg and 24 mg, 231 micromol) and 2-acetoxy-1-propene (0.25 ml each) in dichloromethane were kept 2.5 days at ambient temperature. The mixtures were combined, filtered through florisil, and evaporated under vacuum. The residue was chromatographed on four 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.25 was eluted with ethyl acetate and the eluate evaporated under vacuum to provide 15.9 mg (17%) p-nitrobenzyl 2-(2-acetoxy-2-methylaziridin-1-yl)carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1, NMR (CDCl3): δ 1.69 s (3H), 2.11 s (3H), 2.16 d (J=7 Hz, 1H), 2.22 d (J=7Hz, 1H), 2.74 dd (J=8 Hz, J2 =17 Hz, 1H), 2.79 dd (J1 =3 Hz, J2 =16 Hz, 1H), 2.84 dd (J1 =5 Hz, J2 =17 Hz, 1H), 3.21 dd (J1 =6 Hz, J2 =16 Hz, 1H), 4.30 m (1H), 5.29 d (J=12 Hz, 1H), 5.35 d (J=12 Hz, 1H), 7.57 d (J=9 Hz, 2H), 8.29 d (J=9 Hz, 2H); MS (m/e): 402 (M+), 359, 342, 316, 300, 274, 258, 222.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[N:8]=2)[CH:2]=1.CC1C=CC(C(O)=O)=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.[CH3:46][C:47]1[N:48]=[CH:49][N:50]([C:52]2[CH:53]=[C:54]([C:59]([F:62])([F:61])[F:60])[CH:55]=[C:56]([NH2:58])[CH:57]=2)[CH:51]=1.C(N)C1OC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:58][C:56]3[CH:57]=[C:52]([N:50]4[CH:51]=[C:47]([CH3:46])[N:48]=[CH:49]4)[CH:53]=[C:54]([C:59]([F:62])([F:61])[F:60])[CH:55]=3)=[O:19])[N:8]=2)[CH:2]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: O=C(O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: NCc1ccco1
Product: Cc1cn(-c2cc(NC(=O)c3cccc(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
Utilising the procedure described in example 1, but employing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid and 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of furfurylamine, afforded the title compound as Pale-yellow crystalline solid, m.p. 264-266° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-(tert-butoxycarbonylamino)-2-naphthol, as described above in Step A, (43.2 g, 0.167 mol), tert-butyldimethylsilyl chloride (32.7 g, 0.217 mol), and imidazole (25.0 g, 0.367 mol) in dry, degassed DMF (400 mL) was stirred, under argon, at ambient temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between H2O (1 L) and Et2O (2 L). The aqueous layer was extracted further with Et2O (1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—50% CH2Cl2 to yield the desired product as a pale solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33]SC(C)C)[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:39][S:40]([O-:42])=O.[K+].C(OCC)(=O)C.[CH:50](O)([CH3:52])[CH3:51]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][S:40]([CH:50]([CH3:52])[CH3:51])(=[O:42])=[O:39])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)SCC1C(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC2CN(C(=O)OC(C)(C)C)CC21
Reactant: CC(C)O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)CC1C(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
A solution of 4-isopropylsulfanylmethyl-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester in isopropanol is treated with a solution of Oxone in water, and the mixture is stirred at room temperature until the reaction is complete. Water and ethyl acetate are added, and the organic layer is separated, dried over sodium sulfate and concentrated under vacuum providing the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:42])[CH2:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[O:40]=[C:39]1[CH2:38][CH2:37][C:36](=[O:42])[N:1]1[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(N2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 20 ml of dichloromethane with 0.21 ml (1.5 mmol) of triethylamine, and it is mixed at room temperature drop by drop with a solution of 93 mg (0.6 mmol) of succinic acid dichloride in 3 ml of methylene chloride. After stirring overnight at room temperature, it is diluted with methylene chloride and washed in succession with water, saturated sodium bicarbonate solution and saturated common salt solution. Then, the organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on Isolute (Separtis Company) with a gradient of methylene chloride:ethanol=100:0 to 95:5. 120 mg (51% of theory) of 2-{[2-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained. (MS: m/e 468)
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Br:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[Br-:22].[CH2:15]([N+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CSc2ccccn2)cc1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: [Br-]
Product: c1ccc(CSc2cccc[n+]2Cc2ccccc2)cc1
Reaction time: 96 h
Yield: 59.2 %

Procedure:
