Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:20])[C:5]=2[NH:4][N:3]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].ClC[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=3)[C:6](=[O:20])[C:5]=2[N:4]([C:21](=[O:24])[CH2:29][CH2:30][N:32]2[CH2:33][CH2:34][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:36][CH2:37]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Reactant: CN(C)c1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Agent: [K+]
Product: COc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(c3ccc(N(C)C)cc3)CC4)CC2)cc1

Procedure:
A target compound (22.2 mg, 0.043 mmol, 11.1%) was yielded in the same manner as Example 1 by reacting 3-amino-6-N-(4-(dimethylamino)phenyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (105 mg, 0.387 mmol) with potassium carbonate (80.1 mg, 0.580 mmol) and 3-chloro-1-{4-(4-methoxyphenyl)piperazin-1-yl}propan-1-one (120.1 mg, 0.425 mmol).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C[C:53]1[CH:60]=[C:59]([CH2:61]Br)[CH:58]=[CH:57][C:54]=1[C:55]#[N:56].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[C:55]([C:54]1[CH:57]=[CH:58][C:59]([CH2:61][O:51][C:42]2[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=2)[CH2:39][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])=[CH:60][CH:53]=1)#[N:56]
Reactant: Cc1cc(CBr)ccc1C#N
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C#N)cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3R,4 S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzonitrile (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 16 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOQc in Hex→100% EtOAc) to afford the title compound as a oil
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=1)#[N:34]>>[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[C:5]([F:32])=[CH:4][N:3]=2)=[C:37]([O:44][CH3:45])[CH:36]=1)#[N:34]
Reactant: COc1cc(C#N)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Product: COc1cc(C#N)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (4-cyano-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 1-(4-cyano-2-methoxyphenyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.76 (d, J=1.4 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.48 (s, 1H), 8.00 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.76 (s, 1H), 7.62 (dd, J=1.1, 7.7 Hz, 1H), 7.57-7.52 (m, 1H), 3.72 (s, 3H). m/z (ESI) 442.2 (M+H)+.
Reaction SMILES: F[C:2]1(OC#CC)[CH:7]=C(F)C=C[CH2:3]1.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:7][C:2]#[CH:3]
Reactant: CC#COC1(F)C=C(F)C=CC1
Reactant: Oc1ccc(F)cc1Br
Product: C#CCOc1ccc(F)cc1Br

