Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:61]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])([O:63][CH2:64][C:65]([NH2:68])([CH3:67])[CH3:66])=[O:62].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[C:70]([O:69][P:61]([O:63][CH2:64][C:65]([NH:68][C:20]([C:19]1[CH:23]=[CH:24][C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:14][CH:13]=2)=[C:17]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:18]=1)=[O:21])([CH3:67])[CH3:66])([O:74][C:75]([CH3:77])([CH3:76])[CH3:78])=[O:62])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
To a solution of the product of Example 385E (100 mg, 0.19 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (72 mg, 0.22 mmol), the product of Example 438C (65 mg, 0.23 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (0.065 mL, 0.37 mmol) dropwise at room temperature under N2. The mixture was stirred at room temperature for 12 hours under N2. The reaction was diluted with ethyl acetate and the organic layer was washed sequentially with water (3×) and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-100%) to give the title compound (93 mg, 62%).
Reaction SMILES: [N:1]1([C:53](OC(C)(C)C)=O)[CH2:52][CH2:51][CH2:50][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:49])[C@H:17]([C:25]([N:27]([CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])C)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:49])[C@H:17]([C:25]([NH:27][CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-MePheNHNH2 (0.86 g.) and HSar-Leu-MetNH2 (Example 3, 0.63 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-MePhe-Sar-Leu-MetNH2 in 75% yield. De-t-butoxycarbonylation of BocPro-Phe-MePhe-Sar-Leu-MetNH2 (0.90 g.) using trifluoroacetic acid in methylene dichloride gave HPro-Phe-MePhe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt in 59% yield.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([O-:17])=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[C:22]1(C)[CH:27]=CC=C[CH:23]=1.[C:29](=O)([O-])[O-].[Na+].[Na+].C(B(O)O)=CC(=C)C>C(O)C.O>[C:20]([C:4]1[CH:3]=[C:2]([C:22]([CH3:27])=[CH2:23])[C:10]2[O:9][C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:29])=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:21]
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Agent: C=C(C)C=CB(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=C(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)OC)cc3)oc12
Temperature: 91 °C
Reaction time: 8 h

Procedure:
To a 5-l, 3-neck round-bottom flask fitted with a stirring paddle, a condenser blanketed with nitrogen, and a thermocouple, was added 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)benzoate (55.5 g, INTERMEDIATE 35), toluene (2 l), water (375 ml), ethanol (150 ml), 2M aqueous sodium carbonate (250 ml), and isoprenylboronic acid (83.4 g, INTERMEDIATE 37). The mixture was purged with nitrogen three times and then tetrakis(triphenylphosphine)palladium(0) (9.1 g) was added, and the mixture was purged three times with nitrogen. The mixture was heated to reflux (91° C.) and stirred at this temperature overnight. The mixture was then cooled to 20° C. and the product was filtered, washed with water, dried, and transferred to a 3-l round-bottom flask and rinsed with toluene (1 l). Residual solvent was removed in vacuo. Mass spectrum (ESI) 319.1 (M+1).
Reaction SMILES: CC(S(N)=O)(C)C.O1C2C=CC(C3(C(O)=O)CC3)=CC=2OC1.[C:23]([S@@:27]([NH:29][C@H:30]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[Cl:57])[C:31]1[S:35][C:34]([NH:36][C:37]([C:39]2([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[CH2:41][CH2:40]2)=[O:38])=[N:33][CH:32]=1)=[O:28])([CH3:26])([CH3:25])[CH3:24]>CC#N>[C:23]([S@:27]([NH:29][C@H:30]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[Cl:57])[C:31]1[S:35][C:34]([NH:36][C:37]([C:39]2([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[CH2:40][CH2:41]2)=[O:38])=[N:33][CH:32]=1)=[O:28])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: CC(C)(C)S(N)=O
Agent: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CC#N
Product: CC(C)(C)[S@@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
(R)—N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was prepared from (R)—N—(R)-1-(2-aminothiazol-5-yl)-1-(2-chlorophenyl)methyl)-1,1-dimethylethylsulfinamide and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid using the same protocol for (S)—N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H-NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.62 (dd, J=7.7, 1.7 Hz, 1H), 7.37 (d, J=0.7 Hz, 1H), 7.34 (dd, J=7.8, 1.4 Hz, 1H), 7.31-7.20 (m, 2H), 6.87 (td, J=8.4, 1.7 Hz, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 6.01 (s, 2H), 3.74 (d, J=2.8 Hz, 1H), 1.71-1.68 (m, 2H), 1.24 (s, 9H), 0.88 (t, J=6.9 Hz, 2H). HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 532.1 m/z (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[F:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:25][CH2:24]3)=[CH:21][S:20][C:19]=2[CH:35]=1>N1C=CC=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)=[O:12])[CH2:25][CH2:24]3)=[CH:21][S:20][C:19]=2[CH:35]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1)c1ccc2ccccc2c1
Yield: 91.9 %