A mixture of 2-(benzylthio)pyridine (2.01 g) and benzyl bromide (1.71 g) was kept at ambient temperature for 4 days. Trituration at length with ether gave a solid which was removed by filtration and dried to give the title compound (2.2 g) mp 125°-7° C. (Found: C, 61.6; H, 5.2; N, 3.6%. C19H18BrNS requires C, 61.3; H, 4.9; N, 3.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C@H:17]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:34][CH:35]1[CH2:40][CH2:39][N:38]([C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C@H:17]([NH:16][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[CH3:13])=[O:15])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(C(=O)N[C@@H](CCCC(=O)O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@@H](CCCC(=O)N2CCC(C)CC2)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
A solution of (S)-5-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-5-(3-trifluoromethyl-phenyl)-pentanoic acid (60 mg, 0.13 mmol) and 4-methylpiperidine (40 mg, 0.40 mmol) in DMF (3 mL) is treated with O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU) (64 mg, 0.20 mmol). The reaction mixture is stirred at room temperature for 16 hours. The crude reaction mixture is purified directly by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-5-(4-methyl-piperidin-1-yl)-5-oxo-1-(3-trifluoromethyl-phenyl)-pentyl]-amide (21 mg, 30% over 2 steps).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[Cl:30][C:31]1[C:32]([C:44](O)=[O:45])=[N:33][CH:34]=[C:35]([O:37][CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])[CH:36]=1>>[Cl:30][C:31]1[C:32]([C:44]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:45])=[N:33][CH:34]=[C:35]([O:37][CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])[CH:36]=1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1Cl
Product: C[C@@H](COc1ncc(NC(=O)c2ncc(OC[C@H]3CC3(F)F)cc2Cl)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 3-chloro-5-(((1R)-2,2-difluorocyclopropyl)methoxy)pyridine-2-carboxylic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
Reaction SMILES: CC1NC(C)=CC=1C1C=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[N:8]=1.Cl.[NH2:34]O.[CH2:36](O)[CH3:37]>O>[CH2:25]([N:21]1[CH2:22][CH2:23][CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:9]3[N:8]=[C:37]([NH2:34])[CH:36]=[CH:11][CH:10]=3)=[CH:18][CH:17]=2)[CH2:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCO
Reactant: Cc1cc(-c2cccc(-c3ccc(C4=CCCN(Cc5ccccc5)C4)cc3)n2)c(C)[nH]1
Reactant: NO
Agent: Cl
Solvent: O
Product: Nc1cccc(-c2ccc(C3=CCCN(Cc4ccccc4)C3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 135 mg (0.322 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridine, 112 mg (1.61 mmol) hydroxylamine hydrochloride, 5 mL ethanol, and 1 mL water. The reaction was refluxed 40 hours cooled, and the resulting precipitate, 6-[4-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridin-2-ylamine dihydrochloride, filtered and dried, 22 mg (16.5%), mp 270-272° C. Additional material was recovered from the filtrate, 60 mg (55%) of the free base as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:38]4[CH2:39][CH2:40][CH:35]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:36][CH2:37]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 4-pyrrolidin-1-yl-piperidine gave the title compound as brown solid. MS: 549.3 (MH+, 1 Cl).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.ClCCl.N>Cl.CO>[NH:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:11]2[C:10]3[C:5]([O:4][CH2:3][C:2]([F:1])([F:29])[F:30])=[CH:6][CH:7]=[CH:8][C:9]=3[O:13][N:12]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC(F)(F)F)c23)CC1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)COc1cccc2onc(OCC3CCNCC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl 4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)-piperidine-1-carboxylate (3.0 g, 6.96 mmol, EXAMPLE 2, Step 1) in 10% hydrogen chloride in methanol (100 mL) was added hydrochloric acid (3.0 mL) at ambient temperature. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo to give a solid. The residual solid was dissolved with water and dichloromethane. Sat. aq. ammonia was added to the mixture and extracted with dichloromethane (100 mL×3). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give 2.31 g (quant.) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11]Cl.[OH-].[Na+]>C(#N)C>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: ClCc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: NCCNCc1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Ethylenediamine (30 g) was dissolved in acetonitrile (200 ml), and pyrazinylmethyl chloride (12.9 g) was added dropwise to this solution at 5° to 10° C. After addition, the mixture was stirred at room temperature for 1 hour. Then, a 50% aqueous solution of sodium hydroxide (8 g) was added, and thereafter, volatile materials were removed at a bath temperature of 60° C. under 5 mmHg. The inorganic salt was then removed by filtration. Thus, N-(pyrazinylmethyl)ethylenediamine (14.1 g) was obtained as a colorless oil. nD20 =1.5359.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C(N(CC)CC)C.CS([Cl:22])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:22]
