Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][NH2:26])[CH:21]=[CH:22]2)=[N:17]1>>[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:21]=[CH:22]2)=[N:17]1
Reactant: Cn1cc2ccc(CN)cc2n1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cn(C)nc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (2-methyl-2H-indazol-6-yl)methanamine.
Reaction SMILES: C(OC1C=CC(C2C=CC(C([NH2:24])(C)C)=CC=2)=CC=1)C1C=CC=CC=1.[N:25]1([CH2:30][CH2:31][CH:32]=O)[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:30][CH2:31][CH2:32][NH2:24])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CC(C)(N)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=CCCn1ccnc1
Product: NCCCn1ccnc1

Procedure:
In a similar manner to Example 24, 1-(4′-benzyloxybiphenyl-4-yl)-1-methylethylamine (A15) (1.4 g) and 3-(imidazol-1-yl)propionaldehyde (0.72 g) were reacted to give N-1-(4′-benzyloxybiphenyl-4-yl)-1-methylethyl)-3-(imidazol-1-yl)propylamine, m.p. 93-95° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1.[C:24]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(=[O:26])[CH3:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:31][CH2:32][CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH2:29]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1
Reactant: O=C(O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.22 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid and 0.11 g of 3-acetamidopyrrolidine are added to 12 ml of pyridine, and added with 0.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20 ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction. (next reaction: Example 5)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][CH3:50])[CH2:41][CH2:40]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][N:49]([CH3:50])[C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:43][CH2:44]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNCCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)c1ccc(F)cc1
Reaction time: 16 h
Yield: 41.8 %

Procedure:
0.5 g of 4-fluorobenzoic acid (3.57 mmol) and 1.27 g of triethylamine (12.57 mmol) were dissolved in 40 ml of dimethylformamide. 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.3 g of {4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-methyl-amine hydrochloride (2.77 mmol), and 0.75 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.91 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The residue was re-dissolved in isopropanol, treated with 4 N hydrochloric acid in dioxan. The precipitate was collected by filtration and dried to yield 0.6 g of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]=[C:11]1[C:19]1[C:23]([NH:24][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][NH:21][N:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A mixture of benzoic acid (34 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (5 ml) was stirred at room temperature for 24 h. The solvent was removed in vacuo, the crude product purified by preparative LC/MS and following reduction of the product-containing fractions N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide was obtained as a brown solid (23 mg, 30%). (LC/MS: Rt 3.66, [M+H]+ 303.67).
Reaction SMILES: [Cl-].[CH3:2][C@H:3]1[CH2:5][C@@H:4]1[C@@H:6]([NH3+:8])[CH3:7].Cl[C:10]1[CH:15]=[C:14]([C:16]2[O:17][C:18]([C@@:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:20]=2)[CH:13]=[C:12]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:29][C@:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([C:18]1[O:17][C:16]([C:14]2[CH:13]=[C:12]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:11]=[C:10]([NH:8][C@H:6]([C@H:4]3[CH2:5][C@@H:3]3[CH3:2])[CH3:7])[CH:15]=2)=[N:20][CH:19]=1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(c1cc(-c2ncc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(Cl)n1)S(C)(=O)=O
Reactant: C[C@H]([NH3+])[C@H]1C[C@@H]1C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(-c2ncc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(N(C)S(C)(=O)=O)n1)[C@H]1C[C@@H]1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of (1S)-1-[(1S,2S)-2-methylcyclopropyl]ethanaminium chloride (intermediate P, 0.039 g, 0.29 mmol) and tert-butyl (1R)-1-(2-{2-chloro-6-[methyl(methylsulfonyl)amino]pyridin-4-yl}-1,3-oxazol-5-yl)-1-methyl-2-phenylethylcarbamate (intermediate k, 0.050 g, 0.10 mmol) in 1 mL DMF was added K3PO4 (0.122 g, 0.58 mmol) and Pd(PtBu3)2 (0.007 g, 0.01 mmol). After 16 h at ambient temperature, the sealed reaction was heated at 110° C. for 8.5 h and then filtered over a pad of celite. The celite was washed with EtOAc (60 mL). The filtrate was concentrated in vacuo and the resulting residue taken up in DMF and purified by reverse phase LC. The resulting material was diluted with EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (20 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 0.028 g (50%) of tert-butyl (1R)-1-methyl-1-(2-{2-({(1S)-1-[(1S,2S)-2-methylcyclopropyl]ethyl}amino)-6-[methyl(methylsulfonyl)amino]pyridin-4-yl}-1,3-oxazol-5-yl)-2-phenylethylcarbamate as a yellow residue. (CDCl3, 400 MHz) 7.28 (m 3H); 7.06 (d, J=0.91 Hz, 1H); 7.03 (m, 2H); 6.93 (s, 1H); 6.76 (s, 1H); 3.50 (m, 1H); 3.36 (m, 4H); 14 (m, 4H); 1.60 (s, 3H); 1.42 (s, 9H); LC/MS [M+H]+=584.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)CC(O)C.CO>[CH3:39][O:38][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:22]=1[NH:21][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:4][N:3]=1)[C:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:27]
Reactant: CN1C(=O)CCN(C2CCCC2=O)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1=O)CCC(=O)N2C
Temperature: 150 °C
Yield: 11.1 %