Procedure:
Add slowly a solution of 2-naphthoyl chloride (600 mg, 3.15 mmol) to a solution of 4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazapan-1-yl]butylamine (Example 6) (920 mg, 2.86 mmol), in pyridine-methylene chloride (10 mL,1:1), and stir the solution at room temperature overnight. Evaporate the solvent under vacuum, dissolve the residue in EtOAc and wash the organic layer with water and saturated sodium chloride solution. Combine the organic phases, dry over MgSO4 and evaporate the solvent under vacuum. Purify the crude product by column chromatography (EtOAc/MeOH 7:3) to obtain 1.25 g of a solid LC/MS (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water-gradient 20%→100% (25 min), Flow: 1.5 mL/min) tR=21.11 min, m/z=475.3.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[CH3:13][C:14]1([CH3:32])[C:18]2[N+:19]([O-:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[N:22][C:17]=2[C:16]([CH3:31])([CH3:30])[O:15]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][C:14]1([CH3:32])[C:18]2[N+:19]([O-:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:1]([O-:4])=[O:2])[CH:24]=3)[N:21]=[N:22][C:17]=2[C:16]([CH3:31])([CH3:30])[O:15]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)OC(C)(C)c2c1nnc(-c1ccccc1)[n+]2[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC(C)(C)c2c1nnc(-c1cccc([N+](=O)[O-])c1)[n+]2[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.2 ml (0.005 mole) of fuming nitric acid and 1.5 grams (0.01 mole) of trifluoromethanesulfonic acid in 15 ml. anhydrous methylene chloride, after allowing the resulting mixture to be stirred for 1 hour at 25°C., there is added dropwise maintaining the temperature at -30°C., 0.542 grams (0.002 mole) of 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro [3,4-e]-as-triazine-4-oxide in 15 ml. of anhydrous methylene chloride. The resulting heterogeneous mixture is stirred at 25°C. for 72 hours, poured onto ice, and neutralized with solid sodium bicarbonate. The organic layer is removed and the aqueous phase extracted several times with methylene chloride. The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give a white solid. The resulting solid is recrystallized from methylene chloride/hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-(m-nitrophenyl)-furo[3,4-e]-as-triazine-4-oxide, m.p. 202°-204°C.
Reaction SMILES: [CH:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CCC(C)Sc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCN(CC=C)C(=O)n1cnc(SC(C)CC)n1

Procedure:
A mixture of 7.9 g. 3-sec.butylthio-1,2,4-triazole, 8.0 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-sec.butylthio-1,2,4-triazole, b.p. 121° - 123°C./0.1 mm. (96% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([S:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1)([F:15])[F:14].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:15][C:13]([F:12])([F:14])[S:16]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1ccc2ocnc2c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(c1ccc2ocnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.3 %

Procedure:
0.71 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.50 g of 5-trifluoromethylsulfanylbenzoxazole and 3 ml of chloroform under ice cooling, and then the mixture was stirred at room temperature for 1 day. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.20 g of 5-trifluoromethylsulfinylbenzoxazole.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:18])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:4]12[O:18][CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccccc1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C=CCC12C=CC=CC1O2
Reaction time: 55 h
Yield: 68.9 %

