Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[CH:16]=[C:15]([NH:17][S:18]([C:21]2[S:22][C:23](Br)=[CH:24][CH:25]=2)(=[O:20])=[O:19])[O:14][N:13]=1>>[CH3:11][C:12]1[CH:16]=[C:15]([NH:17][S:18]([C:21]2[S:22][C:23]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)=[CH:24][CH:25]=2)(=[O:20])=[O:19])[O:14][N:13]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc(N)c3)s2)on1

Procedure:
N-(3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 3-amino benzene boronic acid (256 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (55 mg, 1.7 mmol). At Purification by column chromatography using 15% MeOH/CHCl3 gave 318 mg (56%) of the product.
Reaction SMILES: [N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38](O)=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[NH2:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:72][C@H:73]([C:82]([NH:84][C@H:85]([C:98]([O:100][CH3:101])=[O:99])[CH2:86][CH2:87][CH2:88][CH2:89][NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1)=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:59])[CH3:58].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:72][C@H:73]([C:82]([NH:84][C@H:85]([C:98]([O:100][CH3:101])=[O:99])[CH2:86][CH2:87][CH2:88][CH2:89][NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1)=[O:71])[CH:67]([CH3:68])[CH3:69])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@@H](N)CC(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 24 h

Procedure:
840 mg of Boc-Pro-His-Pro-Phe-His-OH, 600 mg of H-Sta-Val-Tyr-Lys(Boc)-OMe (from stage 1.5) and 250 mg of HONB are dissolved in 6 ml of DMF, cooled to 0°, and 290 mg of DCCI are added. The whole is stirred for 6 hours at 0° and for 24 hours at 25° the DCH is filtered off, and the filtrate is concentrated to dryness by evaporation. The residue is dissolved in 18.8 ml of MeOH, 0.6 ml of glacial acetic acid and 0.6 ml of H2O, heated for 1 hour at 60°, concentrated to approximately 3 ml, and the peptide is precipitated in the form of greasy material with 20 ml of diisopropyl ether. It is purified by Craig partitioning in the system MeOH/0.1N AcOH/ethylene chloride/chloroform (10:3:8:4) over 750 stages; K=0.75. The chromatographically pure middle fraction is isolated by strong concentration and lyophilisation, yielding Boc-Pro-His-Pro-Phe-His-Sta-Val-Tyr-Lys(Boc)-OMe in the form of an amorphous powder; Rfn (B)=0.38; Rf (I)=0.46; Rf (C)=0.64.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C(N(CC)CC)C>[CH:8]([NH:21][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)(C)Br
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)C(C)(C)NC(c1ccccc1)c1ccccc1