Procedure:
10-chloro-6-methyl-2-(2-oxocyclopentyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 261; 58 mg, 0.19 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 53 mg, 0.20 mmol) and p-toluene sulphonic acid monohydrate (80 mg, 0.42 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation at 150° C. for 30 minutes. After cooling, the reaction mixture was dissolved in methanol (5 mL) and water (5 mL) and poured directly onto an SCX-3 cartridge (5 g). The cartridge was washed with methanol (50 mL), before elution of products with 2M ammonia in methanol (50 mL). The ammoniacal fraction was evaporated and the residue was purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (11 mg, 7%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:16].[Li]C.[Li+].[Br-].[Li]C(CC)C.CN([CH:29]=[O:30])C>C1COCC1.C(Cl)Cl.O>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:29]=[O:30])=[C:3]([CH3:16])[CH:4]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1Br
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (592 mg) in THF (10 mL) at −78° C. was added MeLi/LiBr (1.5M in Et2O, 1.87 mL) slowly. After 5 min, sec-BuLi (1.4M. in cyclohexane, 2.0 mL) was added slowly to the solution at −78° C. After 5 min DMF (0.31 mL) was added to the solution drowise at −78° C. then the mixture was warmed to room temperature. After 30 min the reaction mixture was partioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried and filtered. Removal of the solvent under reduced pressure to gave a yellow solid which was purified by flash chromatography using hexanes/ethyl acetate (5:1) as eluent which gave 2,2,2-trifluoro-N-(4-formyl-3,5-dimethyl-phenyl)-acetamide as a light yellow solid. MS (ESI)m/z 246 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)=[N:8][CH:9]=1.[Cl:18][C:19]1[C:20]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[N:21][CH:22]=[CH:23][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:18][C:19]1[C:20]([C:25]([CH3:30])([CH3:29])[C:26]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][N:8]=3)[CH2:12][CH2:13]2)=[O:27])=[N:21][CH:22]=[CH:23][N:24]=1
Reactant: Cc1ccc(N[C@H]2CC[C@H](N)CC2)nc1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Temperature: 25 °C

Procedure:
To a round bottom flask was added trans-N1-(5-methylpyridin-2-yl)cyclohexane-1,4-diamine dihydrochloride (intermediate 31, 0.2108 g, 0.758 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (intermediate 29, 0.182 g, 0.909 mmol), HATU (0.375 g, 0.985 mmol), and triethylamine (0.422 ml, 3.03 mmol) in dichloromethane (1.515 ml) to stir at room temperature. After 4 hours the solvent was evaporated off. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 0% to 5% methanol in dichloromethane, to provide 2-(3-chloropyrazin-2-yl)-2-methyl-N-(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)propanamide (0.2148 g, 0.554 mmol, 73.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=O)[O:27]C1C=CC=CC=1.[CH2:35]([NH2:37])[CH3:36].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:25][C:26]([NH:37][CH2:35][CH3:36])=[O:27])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OC
Reactant: CCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1Cl
Yield: 93 %

Procedure:
Phenyl N-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate (1.92 g, 4.00 mmol) and 2 M ethylamine (tetrahydrofuran solution) (4 ml) were stirred in dimethylformamide (8 ml) at room temperature for 30 minutes. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the drying agent was filtered out and the filtrate distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (1.60 g, 3.72 mmol, 93%) as white crystals.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[NH:12][C:11]=1[Si](C)(C)C)(C)C>CC#N>[OH:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[NH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Solvent: CC#N
Product: CCOC(=O)c1ccc2[nH]cc(CCCO)c2c1
Yield: 2777.9 %