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-4-fluoro-phenol (15 g, 78 mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15. g (84%). 29g) 1,3-difluoro-5-prop-2-ynyloxy-benzene
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N+:22]([O-:24])=[O:23])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CCOCC>[C:32]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=[C:11]1[N+:22]([O-:24])=[O:23])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2nc([N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc([N+](=O)[O-])n(C(=O)c3ccccc3)c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3 g, 9.2 mmole) and triethylamine (3.9 ml., 27.6 mmole) in 30 ml. THF at 0° C. under N2 was dropwise added a solution of benzoyl chloride (1.2 ml., 10.1 mmole) in 5 ml THF. The reaction mixture was stirred for 8 hours at 0° C. and then left in the refrigerator overnight. The reaction was then diluted with 30 ml ether and filtered. The filtrate was concentrated on a rotary evaporator and chromatographed on Florisil. Recrystallization from methylcyclohexane gave 1.89 g of 1-benzoyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 161°-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CO)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-methoxy benzoic acid (1 eq) was dissolved in anhydrous THF (0.55M solution) and BH3SMe2 complex (2M in THF, 1 eq) was added dropwise to the solution. The mixture was stirred overnight, then HCl in MeOH was added and the mixture was warmed to 60° C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with 1N HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colourless oil was obtained (94%), which was used without further characterization in the next reaction.
Reaction SMILES: C1(N2CCN(C3N=C(N)C=CN=3)CC2)CCCC1.ClC(OC1C=CC=CC=1)=O.N1C=CC=CC=1.C1([O:41][C:42](=O)[NH:43][C:44]2[CH:49]=[CH:48][N:47]=[C:46]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH2:52][CH2:51]3)[N:45]=2)C=CC=CC=1.Cl.[F:63][C:64]1([F:70])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(Cl)Cl.CCN(CC)CC>[CH:56]1([N:53]2[CH2:52][CH2:51][N:50]([C:46]3[N:45]=[C:44]([NH:43][C:42]([N:67]4[CH2:68][CH2:69][C:64]([F:70])([F:63])[CH2:65][CH2:66]4)=[O:41])[CH:49]=[CH:48][N:47]=3)[CH2:55][CH2:54]2)[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(Nc1ccnc(N2CCN(C3CCCC3)CC2)n1)Oc1ccccc1
Agent: Cl
Agent: Nc1ccnc(N2CCN(C3CCCC3)CC2)n1
Agent: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Nc1ccnc(N2CCN(C3CCCC3)CC2)n1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A mixture of 103 mg (0.42 mmol) 2-(4-cyclopentyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 1), 67 mg (0.428 mmol) phenyl chloroformate (commercially available) and 0.1 g (0.12 mmol) pyridine in 4 mL DCM was shaken for 30 min at room temperature. A fraction of this mixture containing 0.07 mmol of the intermediately built [2-(4-cyclopentyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid phenyl ester was treated with 64.8 mg (0.41 mmol) 4,4-difluoro-piperidine, hydrochloride and 0.05 mL NEt3. The mixture was shaken at room temperature and concentrated. Methanol, DMF and water were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 1.1 mg (5%) of the title compound. MS (m/e): 395.3 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([CH3:40])[CH:33]=2)[C:17]2[S:18][C:19]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.NCCC1C=CC(C#N)=C(C)C=1.CC(OC(N1CCC(CC=O)CC1)=O)(C)C.ClC1SC2C=C(C(F)(F)F)C=CC=2N=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:40][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][N:16]([CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:17]2[S:18][C:19]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:37]=[CH:36][C:35]=1[C:38]#[N:39]
Reactant: Cc1cc(CCN(CCC2CCN(C(=O)OC(C)(C)C)CC2)c2nc3ccc(C(F)(F)F)cc3s2)ccc1C#N
Agent: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: Cc1cc(CCN)ccc1C#N
Agent: FC(F)(F)c1ccc2nc(Cl)sc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCN(CCC2CCNCC2)c2nc3ccc(C(F)(F)F)cc3s2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
1.1 g 4-{2-[[2-(4-Cyano-3-methyl-phenyl)-ethyl]-(6-trifluoromethyl-benzothiazol-2-yl)-amino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester [prepared according to the method described in Example 1 and 5 from 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate, N-boc-piperidinyl-4-acetaldehyde and 2-Chloro-6-trifluoromethyl-benzothiazole] were dissolved in 50 ml dichloromethane. 5 ml trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for one hour. 150 ml ethyl acetate were added and the mixture was washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 325 mg 2-Methyl-4-{2-[(2-piperidin-4-yl-ethyl)-(6-trifluoromethyl-benzothiazol-2-yl)-amino]-ethyl}-benzonitrile.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[CH:22]1([CH:20]([O:21][CH3:30])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclohexyl)-methanol (1.25 g, 3.11 mmol) in THF (5 mL) at 0° C. was added sodium hydride (385 mg, 9.6 mmol). The mixture was stirred at room temperature for 1 hour, cooled to 0° C. and methyl iodide (1.0 mL, 16 mmol) was added. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-5% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.14 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6H) 0.94-0.96 (m, 9H) 0.98-1.29 (m, 6H) 1.54-1.59 (m, 1H) 1.61-1.67 (m, 2H) 1.71-1.79 (m, 1H) 2.00 (d, J=12.03 Hz, 1H) 3.13 (s, 3H) 4.08 (d, J=7.47 Hz, 1H) 4.71 (d, J=13.69 Hz, 1H) 4.85 (d, J=13.69 Hz, 1H) 7.44 (d, J=8.30 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][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])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(Cl)cc1
Yield: 54.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (4.8 g) and 3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (5 g), the title compound (4.5 g) was obtained, melting point: 205–210° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:10]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>CN(C=O)C.COC(C)(C)C>[C:1]([O:4][CH2:21][C:20]1[CH:19]=[CH:18][C:9]([C:10](=[O:11])[NH:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])=[CH:8][C:7]=1[Br:6])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)cc1Br
Yield: 39.1 %