Procedure:
To the above-obtained 3-bromo-3-methylbutan-2-one (5.88 g) in methanol (30 mL), benzhydrylamine (5.0 mL) and triethylamine (7.5 mL) were added. The resultant mixture was stirred at 70° C. for 24 hours, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and to the solid, diethyl ether was added, and then insoluble matter was removed by filtration. The mother liquid was brought to the dryness under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 3-(benzhydrylamino)-3-methylbutan-2-one as an oily product (3.3 g, 34%).
Reaction SMILES: ClC[C:3]1[N:4]([C@@H:16]([CH3:26])[CH2:17][NH:18][C:19](=O)OC(C)(C)C)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.C(Cl)(Cl)Cl>Cl.CCO>[CH3:26][C@@H:16]1[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:19][NH:18][CH2:17]1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@H]1CNCc2nc3cnc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
tert-Butyl (2S)-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (2.54 g, 6.77 mmol) was dissolved in 2.2 M HCl in EtOH (50 mL) and the solution was heated to reflux for 15 minutes. N2 was bubbled through the reaction for 15 minutes, and the remaining volatiles were removed under reduced pressure. The resulting material was partitioned between dichloromethane and water. The organic layer was discarded and the aqueous layer was treated with concentrated NH4OH solution to adjust to pH 11. The aqueous layer was extracted with dichloromethane (3×100 mL), and the combined organic layers were washed with brine. Triethylamine (4 mL) was then added to the solution and it was stirred at ambient temperature overnight. The reaction was washed successively with water (2×100 mL) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange foam. Chromatography (SiO2, 20-50% CMA/CHCl3) gave (11S)-11-methyl-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (1.06 g) as an orange foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([NH:45][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.21 g, 0.66 mmol) and 4-methylmorpholine (0.08 mL, 0.72 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.09 mL, 0.68 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.08 mL, 0.73 mmol) was added. The reaction mixture was kept stirring for 14 hour at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 20% yield (0.050 g): mp 169-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (t, J=5.7 Hz, 1H), 7.35-7.19 (m, 10H), 4.39 (s, 2H), 4.35 (d, J=5.7 Hz, 2H), 3.96 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 157.8, 155.5, 151.4, 140.1, 136.7, 129.1, 128.7, 128.2, 127.9, 127.6, 127.1, 118.2, 47.3, 43.0, 42.4, 42.0, 17.5; MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: Cl.C(N=C=[N:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.N1CCC(N)C1>O.CN(C=O)C.C(N(CC)CC)C>[NH:10]1[CH2:9][CH2:8][CH:7]([NH:6][C:21]([C:17]2[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=2[CH3:20])=[O:23])[CH2:12]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCNC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NC1CCNC1
Temperature: 0 °C
Yield: 68 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then pyrrolidine-3-amine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 159.8 g (680 mmol) of N-(pyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 68.0%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=C[C:29](C#N)=[C:28](N)[CH:27]=1)=[O:4].[N:35]1[CH:40]=[N:39][CH:38]=[N:37][CH:36]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[C:36]2[C:29]([C:40]([NH2:35])=[N:39][CH:38]=[N:37]2)=[CH:28][CH:27]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 38.9 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (42 mg, 0.08 mmol), EXAMPLE 99, 1,3,5-triazine (40 mg, 0.48 mmol), and glacial HOAc (30 mg, 0.48 mmol) in absolute EtOH (1 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated and then dissolved in water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 17 mg (32%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17]CC)=O)[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].BrBr.C([O-])(O)=O.[Na+]>CCO.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([OH:17])[N:23]=[N:22][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCN(Cc2ccccc2)CC1=O
Reactant: NN
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Oc1cc2c(nn1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl (1-benzyl-3-oxopiperidin-4-yl)acetate (11.4 g, 41.4 mmol) and hydrazine monohydrate (3.1 g, 62 mmol) in EtOH (50 mL) is stirred at 80° C. for one hour. The resulting solution is cooled, and concentrated in vacuo to give a white solid. The white solid is dissolved in acetic acid (120 mL) and the mixture is heated at 85° C. To the reaction mixture is added bromine (6.62 g, 41.4 mmol) dropwise. The resulting mixture is heated for another 30 min. The solvent is removed in vacuo to give a residue. A saturated NaHCO3 solution is added until pH ˜8 while stirring. The formed solid is filtered and dried in air to afford the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:44])[NH:18][C:19](=[O:43])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17](=[O:44])[NH:18][C:19](=[O:43])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH2:29][NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CN(Cc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNCc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1

Procedure:
A solution of the product of step (iii) (1.8 g) in trifluoroacetic acid (5 ml) and dichloromethane (30 ml) was stirred overnight at room temperature. Toluene was added and the mixture was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:20][CH2:21][C:22](Cl)=O>C(O)(=O)C>[Cl:20][CH2:21][C:22]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([F:18])=[C:15]([F:19])[CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(F)c(F)cc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2cc(F)c(F)cc2nc(CCl)n1-c1ccccc1Cl
Yield: 25.9 %

Procedure:
Prepared according to Procedure B with 1q (700 mg, 2.48 mmol) and chloroacetyl chloride (0.60 mL, 7.43 mmol) in acetic acid (12 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 219 mg of a yellow crystalline solid (26%). 1H NMR (CDCl3) δ: 8.07 (dd, J=8.5, 9.7 Hz, 1H); 7.64 (dd, J=2.5, 5.6 Hz, 1H); 7.60 (dd, J=3.5, 11 Hz, 1H); 7.55 (q, J=2.9 Hz, 3H); 7.52 (d, J=1.9 Hz, 1H); 7.49-7.51 (m, 1H); 4.36 (d, J=12 Hz, 1H), 4.06 (d, J=12 Hz, 1H). MS (ES): m/z 341.0 (M+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42])[N:35]=[N:34]1>C(Cl)Cl>[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([Br:23])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:42])[N:35]=[N:34]1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (92 mg, 0.220 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.077 mL, 0.441 mmol). 4-(1H-1,2,3-triazol-4-yl)butanoyl chloride (38.2 mg, 0.220 mmol) in DCM (2 mL) was added and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine, and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH/DCM as eluent to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9]C=C(C3N(C(C)C)N=C(C)N=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1.ClC1C=CC(C#N)=C(F)C=1.N[OH:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:9])[NH:12][OH:34])=[C:4]([F:22])[CH:3]=1
Reactant: Cc1nc(-c2c[nH]c(-c3ccc(Cl)cc3F)n2)n(C(C)C)n1
Reactant: NO
Agent: N#Cc1ccc(Cl)cc1F
Product: N=C(NO)c1ccc(Cl)cc1F