Procedure:
A solution of ethyl 3-[3-[(1,1-dimethylethyl)dimethylsilyloxy]prop-1-yl]-2-trimethylsilyl-1H-indole-5-carboxylate (5.0 g, 11.5 mmol), and aqueous 48% HF (1.9 g, 46.0 mmol) in 140 mL of MeCN was stirred at 23° C. for 3.5 h. The solution was quenched with 10% Na2CO3, and the organic material was extracted into ethyl acetate. The organic solution was dried (brine, MgSO4), filtered, and concentrated in vacuo. Silica gel chromatography (50-100% EtOAc-hexanes gradient) of the concentrate yielded the title compound (2 79 g, ) as a white crystalline solid: mp 111°-112° C. Anal. Calcd for C14H17N1O3 : C, 68.00; H, 6.93; N, 5.66. Found: C, 67.94; H, 6.78; N, 5.65.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([N:20]([CH3:33])[C:21]2[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=2[O:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:19])=[CH:16][C:15]=1[C:36]1[CH:37]=[N:38][C:39]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:41]=1[C:42]#[N:43].[C:48]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])(=[O:51])[NH:49][NH2:50].C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.ClCCl>[C:53]([O:52][C:48]([NH:49][NH:50][C:26](=[O:27])[CH2:25][CH2:24][O:23][C:22]1[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=1[N:20]([C:18](=[O:19])[C:17]1[CH:34]=[CH:35][C:14]([Cl:13])=[C:15]([C:36]2[CH:37]=[N:38][C:39]([C:44]([F:45])([F:47])[F:46])=[CH:40][C:41]=2[C:42]#[N:43])[CH:16]=1)[CH3:33])=[O:51])([CH3:56])([CH3:55])[CH3:54]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
EDCl (19.9 mg, 0.104 mmol) was added to a solution of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (36.3 mg, 0.069 mmol), t-butyl carbazate (13.7 mg, 0.104 mmol), HOBt (14.0 mg, 0.104 mmol) and Na2CO3 (8.7 mg, 0.104 mmol) in a mixture of DMF (1 mL) and dichloromethane (4 mL). The mixture was stirred at room temperature for approximately 16 hrs and was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and was dried over MgSO4. The organic filtrate was evaporated and purified by prep. TLC plate eluted with hexane and ethyl acetate (1/1) to yield N′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylic acid tert-butyl ester (40.1 mg, 94%). MS [M+H]+: 619.0; tR=2.40 min. (method 1)
Reaction SMILES: [Si]([O:8][C@H:9]([C:45]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:56])[NH:50]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:44])[C@H:22]1[C@H:26]2[CH2:27][CH2:28][C@@H:23]1[C@H:24]([O:29][C:30](=[O:43])[C:31]([OH:42])([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[CH2:25]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[OH:8][C@H:9]([C:45]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:56])[NH:50]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:44])[C@H:22]1[C@H:26]2[CH2:27][CH2:28][C@@H:23]1[C@H:24]([O:29][C:30](=[O:43])[C:31]([OH:42])([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[CH2:25]2
Reactant: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCCCCCCCNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Reaction time: 0.17 h

Procedure:
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-({9-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]-nonyl}methylamino)bicyclo[2.2.1]hept-2-yl ester (72 mg, 0.087 mmol) and triethylamine trihydrofluoride (60 μL, 0.37 mmol) was stirred in THF/DCM (1:1, 2 mL) at ambient temperature overnight. The reaction mixture was neutralised with satd NaHCO3 (aq) and extracted with DCM. The organic layer was concentrated to dryness to afford a green/brown oil, which was purified by preparative HPLC (system 1, 15% B+1% B/min for 20 min, then 6% B/min for 10 min). The fractions containing pure product were concentrated, neutralised with satd NaHCO3 (aq), and extracted with THF. After concentration in vacuo a light brown oil was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([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][C:10]1[CH:11]=[C:12]([C:2]2[CH:7]=[C:6]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[CH:15]=3)[N:5]=[CH:4][N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(-c2cc(-c3cccc(C)c3)ncn2)c1
Yield: 15 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 4.99 g of 4,6-dichloropyrimidine, 9.23 g of 3-methylphenylboronic acid, 7.18 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 2.31 g of 3-methylphenylboronic acid, 1.82 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 20:1, so that a pyrimidine derivative H5mdppm, which was the objective substance, was obtained (pale yellow powder, yield of 15%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (n-1) of Step 1 is shown below.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)=O.C([Sn](CCCC)(CCCC)[CH:28]=[CH:29][O:30]CC)CCC>>[CH2:29]([O:30][CH:2]=[CH:3][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)[CH3:28]
Reactant: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Product: CCOC=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1

Procedure:
This product is obtained under conditions similar to those described in the first step of preparation of Intermediate 9, replacing the tributyl(1-ethoxyvinyl)tin with tributyl(2-ethoxyvinyl)tin.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH2:4]Cl.C[O:15]CCO>O.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH2:4][OH:15]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc(Cl)c(CCl)c(Cl)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(CO)c(Cl)c1

Procedure:
A suspension of silver carbonate (560 mg), 2,6-dichloro-4-nitrobenzylchloride (440 mg) in 2-methoxyethanol (9 cm3) and water (9 cm3) were heated at reflux for 18 h. After this time the hot reaction mixture was filtered and the filtrate diluted with dichloromethane (30 cm3) and water (20 cm3). The heterogeneous mixture was shaken, separated and the aqueous phase extracted with dichloromethane (30 cm3). Combined organic extracts were washed with saturated brine, dried and evaporated to leave an orange oil which was purified by chromatography over silica gel with an ethyl acetate--petroleum ether gradient. The title compound was obtained as a cream solid, m.p. 111°-114° C.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2C)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (220 mg), 2,4-difluoro-3-methylbenzonitrile (290 mg) and lithium carbonate (210 mg), the title compound was obtained as pale-yellow oil (yield: 97.3 mg, yield: 29%).