Reactant: Cc1c(Cl)cccc1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(Cl)cccc1CCl
Reaction time: 3 h
Yield: 69 %

Procedure:
910 mg of 3-chloro-2-methylbenzylalcohol was dissolved in 10 mL of methylene chloride, 1.21 mL of triethylamine and 495 μL of methanesulfonyl chloride were added thereto at room temperature, followed by stirring for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 700 mg (yield 69%) of a title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:32]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:33]=1[S:42](C1C=CC=C(C(F)(F)F)C=1Cl)(=[O:44])=[O:43]>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:42]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:40])[F:41])[CH:32]=3)(=[O:44])=[O:43])[C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2c(C(=O)OC(C)(C)C)[nH]c3ccccc23)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1Cl)c1cccc(C(F)(F)F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)OC(C)(C)C)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirring solution of tert-butyl-3-(4-methoxyphenyl)indole-2-carboxylate (Example 105, 75 mg, 0.23 mmol) in tetrahydrofuran (0.4 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 0.4 mL) in one aliquot. After 10 minutes chloro[3-(trifluoromethyl)phenyl]sulfone (113 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (4 mL) and quenched with water (2 mL). The organic phase was extracted with ethyl acetate (3×4 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was filtered through a plug of silica gel (30% ethyl acetate/hexane) to provide tert-butyl 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}indole-2-carboxylate (45 mg, 37%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([Mg]Cl)[CH2:12][CH2:11][CH2:10]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cl[Mg]C1CCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Product: Clc1nccc(C2CCC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
2,4-Dichloropyrimidine (250 mg, 1.68 mmol) and ferric acetylacetonate (30 mg, 0.08 mmol) were taken up in tetrahydrofuran (3.4 mL) and the reaction was cooled to −78° C. Cyclobutylmagnesium chloride (0.5 M, 3.4 mL, 1.68 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-5% ethyl acetate in hexanes) to provide 121 mg (0.72 mmol, 43%) of 2-chloro-4-cyclobutylpyrimidine as a colorless oil. MS ESI: [M+H]+ m/z 169.1.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:37])=[N:4][CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-2-phenylacetamide (15 mg, 0.037 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 414.3 (M+H); UV 201.1, 265.8, 297.2, 358.5 nm; t 0.445 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([O:23][CH3:20])=[CH:13][CH:12]=3)[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)ncn2)cc1
Yield: 62 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.01 g of 4,6-dichloropyrimidine, 10.32 g of 4-methoxyphenylboronic acid, 7.22 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.58 g of 4-methoxyphenylboronic acid, 1.81 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that a pyrimidine derivative Hrnodppm, which was the objective substance, was obtained (white powder, yield of 62%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (k-1) of Step 1 is shown below.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:24]=[N:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([NH:21][C:29]([C:28]3[CH:27]=[C:26]([CH3:32])[N:25]=[N:24][C:23]=3[Cl:22])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)O)c(Cl)nn1
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(CN3CCC(C(=O)NC(C)(C)C)CC3)c2)c(Cl)nn1

Procedure:
A solution of 1-(3-amino-benzyl)-piperidine-4-carboxylic acid tert-butylamide BB-4 (400 mg, 1.4 mmol) in DCM (15 mL) is treated successively with 3-chloro-6-methyl-pyridazine-4-carboxylic acid (239 mg, 1.4 mmol), EDC (344 mg, 1.8 mmol) and DMAP (25.3 mg, 0.207 mmol) at RT overnight. The reaction mixture is washed twice with sat.aq. NaHCO3 (15 mL). The aqueous phase is extracted twice with DCM (2×10 mL). The combined organic layers are dried over MgSO4 and filtered. The solvent is evaporated under reduced pressure. The residue is purified by prep HPLC E delivering the title compound (53 mg, 36%) as a light brownish powder, LC-MS A: tR=0.60 min; [M+H]+=444.12.