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH2:21][CH:20]=[CH2:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
To a slurry of hexanes-washed NaH (0.534 g of a 60% suspension in mineral oil, 13.4 mmol) in DMF (10 mL) at 0° C. was added a solution of 4-[(2,2-dimethylpropyl)amino]-2-(trifluoromethyl)benzonitrile (1.71 g, 6.68 mmol) in DMF (4 mL), dropwise over 10 min. The resulting solution was stirred 15 min and neat allyl bromide (1.16 mL, 13.4 mmol) was added dropwise over 3 min. The resulting solution was stirred 1 h, poured into water and the whole was extracted with Et2O (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.82 g of the title compound as a colorless syrup: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 1H), 6.83 (dd, J=8.9, 2.5 Hz, 1H), 5.73 (ddt, J=17.2, 10.6, 4.6 Hz, 1H), 5.23 (app. d, J=10.6 Hz, 1H), 5.05 (app. d, J=17.5 Hz, 1H), 4.09 (overlapping ddd, 2H), 3.26 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:51]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:73])[CH2:64]P(OCC)(OCC)=O)[CH2:59][CH2:58]1)=[O:56])[CH:52]=[CH2:53].[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:64]/[C:63]([N:60]1[CH2:59][CH2:58][N:57]([C:55]([O:54][CH2:51][CH:52]=[CH2:53])=[O:56])[CH2:62][CH2:61]1)=[O:73])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: C=CCOC(=O)N1CCN(C(=O)CP(=O)(OCC)OCC)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCN(C(=O)/C=C/[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCC=C)CC1
Yield: 92.6 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 1.5 g, 3.26 mmol), dimethyl sulfoxide (0.65 ml, 9.14 mmol), oxalyl chloride (0.42 ml, 4.90 mmol), triethylamine (2 ml, 14.9 mmol), N-allyloxycarbonyl-N'-(diethylphosphonoacetyl)piperazine (1.24 g, 3.92 mmol) and 60% sodium hydride (130 mg, 3.26 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate) to give the title compound (1.97 g, 92.6% yield).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[CH3:26]COCC>>[OH:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C(O)CCCCCCCCCCCCC#CCOC1CCCCO1
Reactant: CCOCC
Product: COC(=O)CCCCCCCCCCCCC#CCO
Yield: 83 %

Procedure:
Concomitant esterification of the carboxylic acid and cleavage of the THP ether in 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-ynoic acid (1.0 g, 2.84 mmol) as described above furnished methyl 16-hydroxyhexadec-14-ynoate (665 mg, 83%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.40; 1H NMR (CDCl3, 300 MHz) δ 4.22-4.26 (m, 2H), 3.66 (s, 3H), 2.29 (t, 2H, J=7.3 Hz), 2.20 (tt, 2H, J=2.1 Hz, 6.8 Hz), 1.21-1.66 (m, 20H).
Reaction SMILES: [CH2:1]([O:8]C1C(=O)NC(=O)N(C=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].[C@@H:27]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:31]([CH2:32][OH:33])[C@@H:29]([OH:30])[CH2:28]1>C(O)C.[Pd]>[CH2:1]([O:8][CH2:42][C:41]1[C:39](=[O:40])[NH:38][C:36](=[O:37])[N:35]([CH:43]=1)[C@@H:27]1[O:34][C@H:31]([CH2:32][OH:33])[C@@H:29]([OH:30])[CH2:28]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1OCc1ccccc1
Reactant: [H][H]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1COCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of 5-benzyloxy-2′-deoxyuridine (10 mg) in ethanol (1 mL) was added Pd/C (10%, 10 mg), and the mixture was stirred for five minutes. Hydrogen was introduced to the system via a balloon and the reaction mixture was stirred at room temperature. Aliquots (5 μL) were taken out from the reaction mixture at various time point intervals and were analyzed by thin layer chromatography and HPLC. Complete cleavage to thymidine was observed after ten minutes at room temperature (Scheme 42 and FIG. 4). The intermediate of the cleavage was identified to be 5-hydroxymethyl-dU generated from initial removal of benzyl group, and HOMedU was further reduced to thymidine.
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[NH2:7][C:8]([O:10][CH2:11][CH3:12])=O.S(=O)(=O)(O)O.C(O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][CH:8]=[N:7][C:1]([O:2][CH2:3][CH3:4])=[O:6])[CH3:12]
Reactant: CCOC(N)=O
Reactant: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC=NC(=O)OCC
Reaction time: 2 h
Yield: 32.4 %

Procedure:
In 40 ml toluene was dissolved 44.4 g (0.3 mol) of ethyl orthoformate, and while keeping the temperature at 110°-120° C., 18 g (0.2 ml) of urethane and 200 ml of a mixture of sulfuric acid with toluene were dropped thereto spending about 2 hours, during which produced ethanol was distilled out of the reaction vessel. After the dropping had been finished, toluene was removed by distillation. The intended product (9.5 g) was obtained by distillation of the residue; b.p. 72.4° C. (15 mmHg), yield 38.8%.