Procedure:
A mixed solution of sodium acetate (2.8 g), 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (6.5 g) in DMF (30 ml) was stirred for 3 hours at 70° C. The reaction liquor was returned to room temperature and diluted with t-butyl methyl ether. The mixture was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After separating the drying agent by filtration, the reaction liquor was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-{[(trimethysilyl)methyl]carbamoyl}benzyl acetate (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH2:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=O.I[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>[C:10]([C:5]1[C:6]([C:8]#[N:9])=[CH:7][C:2]2[N:1]([CH2:24][CH2:25][CH3:26])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][C:3]=2[CH:4]=1)#[N:11]
Reactant: N#Cc1cc(N)c(N)cc1C#N
Reactant: O=Cc1ccccc1
Reactant: CCCI
Agent: O=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A 25 mL round-bottom flask was charged with 3 (316 mg, 2.00 mmol), NMP (10 mL), benzaldehyde, (202 μL, 2.00 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still, placed in an oil bath heated to 120° C., and stirred for 1 h. Then FeCl3.6H2O (27 mg, 0.10 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 20 h. The reaction mixture was then removed from heat and added to ethyl acetate. The ethyl acetate solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue (458 mg, 1.88 mmol) was dissolved in NMP (2 mL) and heated to 80° C. Then DBU (280 μL, 1.88 μmol) was added and the mixture was stirred for 2 min, and iodopropane (183 μL, 1.88 mmol) was added. After 20 min, the mixture was treated with a second round of DBU and iodopropane, and after an additional 20 min, a third round of reagents was added. After a final 20 min of heating, the mixture was transferred to ethyl acetate and washed three times with water, followed by brine. After drying the organic layer over Na2SO4, the mixture was filtered, concentrated to dryness, and chromatographed (silica, CH2Cl2, 3% ethyl acetate, 1% isopropanol), yielding an off-white solid (253 mg, 44%): mp 183-185° C.; 1H NMR (CDCl3) δ 0.90 (t, J=7.6 Hz, 2H), 1.81-1.92 (m, 2H), 4.29 (t, J=7.6 Hz, 2H), 7.56-7.62 (m, 3H), 7.70-7.73 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H); 13C NMR (CDCl3) δ 11.4, 23.5, 47.3, 108.7, 109.0, 116.7, 116.8, 116.9, 126.6, 128.8, 129.5, 129.5, 131.4, 137.8, 145.4, 159.5; FAB-MS obsd 287.1302, calcd 287.1297 [(M+H)+; M=C18H14N4]
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[OH:16][C:17]1C=CC(C=O)=CC=1.BrCC(OCC)=O>>[CH:17]([C:15]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:16]
Reactant: CCOC(=O)COc1cccc(C=O)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C=O)cc1
Yield: 52 %

Procedure:
In an analogous manner to compound 47, 4-hydroxy benzaldehyde (1 eq) and ethyl 2-bromoacetate (1.1 eq) were reacted to produce the desired product (52%) as a brown oil. NMR: δ 1.306 (t, J=6.8 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 4.710 (s, 2H), 7.016 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.904 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11].C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C(CCC)C(NCC(NCCCCCCN)=O)=O)CC>>[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:10]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:11])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: CCCC(CCC)C(=O)NCC(=O)NCCCCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Yield: 82.1 %