Procedure:
21.6 g of allylbenzene was dissolved in 200 ml of chloroform and to the mixture was added dropwise 41.4 g of m-chloroperbenzoic acid dissolved in 1l of chloroform at 0° - 5° C. The resulting mixture was reacted with slow stirring for 55 hours while maintaining the temperature at 0° - 5° C. After the completion of the reaction, m-chlorobenzoic acid crystals were filtered off and the filtrate was washed twice with 5% sodium hydroxide solution and then water. After dried over anhydrous sodium sulfate, the solvent was evaporated to obtain the residue. This was distilled under reduced pressure to give 16.9 g (yield 70.5%) of allylbenzene oxide as colourless oil having a boiling point of 60° C/2 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:30]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCc1ccc(NC(=O)c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Yield: 22 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and 4-octylaniline gave the title compound as a colorless oil (22%). 1H NMR (CDCl3, 300 MHz) δ 7.89-6.60 (m, 12H), 4.48 (s, 2H), 4.44-4.21 (m, 4H), 2.65-2.36 (m, 2H), 1.68-1.40 (m, 3H), 1.38-1.08 (m, 13H), 0.81 (t, J=6.9 Hz, 3H). M+(LC/MS(ESI)): 597.7. HPLC (Condition A), Rt: 6.75 min (HPLC purity: 98.9%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.N1C=CC([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=O)=N1.[NH3:25]>>[NH:25]1[CH:5]=[CH:4][C:3]([C:3]2([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[CH:16][CH:17]=3)[O:1][NH:2]2)=[N:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(-c2cc[nH]n2)c1
Reactant: N
Product: c1ccc(C2=NC(c3cccnc3)(c3cc[nH]n3)NO2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(1H-pyrazol-3-yl)benzoic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=2.4 Hz, 1H), 7.62-7.69 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.79-7.92 (m, 1H), 7.82-7.88 (m, 1H), 8.10-8.20 (m, 3H), 8.49 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.64 (s, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 290 (M+H)+.
Reaction SMILES: S1CCCSC1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1([CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CCCCC1=O
Agent: C1CSCSC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Br)CCCCC1=O

Procedure:
Aldehydes 4B and 4C were synthesized by a modification of the procedure reported by Corey and Erickson (Corey, E. J. and Erickson, B. W. (1971) “Oxidative hydrolysis of 1,3-dithiane derivatives to carbonyl compounds using N-halosuccimide reagent,” J. Org. Chem. 36(3):553-560) which is depicted in Scheme 4. Bromination of 2-methylcyclohexanone (7) with 1 equivalent of N-bromosuccinimide (Rinne, W. W. et al., “New methods of preparation of 2-methylcyclohexen-1-one,” J. Am. Chem. Soc. (1950) 72:5759-5760) in refluxing CCl4 for 12 hours gave quantitative yield of 2-bromo-2-methylcyclohexanone. Dehydrobromination of this bromide with three equivalents of Li2CO3 and three equivalents of LiBr in N,N-dimethylformamide (DMF) (Stotter, P. L. and Hill, K. A., “α Halocarbonyl Compounds. II. A Position-Specific Preparation of α-Bromo Ketones by Bromination of Lithium Enolates. A Position-Specific Introduction of α, β-Unsaturation into Unsymmetrical Ketones,” J. Org. Chem. (1973) 38:2576-2578) at 130° C. for 3 h provided a 72% yield of 2-methyl-2-cyclohexen-1-one (8). A 1,2-addition reaction of 8 with 1.5 equivalents of lithiated 1,3-dithiane [generated from 1,3-dithiane (9) with n-BuLi in THF] in THF at −10° C. to give a 96% yield of the 1,2-adduct 10. Rearrangement of 10 with 1% sulfuric acid in p-dioxane (52% yield) followed by removal of the dithiane protecting group of the resulting alcohol, 11, with N-chlorosuccinimide (NCS) and silver nitrate in acetonitrile-water gave aldehyde 4B (50% yield). Alcohol 4B is not a stable compound and decomposes upon standing at room temperature in a few days. A more stable material, 4C, was synthesized in a better yield from the rearrangement reaction of 10 in formic acid-THF in the presence of catalytic amount of p-toluenesulfonic acid (70% yield) followed by removal of the dithiane moiety with NCS-AgNO3 (59% yield) (Scheme 4). In the formic acid rearrangement reaction, besides the desired product, 1-[2-(1,3-dithianyl)]-3-formyloxy-2-methyl-1-cyclohexene, 9% yield of 3-[2-(1,3-dithianyl)]-2-methyl-2-cyclohexen-1-ol (11) was isolated.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:25])[C:18]=2[CH3:33])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:31]([O:30][C:28]([CH2:27][CH2:26][C:24]([NH:23][C:19]1[C:18]([CH3:33])=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:29])[CH3:32]
Reactant: [H][H]
Reactant: CCOC(=O)CCC(=O)Nc1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(=O)Nc1cccc(N2CCNCC2)c1C
Yield: 93.7 %

