Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([S:14]([N:17]2[CH2:22][CH2:21][S:20][C:19]([CH3:24])([CH3:23])[C@@H:18]2[C:25]([OH:27])=O)(=[O:16])=[O:15])[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:35][OH:36].C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[OH:36][NH:35][C:25]([C@H:18]1[C:19]([CH3:24])([CH3:23])[S:20][CH2:21][CH2:22][N:17]1[S:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)(=[O:16])=[O:15])=[O:27]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc3c(c2)oc2ccccc23)[C@H]1C(=O)O
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc3c(c2)oc2ccccc23)[C@H]1C(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A dichloromethane solution of the acid synthesized in Example 1 (0.26 g, 0.64 mmol/10 mL CH2Cl2) was reacted with oxalyl chloride (0.1 mL, 0.77 mmol) and a catalytic amount of N,N-dimethylformamide under an atmosphere of nitrogen. After stirring at room temperature for 30 minutes, the solution was concentrated in vacuo. The crude acid chloride was dissolved in tetrahydrofuran and added to a tetrahydrofuran (60 mL)/water (20 mL) solution containing hydroxylamine hydrochloride (0.44 g, 6.4 mmol) and sodium bicarbonate (0.81 g, 9.6 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude product was diluted with ethyl acetate and washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was recrystallized from hexane/ethyl acetate to give 0.14 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([SH:12])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([S:12][CH3:14])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(S)nc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1nnc(SC)nc1O
Reaction time: 1 h

Procedure:
To a 0° C. solution of 29.0 g (144.1 mmol) of 5-hydroxy-3-mercapto-1,2,4-triazine-6-carboxylic acid ethyl ester in 75 mL of DMF was added 14.4 g (144.1 mmol) of potassium carbonate. The reaction mixture was stirred for 1 hour, and 24.2 mL (389.2 mmol) of methyl iodide was added as fast as the effervescence would allow. The ice bath was removed, and the reaction was covered with a nitrogen filled balloon and stirred at room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)O)C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Yield: 95.7 %

Procedure:
To a suspension of 21 (20.0 g, 0.0735 mol; see Example 46) in 700 mL of anhydrous acetonitrile and 30 mL of anhydrous N,N-dimethylformamide was added anhydrous, powdered K2CO3 (12.68 g, 0.0918 mol) followed by benzyl bromide (13.81 g, 0.0808 mol, 9.61 mL). The mixture was stirred and vigorously refluxed for 6 hrs, cooled, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with a gradient system of 40 to 50% ethyl acetate/hexane to afford 25.50 g (96% yield) of product 40 as a pale yellow oil; TLC (silica gel; ethyl acetate/hexane: 1,1): Rf=0.35.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2

Procedure:
To a well-stirred and ice-cooled solution of 1,4-dioxa-8-azaspiro[4.5]decane (34.9 mmol, 5 g) in dichloromethane (200 mL) under an argon atmosphere, was added triethylamine (52.4 mmol, 7.3 mL) and then benzyloxycarbonyl chloride (42 mmol, 5.93 mL) dropwise. The suspension was stirred at room temperature for 24 hours and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give an oily residue which was chromatographed on silica gel eluting with a mixture of ethyl ether and petroleum ether to afford 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro [4,5] decane in quantitative yield. 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 3.89 (s, 4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:36]/[C:37](=[N:54]\[H])/[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:46]=1[NH:45][CH:44]=[C:43]2[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:54]=[C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[C:42]4[C:46]=3[NH:45][CH:44]=[C:43]4[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:36]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC)c(OC)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 3,4-bis(methyloxy)benzoic acid (547 mg) in tetrahydrofuran (15 mL) stirred at room temp was added EDCI (767 mg) and HOBT (613 mg). The reaction mixture was stirred at room temperature for 2 h. Then ethyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (551 mg) was added. The reaction mixture was stirred at 60° C. for 2 h, and then TBAF (2092 mg) was added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 130° C. for 3 h. After cooling the reaction, the solvent was removed. Water (90 mL) and ethanol (30 mL) was added to the residue, a yellow solid was formed, filtered and dried in vacuo to gave the product ethyl 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D67) (658 mg). δH (CDCl3, 400 MHz): 1.27 (3H, t), 2.76 (2H, t), 3.18 (2H, t), 4.01 (3H, s), 4.13 (3H, s), 4.16 (2H, q), 7.04 (1H, d), 7.20 (1H, d), 7.29 (1H, t), 7.74 (1H, d), 7.81 (1H, d), 7.90 (1H, dd), 8.14 (1H, dd), 9.63 (1H, s). MS (ES): C23H23N3O5 requires 421. found 422.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:6]2[C:5]2[N:11]=[CH:12][C:13]([C:15](OC)=[O:16])=[CH:14][C:4]=2[NH:3]1.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1>[OH:16][CH2:15][C:13]1[CH:12]=[N:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][CH:10]=3)[C:2](=[O:1])[NH:3][C:4]=2[CH:14]=1