Procedure:
The reaction was carried out in the same manner as in Example 7 except for using 9.06 g (69.6 mmole) of 5-fluorouracil, 6.20 g (62.7 mmole) of phosgene, 12.68 g (125.3 mmole) of triethylamine, and 11.36 g (52.5 mmole) of N-(t-butyoxycarbonyl)hexamethylenediamine synthesized in Reference example 13 in place of N-[N-(2-n-propyl-n-pentanoyl)-glycyl]hexamethylenediamine used in Example 7. The reaction mixture was treated in the same manner as in Example 7 to give 16.06 g (Yield: 91.3%) of pale yellowish crystals. 1 g of this crystals was recrystallized from 15 ml of ethyl acetate to give 0.52 g of colorless needle crystals.
Reaction SMILES: N#N.Cl.[C:4]([O:9]CCN)(=O)[C:5]([CH3:7])=[CH2:6].C1(C=CC(O)=CC=1)O.C([N:23](CC)CC)C.[CH:28]([N:30]=[C:31]=[O:32])=[CH2:29]>C(Cl)(Cl)Cl>[C:4]([N:30]([CH:28]=[CH2:29])[C:31]([NH2:23])=[O:32])(=[O:9])[C:5]([CH3:7])=[CH2:6]
Reactant: CCN(CC)CC
Reactant: C=C(C)C(=O)OCCN
Reactant: C=CN=C=O
Agent: Cl
Agent: N#N
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C=CN(C(N)=O)C(=O)C(=C)C

Procedure:
A 500 ml 3-necked round bottom flask equipped with a reflux condenser, a mechanical stirrer, a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 2-aminoethyl methacrylate hydrochloride 41.4 g (0.25 mole), 50mg of hydroquinone and 300 ml of chloroform. The contents are cooled to between 0 and 5 degrees C. and stirred. Through a dropping funnel 25.3 g (0.25 mole) of triethylamine and 13.3 g (0.25 mole) of vinyl isocyanate in 50 ml of chloroform are added into the reaction flask and maintained at between 0 and 5 degrees C. The temperature is allowed to rise to room temperature with the contents stirred constantly overnight, passed through a silica gel column and dried with magnesium sulfate. The contents are then evaporated under reduced pressure to give the named product.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:25][CH2:26][CH3:27])(C)(C)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[C:21]([O:20][C:18]([NH:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:9]([CH2:25][CH2:26][CH3:27])=[N:10][C:11]=2[CH:16]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)O
Temperature: 70 °C

Procedure:
The product of step d.) was dissolved in 3 mL ethanol, treated with 1 M NaOH (500 μL), and heated to 70° C. for one hour. The reaction was diluted in DCM and extracted with water. The aqueous layer was acidified with 1 M HCl and extracted with DCM. The organic layer was washed with water, concentrated and purified by preparative LCMS to give the title compound. MS: ESI (positive): 334 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:7]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)c1
Yield: 88.6 %

Procedure:
3-Methoxybenzoyl chloride 179 (0.20 g, 1.17 mmol) and 178 (0.34 g, 1.17 mmol) were stirred in pyridine (15 mL) at rt for 4 hrs then the pyridine was removed by rotary evaporation and the crude material was purified by column chromatography (25% ethyl acetate in hexanes) to provide the title compound 180 (0.44 g, 89% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.88 (s, 1H), 8.72 (s, 1H), 7.80 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.43 to 7.55 (m, 6H), 7.17 (dd, J=7.6, 1.8 Hz, 1H), 7.11 (dd, J=4.9, 3.5 Hz, 1H), 3.84 (s, 3H), 1.46 (s, 9H). MS: (calc.) 424.15; (obt.) 425.1 (MH)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[OH-].[Na+].[CH2:14]=O.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[Na+].Cl>O>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:14][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2c(C(F)(F)F)nn(C)c2O)cc1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (8.3 g (50 mmol)) synthesized in Reference Example 1 and 3.0 g (75 mmol) of sodium hydroxide were dissolved in 50 mL of water. While stirring the resulting solution at room temperature, 8.5 g (100 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Furthermore, 9.0 g (50 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 25.0 g (250 mmol) of 35% hydrochloric acid was added dropwise thereto, 100 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 20 mL of water and dried by a hot air drier to obtain 14.0 g (yield: 83.8%) of the title compound as a white crystal.