Procedure:
In 50 ml of methanol was dissolved 1.50 g of 1-benzyloxycarbonyl-4-(3-(2-ethoxycarbonylethyl)carbonylamino-2-methylphenyl)piperazine, and 1.0 g of 10% palladium-on-carbon was added thereto, followed by stirring at room temperature in a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the solvent was evaporated to yield 0.99 g of 3-(2-ethoxycarbonylethyl)carbonylamino-2-methylphenylpiperazine, which was used in the next reaction without purification.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Br:8][C:9]1[CH:10]=[C:11]([C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc(I)c1
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1cccc(Br)c1
Reaction time: 1 h
Yield: 24.1 %

Procedure:
Ethyl propiolate (2.15 mL, 21.2 mmol, 1.20 equiv) was added to a mixture of 1-bromo-3-iodobenzene (5.00 g, 17.7 mmol, 1 equiv), PdCl2(CH3CN)2 (367 mg, 1.41 mmol, 0.080 equiv), copper (1) iodide (135 mg, 0.707 mmol, 0.040 equiv) and potassium carbonate (2.93 g, 21.2 mmol, 1.20 equiv) in N,N-dimethylformamide (44 mL) at 22° C. The reaction mixture was stirred for 1 hour, then was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed solution was dried over sodium sulfate, and the dried solution was filtered. The filtrate was concentrated, and the residue was purified by flash-column chromatography on silica gel (hexanes, grading to 40% ethyl acetate-hexanes) to afford ethyl 3-(3-bromophenyl)prop-2-ynoate (1.08 g, 24%). Calc'd (M+1)+: 253.0. Found: 252.9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6]([Cl:16])[N:5]=[C:4]([NH2:17])[N:3]=1.[CH3:18][O-:19].[Na+]>>[Cl:16][C:6]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:2]([O:19][CH3:18])[N:3]=[C:4]([NH2:17])[N:5]=1
Reactant: C[O-]
Reactant: CC(=O)N1CCN=C1c1c(Cl)nc(N)nc1Cl
Agent: [Na+]
Product: COc1nc(N)nc(Cl)c1C1=NCCN1
Reaction time: 3 h

Procedure:
3.5 g 4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are introduced into 30 ml 1% sodium methylate solution. After three hours, the precipitate is vacuum dried, washed with water, and recrystallized from nitromethane. 2.1 g of 4-chloro-6-methoxy-5-(2-imidazolin-2-yl)-aminopyrimidine (melting point 212° C.), is obtained.
Reaction SMILES: C(C(CCCC)C[OH:5])C.C(N(CC)CC)C.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([CH2:23][C:24]([OH:25])=[O:5])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCC(CC)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g, 0.5 mol) and methylene chloride (50 mL). Add, by dropwise addition, 2-phenylacetyl chloride (5 mol) and warm to 50° C. Stir at room temperature overnight, filter and wash the filtercake with methylene chloride (50 mL). Combine the organic phases and wash with 5% aqueous hydrochloric acid (50 mL) and water. Dry (MgSO4), evaporate the solvent in vacuo and purify by distillation to give 2-phenylacetic acid, 2-(2-ethylhexy)1 ester.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (320 mg, 3.6 mmol) and triethyloxonium tetrafluoroborate (0.69 g, 3.6 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of tert-butyl {4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}carbamate (191 mg, 0.527 mmol) and the above made reagent in ethanol (4.8 mL) was heated at reflux for 2 h. The mixture was concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product. LCMS calculated for C21H29N4O3S (M+H)+: m/z=417.2. Found: 417.0.