Reactant: COC(=O)c1cnc2c(c1)[nH]c(=O)n1cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(CO)cnc2c2cccn12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a suspension of methyl 6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine-3-carboxylate (0.62 g, 2.55 mmol) in THF (Volume: 15 mL) was added Sodium hydride (0.092 g, 3.82 mmol) at 0° C. The reaction was stirred at 0° C. for 15 min. The suspension was cooled to −78° C. and Lithium aluminum hydride solution (2.294 mL, 4.59 mmol) was added during 10 min. The reaction was stirred at −10° C. to −30° C. for 3 hr. The suspension was cooled to −60° C. and MeOH (500 μL) was added to quench residual LAH. The resulting suspension was warmed to 0° C. and H2O (0.175 mL), 5N NaOH (0.175 mL), followed by H2O (0.525 mL) was added in order. The suspension was stirred overnight at 23° C., filtered, rinsed with THF (3×10 mL) and MeOH (3×10 mL). The filtrate was concentrated via rotary evaporation, re-constituted in THF (50 mL), neutralized to pH 4-5 with 3N HCl (1.5 mL). The green, turbid solution was partitioned with brine (25 mL). The aqueous layer was washed with THF (2×25 mL), the organic extracts were combined, dried over Na2SO4, filtered, rinsed with THF and concentrated in vacuo. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation to provide 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (0.312 g, 1.450 mmol, 56.9% yield) as a green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.59 (d, J=5.56 Hz, 2 H) 5.45 (t, J=5.68 Hz, 1 H) 6.73 (dd, J=3.54, 3.03 Hz, 1 H) 7.06 (dd, J=3.54, 1.77 Hz, 1 H) 7.54-7.59 (m, 1 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.34 (d, J=1.77 Hz, 1 H) 11.66 (s, 1 H). ESI-MS: m/z 216.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[N:8]=1)([CH3:3])[CH3:2].[NH2:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][CH:45]=1)=[O:41])[CH2:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([NH:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]2[S:48][CH:47]=[N:46][CH:45]=2)=[O:41])[CH2:33][C:34]2[S:38][CH:37]=[N:36][CH:35]=2)[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])[CH:15]([CH3:16])[CH3:17])=[O:12])[N:8]=1)([CH3:2])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cncs1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](Cc2cncs2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane provided, after silica gel chromatography using 1% methanol in chloroform, 54 mg (66%) of the desired compound (Rf 0.6, 10% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ 0.69 (d, 3H), 0.74 (d, 3H), 1.31 (d, 6H), 1.47 (m, 2H), 1.85 (m, 1H), 2.75 (m, 4H), 2.95 (m, 1H), 3.57 (m, 1H), 3.80 (m, 2H), 4.08 (m, 1H), 4.95 (d, 1H), 5.03 (s, 2H), 5.19 (s, 2H), 7.12-7.29 (m), 7.45 (s, 1H), 7.47 (s, 1H). Mass spectrum: (M+H)+=715.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[Mg].C[O:15][B:16](OC)[O:17]C.Cl>O1CCCC1.C(Br)CBr>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([B:16]([OH:17])[OH:15])=[CH:4][C:3]=1[F:12]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)c2occc2c1F
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(F)c2ccoc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
Alternatively, a mixture of 0.484 gm (2.08 mMol) 4,5-difluoro-7-bromobenzofuran and 0.065 gm (2.67 mMol) magnesium in 5 mL tetrahydrofuran was heated at reflux. Two drops of 1,2-dibromomethane were added and the mixture heated at reflux for 45 minutes. To this mixture were added 260 μL (2.29 mMol) trimethylborate and heating was continued for an additional 45 minutes. After cooling to room temperature, 2.3 mL 1N hydrochloric acid were added and the mixture stirred for 45 minutes. The mixture was then extracted well with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried in 4 mL hexanes, the solvent removed by decantation, and the residual solid dried under reduced pressure to provide 0.402 gm (97.8%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[H-].[Na+].O1CCCC1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O.C(#N)C.C(O)(=O)C>[CH3:38][S:39]([N:11]1[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:2]1=[O:1])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
4-(2,5-Dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 14, 40 mg, 97 μmol) is added to a mixture of sodium hydride (60% in mineral oil, 15 mg, 0.19 mmol) and tetrahydrofuran (1 mL), and the mixture is stirred at room temperature for 3 min. Methanesulfonyl chloride (15 μL, 0.19 mmol) is added, and the mixture is heated at 50° C. for 1 h. The mixture is cooled at room temperature, diluted with water, acetonitrile and acetic acid and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 32 mg; ESI mass spectrum [M+H]+=491; Retention time HPLC: 1.01 min (Z018_S04).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:38])([CH3:37])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[CH3:39][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C@@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:37])([CH3:38])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:36])([CH3:39])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[CH2:10][CH2:9][OH:8]
Reactant: CC(=O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3F)=NS2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)ethanone (174 mg) in THF (2.5 ml) was added dropwise, at −78° C., a solution of methylmagnesium bromide (1.4 M, 0.44 ml). After 30 min at −78° C., ammonium chloride solution was added to the mixture. After the addition of water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (2 ml), and 0.2 ml of conc. HCl was added. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product (28 mg) with a molecular weight of 464.6 g/mol (C23H29FN2O5S); MS (ESI): m/e=465 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=O)C.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[OH:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2c1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2cc3c(n2CCN1c1nccc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4c2)c1CO)CCCC3
Temperature: 130 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A microwave vial was charged with 121a (100 mg, 0.26 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (150 mg, 0.39 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), P(Cy)3 (7 mg, 0.025 mmol), Cs2CO3 (170 mg, 0.52 mmol), dioxane (5 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the reaction mixture was stirred at 130° C. under microwave irradiation for 1 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 121 (66 mg, 39%). MS-ESI: [M+H]+ 646.3. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.0 Hz, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.35 (d, J=9.0 Hz, 1H), 6.58 (s, 1H), 4.95 (bs, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.5 Hz, 2H), 4.42-4.40 (m, 2H), 4.28-4.09 (m, 3H), 3.94-3.87 (m, 1H), 3.45-3.42 (m, 1H), 3.10-3.08 (m, 4H), 2.66-2.56 (m, 2H), 2.50-2.47 (m, underneath solvent peak, 2H), 2.40-2.38 (m, 4H), 1.80-1.69 (m, 4H).
Reaction SMILES: C1C=C(C(O)=[O:8])C(C(OO)=O)=CC=1.[C:14]1([S:20][CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:14]1([S:20]([CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: CCOC(=O)C1=C(C)NC(CSc2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(CS(=O)c2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of monoperphtalic acid in AcOEt (0.37 M solution; 20 ml) is added at 0° C. to a mixture of 2-(phenylthio)methyl-3, 5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (3.5 g) and NaHCO3 (3 g) in AcOEt (20 ml). After 30 minutes the mixture is filtered and the eluate is washed with 1N solution of sodium thiosulfate (2 ×10 ml), with a saturated solution of NaHCO3 (2×20 ml) and then with water (3×10 ml). The organic layer is dried on Na2SO4 and evaporated to dryness; the residue is purified by chromatography on SiO2 (hexane/AcOEt 85/15, as eluent) to give 3.5 g of 2-(phenylsulfinyl)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+].CN(C=O)C>O>[N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[O:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1
Reactant: OC1(CNc2c(Br)cnc3ccccc23)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=Nc2c(cnc3ccccc23)OC12CCCCC2
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 5.5 g of 3-bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine, 2.2 g of potassium tert-butoxide and 50 ml of DMF was heated at 130° C. for 1 hour and then poured into 250 ml of water. The product was extracted with dichloromethane and ethyl acetate, dried and concentrated, and the residue was purifed by HPLC using dichloromethane:MeOH=95:5 as the eluent. The fractions containing the product were combined and concentrated. The residue was taken up in water and stirred for 1 hour, and the solid was filtered and recrystallized from toluene. The yield was 2.6 g, mp 164°-165° C.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.CO.O>[C:1]1([CH:7]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 2-(3-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetate (0.5 g, 1.23 mmol) in THF/MeOH/water (12 mL, 7:3:2) at 5° C. was added LiOH.H2O (0.15 g, 3.7 mmol). After stirring at rt for 4 h, the solvent was removed under vacuum. The residue was diluted with water and the pH was adjusted to 4 with diluted HCl, extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in ethyl acetate and crashed out of pentane at cool condition to afford pure 2-(3-(phenyl(4-(trifluoromethyl)-phenyl)methyl)piperidin-1-yl)acetic acid (0.3 g, 65% yield) as an off white solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH:9][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])=[N:6][CH:7]=1
Reactant: NCc1cc(O)c(N)cn1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-2-aminomethyl-pyridin-4-ol (60 mg, 0.19 mmole as the dihydrobromide), 3 mL of N,N-dimethylformamide and triethylamine (101 uL, 0.72 mmole) were stirred for 15 mins, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (63 mg, 0.19 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in dimethylsulfoxide and purified by HPLC (acetonitrile-water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a brown solid, 5.5 mg, (5%); MS (ES+): m/z 437.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])[N:18]=1)[C:11]([NH2:13])=[NH:12].[CH3:24][O:25][C:26](OC)=[N:27][C:28]#[N:29]>CO>[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:26](=[N:27][C:28]#[N:29])[O:25][CH3:24])[N:18]=1)[C:11]([NH2:13])=[NH:12]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC(=NC#N)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Yield: 69 %

Procedure:
Triethylamine (2.02 g.) was added to a suspension of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride (3.04 g.) in methanol (30 ml.) stirred at room temperature. Dimethyl (N-cyanoimido)carbonate (1.14 g.) was added and the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was extracted with ethyl acetate (35 ml.) and the solution was washed with water (25 ml., 10 ml.) then dried (magnesium sulphate) and evaporated under reduced pressure to give 2-guanidino-4-[2-(3-cyano-2-methylisoureido)ethylthiomethyl]thiazole (2.16 g.). The n.m.r. spectrum in CDCl3 /d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 7.7 (1H, very broad); 6.7 (4H, broad); 6.4 (1H, singlet); 3.8 (3H, singlet); 3.6 (2H, singlet); 3.4 (obscured by H2O); 2.7 (2H, broad triplet).